Ant Trail Pheromone Biosynthesis Is Triggered by a Neuropeptide Hormone

PubMed Central

Choi, Man-Yeon; Vander Meer, Robert K.

2012-01-01

Our understanding of insect chemical communication including pheromone identification, synthesis, and their role in behavior has advanced tremendously over the last half-century. However, endocrine regulation of pheromone biosynthesis has progressed slowly due to the complexity of direct and/or indirect hormonal activation of the biosynthetic cascades resulting in insect pheromones. Over 20 years ago, a neurohormone, pheromone biosynthesis activating neuropeptide (PBAN) was identified that stimulated sex pheromone biosynthesis in a lepidopteran moth. Since then, the physiological role, target site, and signal transduction of PBAN has become well understood for sex pheromone biosynthesis in moths. Despite that PBAN-like peptides (∼200) have been identified from various insect Orders, their role in pheromone regulation had not expanded to the other insect groups except for Lepidoptera. Here, we report that trail pheromone biosynthesis in the Dufour's gland (DG) of the fire ant, Solenopsis invicta, is regulated by PBAN. RNAi knock down of PBAN gene (in subesophageal ganglia) or PBAN receptor gene (in DG) expression inhibited trail pheromone biosynthesis. Reduced trail pheromone was documented analytically and through a behavioral bioassay. Extension of PBAN's role in pheromone biosynthesis to a new target insect, mode of action, and behavioral function will renew research efforts on the involvement of PBAN in pheromone biosynthesis in Insecta. PMID:23226278

Glycerol-3-phosphate O-acyltransferase is required for PBAN-induced sex pheromone biosynthesis in Bombyx mori

PubMed Central

Du, Mengfang; Liu, Xiaoguang; Liu, Xiaoming; Yin, Xinming; Han, Shuangyin; Song, Qisheng; An, Shiheng

2015-01-01

Female moths employ their own pheromone blends as a communicational medium in mating behavior. The biosynthesis and release of sex pheromone in female moths are regulated by pheromone biosynthesis activating neuropeptide (PBAN) and the corresponding action of PBAN has been well elucidated in Bombyx mori. However, very little is known about the molecular mechanism regarding the biosynthesis of sex pheromone precursor. In this study, quantitative proteomics was utilized to comprehensively elucidate the expression dynamics of pheromone glands (PGs) during development. Proteomic analysis revealed a serial of differentially expressed sex pheromone biosynthesis-associated proteins at the different time points of B. mori development. Most interestingly B. mori glycerol-3-phosphate O-acyltransferase (BmGPAT) was found to be expressed during the key periods of sex pheromone biosynthesis. RNAi knockdown of BmGPAT confirmed the important function of this protein in the biosynthesis of sex pheromone precursor, triacylglcerol (TAG), and subsequently PBAN-induced production of sex pheromone, bombykol. Behavioral analysis showed that RNAi knockdown of GPAT significantly impaired the ability of females to attract males. Our findings indicate that GPAT acts to regulate the biosynthesis of sex pheromone precursor, TAG, thus influencing PBAN-induced sex pheromone production and subsequent mating behavior. PMID:25630665

Stage-dependent and temperature-controlled expression of the gene encoding the precursor protein of diapause hormone and pheromone biosynthesis activating neuropeptide in the silkworm, Bombyx mori.

PubMed

Xu, W H; Sato, Y; Ikeda, M; Yamashita, O

1995-02-24

Embryonic diapause and sex pheromone biosynthesis in the silkworm, Bombyx mori, are, respectively, induced by diapause hormone (DH) and pheromone biosynthesis activating neuropeptide (PBAN), which are produced in the subesophageal ganglion from a common polyprotein precursor (DH-PBAN precursor) encoded by a single gene (DH-PBAN gene). Using DH-PBAN cDNA as a probe, we quantitatively measured DH-PBAN mRNA content throughout embryonic and postembryonic development and observed the effects of incubation temperature, which is a key factor for determination of diapause, on DH-PBAN gene expression. The silkworm, which is programmed to lay diapause eggs by being incubated at 25 degrees C, showed peaks of DH-PBAN mRNA content at five different stages throughout the life cycle: at the late embryonic stage, at the middle of the fourth and the fifth larval instars, and at early and late stages of pupal-adult development. In the non-diapause type silkworms programmed by a 15 degrees C incubation, only the last peak of DH-PBAN mRNA in pupal-adult development was found, and the other peaks were absent. Furthermore, interruption of the incubation period at 25 degrees C by incubation at 15 degrees C decreased both DH-PBAN mRNA content in mature embryos and in subesophageal ganglia of day 3 pupae and the incidence of diapause eggs. Thus, there were two types of regulatory mechanisms for DH-PBAN gene expression. One is a temperature-controlled expression that is responsible for diapause induction, and the other is a temperature-independent, stage-dependent expression related to pheromone production.

Investigation of the Explosive Potential of the Hybrid Propellant Combinations N2O4/PBAN and CTF/PBAN

DTIC Science & Technology

1967-03-01

nitrogen tetroxide (N„0 ) and polybutadyne-aluminum (PBAN), and chlorine trifluoride (CTF) and PBAN. This program consisted of a series of eight...explosive potential of two hybrid propellant combinations; nitrogen tetroxide QLOL) and polybutadyne - aluminum (PBAN) and chlorine triflouride (CTF...or positive-phase impulse yield. FREE AIR OVERPRESSURE: (OR FREE FIELD OVERPRESSURE): The unreflected pressure, in excess of the ambient atmospheric

Re-Evaluation of the PBAN Receptor Molecule: Characterization of PBANR Variants Expressed in the Pheromone Glands of Moths

PubMed Central

Lee, Jae Min; Hull, J. Joe; Kawai, Takeshi; Goto, Chie; Kurihara, Masaaki; Tanokura, Masaru; Nagata, Koji; Nagasawa, Hiromichi; Matsumoto, Shogo

2011-01-01

Sex pheromone production in most moths is initiated following pheromone biosynthesis activating neuropeptide receptor (PBANR) activation. PBANR was initially cloned from pheromone glands (PGs) of Helicoverpa zea and Bombyx mori. The B. mori PBANR is characterized by a relatively long C-terminus that is essential for ligand-induced internalization, whereas the H. zea PBANR has a shorter C-terminus that lacks features present in the B. mori PBANR critical for internalization. Multiple PBANRs have been reported to be concurrently expressed in the larval CNS of Heliothis virescens. In the current study, we sought to examine the prevalence of multiple PBANRs in the PGs of three moths and to ascertain their potential functional relevance. Multiple PBANR variants (As, A, B, and C) were cloned from the PGs of all species examined with PBANR-C the most highly expressed. Alternative splicing of the C-terminal coding sequence of the PBAN gene gives rise to the variants, which are distinguishable only by the length and composition of their respective C-terminal tails. Transient expression of fluorescent PBANR chimeras in insect cells revealed that PBANR-B and PBANR-C localized exclusively to the cell surface while PBANR-As and PBANR-A exhibited varying degrees of cytosolic localization. Similarly, only the PBANR-B and PBANR-C variants underwent ligand-induced internalization. Taken together, our results suggest that PBANR-C is the principal receptor molecule involved in PBAN signaling regardless of moth species. The high GC content of the C-terminal coding sequence in the B and C variants, which makes amplification using conventional polymerases difficult, likely accounts for previous “preferential” amplification of PBANR-A like receptors from other species. PMID:22654850

Establishment of Sf9 Transformants Constitutively Expressing PBAN Receptor Variants: Application to Functional Evaluation

PubMed Central

Lee, Jae Min; Hull, J. Joe; Kawai, Takeshi; Tsuneizumi, Kazuhide; Kurihara, Masaaki; Tanokura, Masaru; Nagata, Koji; Nagasawa, Hiromichi; Matsumoto, Shogo

2012-01-01

To facilitate further evaluation of pheromone biosynthesis activating neuropeptide receptor (PBANR) functionality and regulation, we generated cultured insect cell lines constitutively expressing green fluorescent protein chimeras of the recently identified Bombyx mori PBANR (BommoPBANR) and Pseudaletia separata PBANR (PsesePBANR) variants. Fluorescent chimeras included the BommoPBANR-A, -B, and -C variants and the PsesePBANR-B and -C variants. Cell lines expressing non-chimeric BommoPBANR-B and -C variants were also generated. Functional evaluation of these transformed cell lines using confocal laser microscopy revealed that a Rhodamine Red-labeled PBAN derivative (RR-C10PBANR2K) specifically co-localized with all of the respective PBANR variants at the plasma membrane. Near complete internalization of the fluorescent RR-C10PBANR2K ligand 30 min after binding was observed in all cell lines except those expressing the BommoPBANR-A variant, in which the ligand/receptor complex remained at the plasma membrane. Fluorescent Ca2+ imaging further showed that the BommoPBANR-A cell line exhibited drastically different Ca2+ mobilization kinetics at a number of RR-C10PBANR2K concentrations including 10 μM. These observations demonstrate a clear functional difference between the BommoPBANR-A variant and the BommoPBANR-B and -C variants in terms of receptor regulation and activation of downstream effector molecules. We also found that, contrary to previous reports, ligand-induced internalization of BommoPBANR-B and BommoPBANR-C in cell lines stably expressing these variants occurred in the absence of extracellular Ca2+. PMID:22654874

Activity Induces Fmr1-Sensitive Synaptic Capture of Anterograde Circulating Neuropeptide Vesicles.

PubMed

Cavolo, Samantha L; Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

2016-11-16

Synaptic neuropeptide and neurotrophin stores are maintained by constitutive bidirectional capture of dense-core vesicles (DCVs) as they circulate in and out of the nerve terminal. Activity increases DCV capture to rapidly replenish synaptic neuropeptide stores following release. However, it is not known whether this is due to enhanced bidirectional capture. Here experiments at the Drosophila neuromuscular junction, where DCVs contain neuropeptides and a bone morphogenic protein, show that activity-dependent replenishment of synaptic neuropeptides following release is evident after inhibiting the retrograde transport with the dynactin disruptor mycalolide B or photobleaching DCVs entering a synaptic bouton by retrograde transport. In contrast, photobleaching anterograde transport vesicles entering a bouton inhibits neuropeptide replenishment after activity. Furthermore, tracking of individual DCVs moving through boutons shows that activity selectively increases capture of DCVs undergoing anterograde transport. Finally, upregulating fragile X mental retardation 1 protein (Fmr1, also called FMRP) acts independently of futsch/MAP-1B to abolish activity-dependent, but not constitutive, capture. Fmr1 also reduces presynaptic neuropeptide stores without affecting activity-independent delivery and evoked release. Therefore, presynaptic motoneuron neuropeptide storage is increased by a vesicle capture mechanism that is distinguished from constitutive bidirectional capture by activity dependence, anterograde selectivity, and Fmr1 sensitivity. These results show that activity recruits a separate mechanism than used at rest to stimulate additional synaptic capture of DCVs for future release of neuropeptides and neurotrophins. Synaptic release of neuropeptides and neurotrophins depends on presynaptic accumulation of dense-core vesicles (DCVs). At rest, DCVs are captured bidirectionally as they circulate through Drosophila motoneuron terminals by anterograde and retrograde

Activity Induces Fmr1-Sensitive Synaptic Capture of Anterograde Circulating Neuropeptide Vesicles

PubMed Central

Cavolo, Samantha L.; Bulgari, Dinara; Deitcher, David L.

2016-01-01

Synaptic neuropeptide and neurotrophin stores are maintained by constitutive bidirectional capture of dense-core vesicles (DCVs) as they circulate in and out of the nerve terminal. Activity increases DCV capture to rapidly replenish synaptic neuropeptide stores following release. However, it is not known whether this is due to enhanced bidirectional capture. Here experiments at the Drosophila neuromuscular junction, where DCVs contain neuropeptides and a bone morphogenic protein, show that activity-dependent replenishment of synaptic neuropeptides following release is evident after inhibiting the retrograde transport with the dynactin disruptor mycalolide B or photobleaching DCVs entering a synaptic bouton by retrograde transport. In contrast, photobleaching anterograde transport vesicles entering a bouton inhibits neuropeptide replenishment after activity. Furthermore, tracking of individual DCVs moving through boutons shows that activity selectively increases capture of DCVs undergoing anterograde transport. Finally, upregulating fragile X mental retardation 1 protein (Fmr1, also called FMRP) acts independently of futsch/MAP-1B to abolish activity-dependent, but not constitutive, capture. Fmr1 also reduces presynaptic neuropeptide stores without affecting activity-independent delivery and evoked release. Therefore, presynaptic motoneuron neuropeptide storage is increased by a vesicle capture mechanism that is distinguished from constitutive bidirectional capture by activity dependence, anterograde selectivity, and Fmr1 sensitivity. These results show that activity recruits a separate mechanism than used at rest to stimulate additional synaptic capture of DCVs for future release of neuropeptides and neurotrophins. SIGNIFICANCE STATEMENT Synaptic release of neuropeptides and neurotrophins depends on presynaptic accumulation of dense-core vesicles (DCVs). At rest, DCVs are captured bidirectionally as they circulate through Drosophila motoneuron terminals by

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

PubMed Central

2017-01-01

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity. PMID:28154473

Introduction of a neurohormone in the fire ants

USDA-ARS?s Scientific Manuscript database

Neuropeptides are the largest group of insect hormones, and are synthesized in the central and peripheral nervous systems. One neuropeptide family is the PBAN/pyrokinin family defined by a common FXPRLamide or similar amino acid fragment at the C-terminal end. Over the past years we have extended kn...

Neuropeptides, Microbiota, and Behavior.

PubMed

Holzer, P

2016-01-01

The gut microbiota and the brain interact with each other through multiple bidirectional signaling pathways in which neuropeptides and neuroactive peptide messengers play potentially important mediator roles. Currently, six particular modes of a neuropeptide link are emerging. (i) Neuropeptides and neurotransmitters contribute to the mutual microbiota-host interaction. (ii) The synthesis of neuroactive peptides is influenced by microbial control of the availability of amino acids. (iii) The activity of neuropeptides is tempered by microbiota-dependent autoantibodies. (iv) Peptide signaling between periphery and brain is modified by a regulatory action of the gut microbiota on the blood-brain barrier. (v) Within the brain, gut hormones released under the influence of the gut microbiota turn into neuropeptides that regulate multiple aspects of brain activity. (vi) Cerebral neuropeptides participate in the molecular, behavioral, and autonomic alterations which the brain undergoes in response to signals from the gut microbiota. © 2016 Elsevier Inc. All rights reserved.

Molecular and pharmacological characterization of the Chelicerata pyrokinin receptor from the southern cattle tick, Rhipicephalus (Boophilus) microplus.

PubMed

Yang, Yunlong; Nachman, Ronald J; Pietrantonio, Patricia V

2015-05-01

We identified the first pyrokinin receptor (Rhimi-PKR) in Chelicerata and analyzed structure-activity relationships of cognate ligand neuropeptides and their analogs. Based on comparative and phylogenetic analyses, this receptor, which we cloned from larvae of the cattle tick Rhipicephalus microplus (Acari: Ixodidae), is the ortholog of the insect pyrokinin (PK)/pheromone biosynthesis activating neuropeptide (PBAN)/diapause hormone (DH) neuropeptide family receptor. Rhimi-PKR functional analyses using calcium bioluminescence were performed with a developed stable recombinant CHO-K1 cell line. Rhimi-PKR was activated by four endogenous PKs from the Lyme disease vector, the tick Ixodes scapularis (EC50s range: 85.4 nM-546 nM), and weakly by another tick PRX-amide peptide, periviscerokinin (PVK) (EC50 = 24.5 μM). PK analogs with substitutions of leucine, isoleucine or valine at the C-terminus for three tick PK peptides, Ixosc-PK1, Ixosc-PK2, and Ixosc-PK3, retained their potency on Rhimi-PKR. Therefore, Rhimi-PKR is less selective and substantially more tolerant than insect PK receptors of C-terminal substitutions of leucine to isoleucine or valine, a key structural feature that serves to distinguish insect PK from PVK/CAP2b receptors. In females, ovary and synganglion had the highest Rhimi-PKR relative transcript abundance followed by the rectal sac, salivary glands, Malpighian tubules, and midgut. This is the first pharmacological analysis of a PK/PBAN/DH-like receptor from the Chelicerata, which will now permit the discovery of the endocrinological roles of this neuropeptide family in vectors of vertebrate pathogens. Copyright © 2015 Elsevier Ltd. All rights reserved.

Neuropeptide transmission in brain circuits

PubMed Central

van den Pol, Anthony N.

2014-01-01

Neuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G-protein coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation. PMID:23040809

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis.

PubMed

Grund, Thomas; Goyon, Stephanie; Li, Yuting; Eliava, Marina; Liu, Haikun; Charlet, Alexandre; Grinevich, Valery; Neumann, Inga D

2017-12-13

Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca 2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus. SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca 2+ increase and

Neuropeptide Levels as well as Neprilysin Activity Decrease in Renal Cell Carcinoma.

PubMed

Erin, Nuray; İpekçi, Tümay; Akkaya, Bahar; Özbudak, İrem Hicran; Baykara, Mehmet

2016-12-01

Calcitonin Gene-related Peptide (CGRP), Vasoactive Intestinal Peptide (VIP) and Substance P (SP) are sensory neuropeptides which may alter cancer growth through modulation of chronic inflammation. We recently reported that SP suppresses breast cancer growth and metastasis through neuroimmune modulation. These neuropeptides are hydrolyzed by Neprilysin (NEP) to bioactive fragments. Decreased activity of NEP was reported in clear cell and chromophobe type renal cell carcinoma (RCC). It is however not known how the levels of neuropeptides hydrolyzed with NEP changes in RCC. Decrease activity of SP and CGRP containing sensory nerve endings was previously reported to increase cancer metastasis in animal models. It is however not known how peptidergic nerve endings are altered in RCC. Hence we here evaluated the levels of neuronal and non-neuronal neuropeptides and NEP activity in RCC including papillary type as well as neighboring uninvolved kidney. A cross-sectional study was conducted in 57 patients undergoing radical nephrectomy and diagnosed with RCC. NEP activity, levels and expression were determined using flourogenic substrate, western blot and qPCR respectively in freshly-frozen tissues. Immunohistochemical analyses were also performed. Neuronal and non-neuronal levels of CGRP, SP and VIP levels were determined using two-step acetic acid extraction. Levels and activity of NEP were markedly decreased in RCC regardless of subtype. Similar levels of VIP were detected in first and second extractions. VIP levels were higher in clear cell and papillary RCC compared to nearby kidney tissue. VIP levels of neighboring kidney tissue of papillary type RCC was significantly lower compared to kidney samples from clear cell RCC. CGRP levels were higher in second extraction. Similar to VIP levels, CGRP levels of neighboring kidney tissue from clear cell and chromophobe type RCC was significantly lower compared to corresponding tumor samples, an effect observed in the second

Penultimate proline in neuropeptides.

PubMed

Glover, Matthew S; Bellinger, Earl P; Radivojac, Predrag; Clemmer, David E

2015-08-18

A recent ion mobility spectrometry-mass spectrometry (IMS-MS) study revealed that tryptic peptide ions containing a proline residue at the second position from the N-terminus (i.e., penultimate proline) frequently adopt multiple conformations, owing to the cis-trans isomerization of Xaa(1)-Pro(2) peptide bonds [J. Am. Soc. Mass Spectrom. 2015, 26, 444]. Here, we present a statistical analysis of a neuropeptide database that illustrates penultimate proline residues are frequently found in neuropeptides. In order to probe the effect of penultimate proline on neuropeptide conformations, IMS-MS experiments were performed on two model peptides in which penultimate proline residues were known to be important for biological activity: the N-terminal region of human neuropeptide Y (NPY1-9, Tyr(1)-Pro(2)-Ser(3)-Lys(4)-Pro(5)-Asp(6)-Asn(7)-Pro(8)-Gly(9)-NH2) and a tachykinin-related peptide (CabTRP Ia, Ala(1)-Pro(2)-Ser(3)-Gly(4)-Phe(5)-Leu(6)-Gly(7)-Met(8)-Arg(9)-NH2). From these studies, it appears that penultimate prolines allow neuropeptides to populate multiple conformations arising from the cis-trans isomerization of Xaa(1)-Pro(2) peptide bonds. Although it is commonly proposed that the role of penultimate proline residues is to protect peptides from enzymatic degradation, the present results indicate that penultimate proline residues also are an important means of increasing the conformational heterogeneity of neuropeptides.

Neuropeptides in Lower Urinary Tract (LUT) Function

PubMed Central

Arms, Lauren; Vizzard, Margaret A.

2014-01-01

Numerous neuropeptide/receptor systems including vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, substance P, neurokinin A, bradykinin, and endothelin-1 are expressed in the lower urinary tract (LUT) in both neural and non-neural (e.g., urothelium) components. LUT neuropeptide immunoreactivity is present in afferent and autonomic efferent neurons innervating the bladder and urethra and in the urothelium of the urinary bladder. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction following neural injury, inflammation and disease. LUT dysfunction with abnormal voiding including urinary urgency, increased voiding frequency, nocturia, urinary incontinence and pain may reflect a change in the balance of neuropeptides in bladder reflex pathways. LUT neuropeptide/receptor systems may represent potential targets for therapeutic intervention. PMID:21290237

Neuropeptide action in insects and crustaceans.

PubMed

Mykles, Donald L; Adams, Michael E; Gäde, Gerd; Lange, Angela B; Marco, Heather G; Orchard, Ian

2010-01-01

Physiological processes are regulated by a diverse array of neuropeptides that coordinate organ systems. The neuropeptides, many of which act through G protein-coupled receptors, affect the levels of cyclic nucleotides (cAMP and cGMP) and Ca(2+) in target tissues. In this perspective, their roles in molting, osmoregulation, metabolite utilization, and cardiovascular function are highlighted. In decapod crustaceans, inhibitory neuropeptides (molt-inhibiting hormone and crustacean hyperglycemic hormone) suppress the molting gland through cAMP- and cGMP-mediated signaling. In insects, the complex movements during ecdysis are controlled by ecdysis-triggering hormone and a cascade of downstream neuropeptides. Adipokinetic/hypertrehalosemic/hyperprolinemic hormones mobilize energy stores in response to increased locomotory activity. Crustacean cardioacceleratory (cardioactive) peptide, proctolin, and FMRFamide-related peptides act on the heart, accessory pulsatile organs, and excurrent ostia to control hemolymph distribution to tissues. The osmoregulatory challenge of blood gorging in Rhodnius prolixus requires the coordinated release of serotonin and diuretic and antidiuretic hormones acting on the midgut and Malpighian tubules. These studies illustrate how multiple neuropeptides allow for flexibility in response to physiological challenges.

Neuropeptides and breathing in health and disease.

PubMed

Kaczyńska, Katarzyna; Zając, Dominika; Wojciechowski, Piotr; Kogut, Ewelina; Szereda-Przestaszewska, Małgorzata

2018-02-01

Regulatory neuropeptides control and regulate breathing in physiological and pathophysiological conditions. While they have been identified in the neurons of major respiratory areas, they can be active not only at the central level, but also at the periphery via chemoreceptors, vagal afferents, or locally within lungs and airways. Some neuropeptides, such as leptin or substance P, are respiratory stimulants; others, such as neurotensin, produce variable effects on respiration depending on the site of application. Some neuropeptides have been implicated in pathological states, such as obstructive sleep apnea or asthma. This article provides a concise review of the possible role and functions of several selected neuropeptides in the process of breathing in health and disease and in lung pathologies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of novel inhibitors of calling and in vitro [14C]acetate incorporation by pheromone glands of Plodia interpunctella.

PubMed

Hirashima, A; Eiraku, T; Watanabe, Y; Kuwano, E; Taniguchi, E; Eto, M

2001-08-01

Some octopamine agonists were found to suppress in vitro biosynthesis of the calling pheromone of the Indian meal moth, Plodia interpunctella. Isolated pheromone-gland preparations incorporated sodium [14C]acetate at a linear rate for 3 h when incubated with the pheromone biosynthesis activating neuropeptide (PBAN). This incorporation was dependent on the dose of PBAN (up to 0.5 microM). Thin-layer chromatography of a pheromone-gland extract revealed quantitative incorporation of radioactivity into a product exhibiting the same mobility as (Z,E)-9,12-tetradecadienyl acetate, the main component of the calling pheromone of P interpunctella. Twenty-seven octopamine agonists were initially screened using a calling behaviour bioassay of female P interpunctella. Four derivatives with activity in the nanomolar range were identified which were, in order of decreasing pheromonostatic activity: 2-(2,6-diethylphenylimino)thiazolidine > 2-(2,6-diethylphenylimino)oxazolidine > 2-(2,6-dimethylphenylimino)thiazolidine > 2-(2-ethylphenylimino)oxazolidine. These compounds also showed in vitro inhibitory activity in intracellular de novo pheromone biosynthesis. The results of the present study indicate that these derivatives could provide useful information in the characterization and differentiation of octopaminergic receptor types and subtypes.

[Identification of mouse brain neuropeptides by high throughput mass spectrometry].

PubMed

Shao, Xianfeng; Ma, Min; Chen, Ruibing; Jia, Chenxi

2018-04-25

Neuropeptides play an important role in the physiological functions of the human body. The physiological activities such as pain, sleep, mood, learning and memory are affected by neuropeptides. Neuropeptides mainly exist in the nerve tissue of the body, and a small amount of them are distributed in body fluid and organs. At present, analysis of large-scale identification of neuropeptides in whole brain tissue is still challenging. Therefore, high-throughput detection of these neuropeptides is greatly significant to understand the composition and function of neuropeptides. In this study, 1 830 endogenous peptides and 99 novel putative neuropeptides were identified by extraction of endogenous peptides from whole brain tissue of mice by liquid phase tandem mass spectrometry (LC-MS / MS). The identification of these endogenous peptides provides not only a reference value in the treatment and mechanism studies of diseases and the development of drugs, but also the basis for the study of a new neuropeptides and their functions.

Establishment of Sf9 transformants constitutively expressing PBAN receptor variants: application to functional evaluation

USDA-ARS?s Scientific Manuscript database

To facilitate further evaluation of pheromone biosynthesis activating neuropeptide receptor (PBANR) functionality and regulation, we generated cultured insect cell lines stably expressing a number of fluorescent Bombyx mori PBANR (BommoPBANR) and Pseudaletia separata PBANR (PsesePBANR) variants incl...

Neuropeptide Regulation of Fear and Anxiety: Implications of Cholecystokinin, Endogenous Opioids, and Neuropeptide Y

PubMed Central

Bowers, Mallory E.; Choi, Dennis C.; Ressler, Kerry J.

2012-01-01

The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the μ opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the amygdala to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation. PMID:22429904

Introduction: Invertebrate Neuropeptides XIV

USDA-ARS?s Scientific Manuscript database

This publication represents an introduction to the thirteenth in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel invertebrate neuropeptide sequ...

Introduction: Invertebrate Neuropeptides XVI

USDA-ARS?s Scientific Manuscript database

This publication represents an introduction to the sixteenth in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel invertebrate neuropeptide seque...

Introduction: Invertebrate Neuropeptides XV

USDA-ARS?s Scientific Manuscript database

This publication represents an introduction to the fifteenth in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel invertebrate neuropeptide seque...

A secreted antibacterial neuropeptide shapes the microbiome of Hydra.

PubMed

Augustin, René; Schröder, Katja; Murillo Rincón, Andrea P; Fraune, Sebastian; Anton-Erxleben, Friederike; Herbst, Eva-Maria; Wittlieb, Jörg; Schwentner, Martin; Grötzinger, Joachim; Wassenaar, Trudy M; Bosch, Thomas C G

2017-09-26

Colonization of body epithelial surfaces with a highly specific microbial community is a fundamental feature of all animals, yet the underlying mechanisms by which these communities are selected and maintained are not well understood. Here, we show that sensory and ganglion neurons in the ectodermal epithelium of the model organism hydra (a member of the animal phylum Cnidaria) secrete neuropeptides with antibacterial activity that may shape the microbiome on the body surface. In particular, a specific neuropeptide, which we call NDA-1, contributes to the reduction of Gram-positive bacteria during early development and thus to a spatial distribution of the main colonizer, the Gram-negative Curvibacter sp., along the body axis. Our findings warrant further research to test whether neuropeptides secreted by nerve cells contribute to the spatial structure of microbial communities in other organisms.Certain neuropeptides, in addition to their neuromodulatory functions, display antibacterial activities of unclear significance. Here, the authors show that a secreted neuropeptide modulates the distribution of bacterial communities on the body surface during development of the model organism Hydra.

Neuropeptides in Obesity and Metabolic Disease.

PubMed

van der Klaauw, Agatha A

2018-01-01

The global rise in the prevalence of obesity and associated comorbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. Studies in rodents with the use of global and targeted gene disruption, and mapping of neurocircuitry by using optogenetics and designer receptors exclusively activated by designer drugs (DREADDs) have greatly advanced our understanding of the neural control of body weight. In conjunction with analytical chemistry techniques involving classical immunoassays and mass spectrometry, many neuropeptides that are key to energy homeostasis have been identified. The actions of neuropeptides are diverse, from paracrine modulation of local neurotransmission to hormonal control of distant target organs. Multiple hormones, such as the adipocyte-derived leptin, insulin, and gut hormones, and nutrients signal peripheral energy state to the central nervous system. Neurons in distinct areas of the hypothalamus and brainstem integrate and translate this information by both direct inhibitory/excitatory projections and anorexigenic or orexigenic neuropeptides into actions on food intake and energy expenditure. The importance of these neuropeptides in human energy balance is most powerfully illustrated by genetic forms of obesity that involve neuropeptides such as melanocortin-4-receptor (MC4R) deficiency. Drugs that mimic the actions of neuropeptides are being tested for the treatment of obesity. Successful therapeutic strategies in obesity will require in-depth knowledge of the neuronal circuits they are working in, the downstream targets, and potential compensatory mechanisms. © 2017 American Association for Clinical Chemistry.

Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.

PubMed

Tsapakidis, Konstantinos; Vlachostergios, Panagiotis J; Voutsadakis, Ioannis A; Befani, Christina D; Patrikidou, Anna; Hatzidaki, Eleana; Daliani, Danai D; Moutzouris, George; Liakos, Panagiotis; Papandreou, Christos N

2012-06-01

Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells. Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome. © 2012 The Japanese Urological

Neuropeptides in tendinopathy

PubMed Central

Scott, Alexander; Bahr, Roald

2014-01-01

Tendinopathy is a clinical syndrome of pain, tendon thickening, and increased blood flow. The current review highlights evidence supporting an underlying role of neuropeptides in the etiology, clinical presentation, and treatment of painful overuse tendinopathy. Painful tendons demonstrate an increased presence of Substance P-containing nerves which are strongly implicated as a potential source of pain, but which also play important roles in the tendon’s attempt to self-repair. Recent findings have identified potential roles of additional sensory and autonomic neuropeptides which regulate pain, tissue remodeling, and vascular flow, including acetylcholine, noradrenaline and neuropeptide Y. Neuropeptide production within tendons is stimulated by mechanical load and exercise, and both direct and indirect neuropeptide effects may be responsible for the potential benefits of heavy-load eccentric loading. A model is presented which delineates the physiologic basis for signalling pathways between tenocytes, mast cells and sensory and autonomic nerves, with implications for understanding the mechanisms of traditional as well as emerging treatment strategies including sclerosing therapy and nitric oxide. PMID:19273194

Sensory neuropeptides modulate cigarette smoke-induced decrease in neutral endopeptidase activity in guinea pig airways.

PubMed

Kuo, H P; Lu, L C

1995-01-01

Cigarette smoke (CS) inhalation stimulates C-fibers to release sensory neuropeptides which mediate airway reflex responses to prevent irritants from entering the lower airways. When CS is inhaled via the upper airways, these airway defense responses may modulate the effect of CS on airway NEP activity and related airway hyperresponsiveness. To examine this possibility, we exposed guinea pigs to 1:10 diluted mid-tar cigarette smoke 100 puffs per day for 7 days and recorded pulmonary resistance of cumulative doses of neurokinin A (NKA, 10(-12)-10(-8) mol/kg, i.v.) or methacholine (Mch, 1-50 micrograms/kg, i.v.). NEP activity in the tracheobronchi was measured using fluorometric assay. Exposure of CS alone failed to alter the dose-response to NKA or Mch compared with air control. NEP activity in the airways after CS exposure was slightly but significantly lower than that of air control. Capsaicin pretreatment 1 week before CS exposure significantly shifted the dose-response curves of NKA, but not Mch, to the left and decreased NEP activity in the airways to a greater extent compared with CS exposure alone group. Capsaicin pretreatment alone failed to alter the responsiveness to NKA or NEP activity. CS also induced a significant increase in neutrophil counts in airways. Capsaicin pretreatment enhanced the effect of CS on neutrophil recruitment. We conclude that sensory neuropeptides may have a protective role in modulation of airways NEP activity downregulation induced by CS, probably by preventing CS from entering the lower airways or the chronic release of sensory neuropeptides induced by CS providing increased amount of substrata for NEP upregulation, and therefore modify the direct effect of CS on NEP activity and related airway hyperresponsiveness.

Discovery of novel representatives of bilaterian neuropeptide families and reconstruction of neuropeptide precursor evolution in ophiuroid echinoderms

PubMed Central

Abylkassimova, Nikara; Hugall, Andrew F.; O'Hara, Timothy D.; Elphick, Maurice R.

2017-01-01

Neuropeptides are a diverse class of intercellular signalling molecules that mediate neuronal regulation of many physiological and behavioural processes. Recent advances in genome/transcriptome sequencing are enabling identification of neuropeptide precursor proteins in species from a growing variety of animal taxa, providing new insights into the evolution of neuropeptide signalling. Here, detailed analysis of transcriptome sequence data from three brittle star species, Ophionotus victoriae, Amphiura filiformis and Ophiopsila aranea, has enabled the first comprehensive identification of neuropeptide precursors in the class Ophiuroidea of the phylum Echinodermata. Representatives of over 30 bilaterian neuropeptide precursor families were identified, some of which occur as paralogues. Furthermore, homologues of endothelin/CCHamide, eclosion hormone, neuropeptide-F/Y and nucleobinin/nesfatin were discovered here in a deuterostome/echinoderm for the first time. The majority of ophiuroid neuropeptide precursors contain a single copy of a neuropeptide, but several precursors comprise multiple copies of identical or non-identical, but structurally related, neuropeptides. Here, we performed an unprecedented investigation of the evolution of neuropeptide copy number over a period of approximately 270 Myr by analysing sequence data from over 50 ophiuroid species, with reference to a robust phylogeny. Our analysis indicates that the composition of neuropeptide ‘cocktails’ is functionally important, but with plasticity over long evolutionary time scales. PMID:28878039

Neuropeptide physiology in helminths.

PubMed

Mousley, Angela; Novozhilova, Ekaterina; Kimber, Michael J; Day, Tim A

2010-01-01

Parasitic worms come from two distinct, distant phyla, Nematoda (roundworms) and Platyhelminthes (flatworms). The nervous systems of worms from both phyla are replete with neuropeptides and there is ample physiological evidence that these neuropeptides control vital aspects of worm biology. In each phyla, the physiological evidence for critical roles for helminth neuropeptides is derived from both parasitic and free-living members. In the nematodes, the intestinal parasite Ascaris suum and the free-living Caenorhabditis elegans have yielded most of the data; in the platyhelminths, the most physiological data has come from the blood fluke Schistosoma mansoni. FMRFamide-like peptides (FLPs) have many varied effects (excitation, relaxation, or a combination) on somatic musculature, reproductive musculature, the pharynx and motor neurons in nematodes. Insulin-like peptides (INSs) play an essential role in nematode dauer formation and other developmental processes. There is also some evidence for a role in somatic muscle control for the somewhat heterogeneous grouping ofpeptides known as neuropeptide-like proteins (NLPs). In platyhelminths, as in nematodes, FLPs have a central role in somatic muscle function. Reports of FLP physiological action in platyhelminths are limited to a potent excitation of the somatic musculature. Platyhelminths are also abundantly endowed with neuropeptide Fs (NPFs), which appear absent from nematodes. There is not yet any data linking platyhelminth NPF to any particular physiological outcome, but this neuropeptide does potently and specifically inhibit cAMP accumulation in schistosomes. In nematodes and platyhelminths, there is an abundance of physiological evidence demonstrating that neuropeptides play critical roles in the biology of both free-living and parasitic helminths. While it is certainly true that there remains a great deal to learn about the biology of neuropeptides in both phyla, physiological evidence presently available points

Neuropeptide Y distribution in human brain.

PubMed

Adrian, T E; Allen, J M; Bloom, S R; Ghatei, M A; Rossor, M N; Roberts, G W; Crow, T J; Tatemoto, K; Polak, J M

Tatemoto and Mutt recently used the presence of a C-terminal NH2 group to identify and isolate a new peptide, neuropeptide Y (NPY), from porcine brain. This 36 amino acid peptide was subsequently shown to be active on isolated vas deferens, vascular smooth muscle and pancreatic acinar cells in very low molar concentrations. In view of these potent effects we have now investigated its distribution in the human brain by radioimmunoassay and immunocytochemistry. High concentrations of NPY have been found, exceeding those of cholecystokinin and somatostatin, hitherto considered to be the most abundant neuropeptides. The distribution of NPY was different from that of any other peptide system described, being particularly concentrated in the basal ganglia, amygdala and nucleus accumbens. Immunocytochemistry demonstrated a large number of NPY neuronal cell bodies especially in the caudate and putamen. Immunoreactive neuronal cell bodies were also clearly localized in cortical areas, particularly layers V and VI. NPY, a newly discovered peptide with potent biological activity, thus seems to be among the most abundant of human neuropeptides. The massive numbers of NPY neurones in the basal ganglia suggest NPY to be of fundamental importance in the control of human motor function.

Bombyx neuropeptide G protein-coupled receptor A7 is the third cognate receptor for short neuropeptide F from silkworm.

PubMed

Ma, Qiang; Cao, Zheng; Yu, Yena; Yan, Lili; Zhang, Wenjuan; Shi, Ying; Zhou, Naiming; Huang, Haishan

2017-12-15

The short neuropeptide F (sNPF) neuropeptides, closely related to vertebrate neuropeptide Y (NPY), have been suggested to exert pleiotropic effects on many physiological processes in insects. In the silkworm ( Bombyx mori ) two orphan G protein-coupled receptors, Bombyx neuropeptide G protein-coupled receptor (BNGR) A10 and A11, have been identified as cognate receptors for sNPFs, but other sNPF receptors and their signaling mechanisms in B. mori remain unknown. Here, we cloned the full-length cDNA of the orphan receptor BNGR-A7 from the brain of B. mori larvae and identified it as a receptor for Bombyx sNPFs. Further characterization of signaling and internalization indicated that BNGR-A7, -A10, and -A11 are activated by direct interaction with synthetic Bombyx sNPF-1 and -3 peptides. This activation inhibited forskolin or adipokinetic hormone-induced adenylyl cyclase activity and intracellular Ca 2+ mobilization via a G i/o -dependent pathway. Upon activation by sNPFs, BNGR-A7, -A10, and -A11 evoked ERK1/2 phosphorylation and underwent internalization. On the basis of these findings, we designated the receptors BNGR-A7, -A10, and -A11 as Bommo -sNPFR-1, -2, and -3, respectively. Moreover, the results obtained with quantitative RT-PCR analysis revealed that the three Bombyx sNPF receptor subtypes exhibit differential spatial and temporal expression patterns, suggesting possible roles of sNPF signaling in the regulation of a wide range of biological processes. Our findings provide the first in-depth information on sNPF signaling for further elucidation of the roles of the Bombyx sNPF/sNPFR system in the regulation of physiological activities. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Myopic (HD-PTP, PTPN23) selectively regulates synaptic neuropeptide release.

PubMed

Bulgari, Dinara; Jha, Anupma; Deitcher, David L; Levitan, Edwin S

2018-02-13

Neurotransmission is mediated by synaptic exocytosis of neuropeptide-containing dense-core vesicles (DCVs) and small-molecule transmitter-containing small synaptic vesicles (SSVs). Exocytosis of both vesicle types depends on Ca 2+ and shared secretory proteins. Here, we show that increasing or decreasing expression of Myopic (mop, HD-PTP, PTPN23), a Bro1 domain-containing pseudophosphatase implicated in neuronal development and neuropeptide gene expression, increases synaptic neuropeptide stores at the Drosophila neuromuscular junction (NMJ). This occurs without altering DCV content or transport, but synaptic DCV number and age are increased. The effect on synaptic neuropeptide stores is accounted for by inhibition of activity-induced Ca 2+ -dependent neuropeptide release. cAMP-evoked Ca 2+ -independent synaptic neuropeptide release also requires optimal Myopic expression, showing that Myopic affects the DCV secretory machinery shared by cAMP and Ca 2+ pathways. Presynaptic Myopic is abundant at early endosomes, but interaction with the endosomal sorting complex required for transport III (ESCRT III) protein (CHMP4/Shrub) that mediates Myopic's effect on neuron pruning is not required for control of neuropeptide release. Remarkably, in contrast to the effect on DCVs, Myopic does not affect release from SSVs. Therefore, Myopic selectively regulates synaptic DCV exocytosis that mediates peptidergic transmission at the NMJ.

Re-evaluation of the PBAN receptor molecule: characterization of PBANR variants expressed in the pheromone glands of moths

USDA-ARS?s Scientific Manuscript database

Sex pheromone production in most moths is initiated following pheromone biosynthesis activating neuropeptide receptor (PBANR) activation. PBANR was initially cloned from pheromone glands (PGs) of Helicoverpa zea and Bombyx mori. The B. mori PBANR is characterized by a relatively long C-terminus that...

Effects of neuropeptides on human lung fibroblast proliferation and chemotaxis.

PubMed

Harrison, N K; Dawes, K E; Kwon, O J; Barnes, P J; Laurent, G J; Chung, K F

1995-02-01

An increase in subepithelial mesenchymal cells and associated connective tissue is a feature of bronchial asthma. We determined whether neuropeptides could modulate fibroblast activity, particularly with respect to proliferation and chemotaxis. Human lung fibroblasts were cultured with neurokinin A (NKA), substance P (SP), vasoactive intestinal peptide (VIP), and calcitonin-gene-related peptide (CGRP). After 48 h, fibroblast proliferation was measured by a colorimetric assay based on the uptake and subsequent release of methylene blue. The chemotactic response to neuropeptides was determined with the use of a modified Boyden chamber. Both NKA and SP (10(-7)-10(-4) M) stimulated human lung fibroblast proliferation in HFL1 and IMR-90 fibroblasts. VIP and CGRP had no effect on fibroblast proliferation. NKA alone stimulated fibroblast chemotaxis maximally at 10(-10) M. Neutral endopeptidase (NEP) activity of 0.52 and 5.2 pmol/10(6) cells was assayed in IMR-90 and Hs68 fibroblasts, respectively. Phosphoramidon (5 x 10(-6)-10(-5) M), an NEP inhibitor, enhanced fibroblast proliferation in a dose-dependent manner. Thus neuropeptides have the potential to cause activation of mesenchymal cells, and neuropeptide release may contribute to the structural abnormalities observed in asthmatic airways.

Introduction: Invertebrate Neuropeptides XI

USDA-ARS?s Scientific Manuscript database

This publication represents an introduction to the eleventh in a series of special issues of the Peptides journal dedicated to invertebrate neuropeptides. The issue addresses a number of aspects of invertebrate neuropeptide research including identification of novel characterization of new biologic...

Expression of neuropeptides and their degrading enzymes in ACD.

PubMed

Bak, H; Lee, W J; Lee, Y W; Chang, S-E; Choi, J-H; Kim, M N; Kim, B J; Choi, Y S; Suh, H S

2010-04-01

Sensory neuropeptides such as neurokinin A or substance P modulate skin and immune cells the functions of neurokinin receptor activation during neurogenic inflammation. Zinc metalloproteases, such as neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), effectively control the bioavailability of these neuropeptide mediators, which are released from sensory nerves, immune and skin cells during cutaneous responses to endogenous or exogenous noxious stimuli. Recently, studies have suggested that neuropeptides are one of the major pathogenetic fact in many dermatoses, such as allergic contact dermatitis (ACD), atopic dermatitis and psoriasis. To investigate the expression of major neuropeptides, SP and its degrading enzymes such as NEP and ACE, in the lesions of ACD. A skin biopsy was obtained from 10 patients with ACD. We analysed the expression of these molecules by immunohistochemical staining, confocal laser scanning microscopy, western blotting and reverse transcription PCR. There was a significant increase in expression of SP in keratinocytes from ACD lesions compared with those in control skin. There was also increased expression of ACE but not NEP in ACD. Neuropeptides and their degrading enzymes, particularly SP and ACE, have a significant role in the pathogenesis of ACD.

Transcriptomic identification of starfish neuropeptide precursors yields new insights into neuropeptide evolution

PubMed Central

Semmens, Dean C.; Mirabeau, Olivier; Moghul, Ismail; Pancholi, Mahesh R.; Wurm, Yannick; Elphick, Maurice R.

2016-01-01

Neuropeptides are evolutionarily ancient mediators of neuronal signalling in nervous systems. With recent advances in genomics/transcriptomics, an increasingly wide range of species has become accessible for molecular analysis. The deuterostomian invertebrates are of particular interest in this regard because they occupy an ‘intermediate' position in animal phylogeny, bridging the gap between the well-studied model protostomian invertebrates (e.g. Drosophila melanogaster, Caenorhabditis elegans) and the vertebrates. Here we have identified 40 neuropeptide precursors in the starfish Asterias rubens, a deuterostomian invertebrate from the phylum Echinodermata. Importantly, these include kisspeptin-type and melanin-concentrating hormone-type precursors, which are the first to be discovered in a non-chordate species. Starfish tachykinin-type, somatostatin-type, pigment-dispersing factor-type and corticotropin-releasing hormone-type precursors are the first to be discovered in the echinoderm/ambulacrarian clade of the animal kingdom. Other precursors identified include vasopressin/oxytocin-type, gonadotropin-releasing hormone-type, thyrotropin-releasing hormone-type, calcitonin-type, cholecystokinin/gastrin-type, orexin-type, luqin-type, pedal peptide/orcokinin-type, glycoprotein hormone-type, bursicon-type, relaxin-type and insulin-like growth factor-type precursors. This is the most comprehensive identification of neuropeptide precursor proteins in an echinoderm to date, yielding new insights into the evolution of neuropeptide signalling systems. Furthermore, these data provide a basis for experimental analysis of neuropeptide function in the unique context of the decentralized, pentaradial echinoderm bauplan. PMID:26865025

Neuropeptide Y in the human male genital tract.

PubMed

Adrian, T E; Gu, J; Allen, J M; Tatemoto, K; Polak, J M; Bloom, S R

1984-12-24

Neuropeptide Y (NPY) was found in high concentrations in the male genital tract. NPY levels were highest in the seminal vesicles, prostate, corpus cavernosum and vas deferens, where large numbers of immunoreactive nerve fibres were detected. Considerable quantities were also found in the epididymis and spongiosum. Lower concentrations were found in the glans penis, testis and foreskin. The presence of a large number of nerves containing NPY suggest that this active neuropeptide may play a role in control of genital function.

Differential Activation of Enkephalin, Galanin, Somatostatin, NPY, and VIP Neuropeptide Production by Stimulators of Protein Kinases A and C in Neuroendocrine Chromaffin Cells

PubMed Central

Hook, Vivian; Toneff, Thomas; Baylon, Sheley; Sei, Catherine

2009-01-01

Neuropeptides function as peptide neurotransmitters and hormones to mediate cell-cell communication. The goal of this study was to understand how different neuropeptides may be similarly or differentially regulated by protein kinase A (PKA) and protein kinase C (PKC) intracellular signaling mechanisms. Therefore, this study compared the differential effects of treating neuroendocrine chromaffin cells with stimulators of PKA and PKC on the production of the neuropeptides (Met)enkephalin, galanin, somatostatin, NPY, and VIP. Significantly, selective increases in production of these neuropeptides was observed by forskolin or PMA (phorbol myristate acetate) which stimulate PKA and PKC mechanisms, respectively. (Met)enkephalin production was stimulated by up to 2-fold by forskolin treatment, but not by PMA. In contrast, PMA treatment (but not forskolin) resulted in a 2-fold increase in production of galanin and somatostatin, and a 3-fold increase in NPY production. Notably, VIP production was highly stimulated by forskolin and PMA, with increases of 3-fold and 10–15-fold, respectively. Differences in elevated neuropeptides occurred in cell extracts compared to secretion media, which consisted of (i) increased NPY primarily in cell extracts, (ii) increased (Met)enkephalin and somatostatin in secretion media (not cell extracts), and (iii) increased galanin and VIP in both cell extracts and secretion media. Involvement of PKA or PKC for forskolin or PMA regulation of neuropeptide biosynthesis, respectively, was confirmed with direct inhibitors of PKA and PKC. The selective activation of neuropeptide production by forskolin and PMA demonstrates that PKA and PKC pathways are involved in the differential regulation of neuropeptide production. PMID:18619673

Settlement induction of Acropora palmata planulae by a GLW-amide neuropeptide

NASA Astrophysics Data System (ADS)

Erwin, P. M.; Szmant, A. M.

2010-12-01

Complex environmental cues dictate the settlement of coral planulae in situ; however, simple artificial cues may be all that is required to induce settlement of ex situ larval cultures for reef re-seeding and restoration projects. Neuropeptides that transmit settlement signals and initiate the metamorphic cascade have been isolated from hydrozoan taxa and shown to induce metamorphosis of reef-building Acropora spp. in the Indo-Pacific, providing a reliable and efficient settlement cue. Here, the metamorphic activity of six GLW-amide cnidarian neuropeptides was tested on larvae of the Caribbean corals Acropora palmata, Montastraea faveolata and Favia fragum. A. palmata planulae were induced to settle by the exogenous application of the neuropeptide Hym-248 (concentrations ≥1 × 10-6 M), achieving 40-80% attachment and 100% metamorphosis of competent planulae (≥6 days post-fertilization) during two spawning seasons; the remaining neuropeptides exhibited no activity. Hym-248 exposure rapidly altered larval swimming behavior (<1 h) and resulted in >96% metamorphosis after 6 h. In contrast , M. faveolata and F. fragum planulae did not respond to any GLW-amides tested, suggesting a high specificity of neuropeptide activators on lower taxonomic scales in corals. Subsequent experiments for A. palmata revealed that (1) the presence of a biofilm did not enhance attachment efficiency when coupled with Hym-248 treatment, (2) neuropeptide-induced settlement had no negative effects on early life-history developmental processes: zooxanthellae acquisition and skeletal secretion occurred within 12 days, colonial growth occurred within 36 days, and (3) Hym-248 solutions maintained metamorphic activity following storage at room temperature (10 days), indicating its utility in remote field settings. These results corroborate previous studies on Indo-Pacific Acropora spp. and extend the known metamorphic activity of Hym-248 to Caribbean acroporids. Hym-248 allows for directed and

Neutral endopeptidase inhibits neuropeptide-mediated transactivation of the insulin-like growth factor receptor-Akt cell survival pathway.

PubMed

Sumitomo, M; Milowsky, M I; Shen, R; Navarro, D; Dai, J; Asano, T; Hayakawa, M; Nanus, D M

2001-04-15

G-protein coupled receptor (GPCR) agonists such as neuropeptides activate the insulin-like growth factor-1 receptor (IGF-IR) or the serine-threonine protein kinase Akt, suggesting that neuropeptides-GPCR signaling can cross-communicate with IGF-IR-Akt signaling pathways. Neutral endopeptidase 24.11 (NEP) is a cell-surface peptidase that cleaves and inactivates the neuropeptides endothelin-1 (ET-1) and bombesin, which are implicated in progression to androgen-independent prostate cancer (PC). We investigated the mechanisms of NEP regulation of neuropeptide-mediated cell survival in PC cells, including whether neuropeptide substrates of NEP induce phosphorylations of IGF-IR and Akt in PC cells. Western analyses revealed ET-1 and bombesin treatment induced phosphorylation of IGF-IRbeta and Akt independent of IGF-I in TSU-Pr1, DU145, and PC-3 PC cells, which lack NEP expression, but not in NEP-expressing LNCaP cells. Recombinant NEP and induced NEP expression in TSU-Pr1 cells using a tetracycline-repressive expression system inhibited ET-1-mediated phosphorylation of IGF-IRbeta and Akt, and blocked the protective effects of ET-1 against apoptosis induced by serum starvation. Incubation of TSU-Pr1 cells with specific kinase inhibitors together with ET-1 or bombesin showed that IGF-IR activation is required for neuropeptide-induced Akt phosphorylation, and that neuropeptide-induced Akt activation is predominantly mediated by Src and phosphatidylinositol 3-kinase but not by mitogen-activated protein kinase or protein kinase C. These data show that the neuropeptides ET-1 and bombesin stimulate ligand-independent activation of the IGF-IR, which results in Akt activation, and that this cross-communication between GPCR and IGF-IR signaling is inhibited by NEP.

Molecular identification of a pancreatic lipase-like gene involved in sex pheromone biosynthesis of Bombyx mori.

PubMed

Zhang, Song-Dou; Li, Xun; Bin, Zhu; Du, Meng-Fang; Yin, Xin-Ming; An, Shi-Heng

2014-08-01

Cytoplasmic lipid droplet (LD) lipolysis is regulated by pheromone biosynthesis activating neuropeptide (PBAN) in Bombyx mori. To elucidate the molecular mechanism of cytoplasm LD lipolysis, the pancreatic lipase-like gene in B. mori pheromone glands (PGs), designated as B. mori pancreatic lipase-like gene (BmPLLG), was identified in this study. Spatial expression analysis revealed that BmPLLG is a ubiquitous gene present in all studied tissues, such as PGs, brain, epidermis, egg, midgut, flight muscle and fat body. Temporal expression analysis showed that the BmPLLG transcript begins to express 96 h before eclosion (-96 h), continues to increase, peaks in newly emerged females and steadily decreases after eclosion. Translational expression analysis of BmPLLG using a prepared antiserum demonstrated that BmPLLG was expressed in an age-dependent pattern at different development stages in B. mori. This finding was similar to the transcript expression pattern. Further RNA interference-mediated knockdown of BmPLLG significantly inhibited bombykol production. Overall, these results demonstrated that BmPLLG is involved in PBAN-induced sex pheromone biosynthesis and release. © 2013 Institute of Zoology, Chinese Academy of Sciences.

Neuropeptides as Regulators of Behavior in Insects.

PubMed

Schoofs, Liliane; De Loof, Arnold; Van Hiel, Matthias Boris

2017-01-31

Neuropeptides are by far the largest and most diverse group of signaling molecules in multicellular organisms. They are ancient molecules important in regulating a multitude of processes. Their small proteinaceous character allowed them to evolve and radiate quickly into numerous different molecules. On average, hundreds of distinct neuropeptides are present in animals, sometimes with unique classes that do not occur in distantly related species. Acting as neurotransmitters, neuromodulators, hormones, or growth factors, they are extremely diverse and are involved in controlling growth, development, ecdysis, digestion, diuresis, and many more physiological processes. Neuropeptides are also crucial in regulating myriad behavioral actions associated with feeding, courtship, sleep, learning and memory, stress, addiction, and social interactions. In general, behavior ensures that an organism can survive in its environment and is defined as any action that can change an organism's relationship to its surroundings. Even though the mode of action of neuropeptides in insects has been vigorously studied, relatively little is known about most neuropeptides and only a few model insects have been investigated. Here, we provide an overview of the roles neuropeptides play in insect behavior. We conclude that multiple neuropeptides need to work in concert to coordinate certain behaviors. Additionally, most neuropeptides studied to date have more than a single function.

Neuropeptides in the Gonads: From Evolution to Pharmacology

PubMed Central

McGuire, Nicolette L.; Bentley, George E.

2010-01-01

Vertebrate gonads are the sites of synthesis and binding of many peptides that were initially classified as neuropeptides. These gonadal neuropeptide systems are neither well understood in isolation, nor in their interactions with other neuropeptide systems. Further, our knowledge of the control of these gonadal neuropeptides by peripheral hormones that bind to the gonads, and which themselves are under regulation by true neuropeptide systems from the hypothalamus, is relatively meager. This review discusses the existence of a variety of neuropeptides and their receptors which have been discovered in vertebrate gonads, and the possible way in which such systems could have evolved. We then focus on two key neuropeptides for regulation of the hypothalamo-pituitary-gonadal axis: gonadotropin-releasing hormone (GnRH) and gonadotropin-inhibitory hormone (GnIH). Comparative studies have provided us with a degree of understanding as to how a gonadal GnRH system might have evolved, and they have been responsible for the discovery of GnIH and its gonadal counterpart. We attempt to highlight what is known about these two key gonadal neuropeptides, how their actions differ from their hypothalamic counterparts, and how we might learn from comparative studies of them and other gonadal neuropeptides in terms of pharmacology, reproductive physiology and evolutionary biology. PMID:21607065

Neuropeptide secreted from a pacemaker activates neurons to control a rhythmic behavior.

PubMed

Wang, Han; Girskis, Kelly; Janssen, Tom; Chan, Jason P; Dasgupta, Krishnakali; Knowles, James A; Schoofs, Liliane; Sieburth, Derek

2013-05-06

Rhythmic behaviors are driven by endogenous biological clocks in pacemakers, which must reliably transmit timing information to target tissues that execute rhythmic outputs. During the defecation motor program in C. elegans, calcium oscillations in the pacemaker (intestine), which occur about every 50 s, trigger rhythmic enteric muscle contractions through downstream GABAergic neurons that innervate enteric muscles. However, the identity of the timing signal released by the pacemaker and the mechanism underlying the delivery of timing information to the GABAergic neurons are unknown. Here, we show that a neuropeptide-like protein (NLP-40) released by the pacemaker triggers a single rapid calcium transient in the GABAergic neurons during each defecation cycle. We find that mutants lacking nlp-40 have normal pacemaker function, but lack enteric muscle contractions. NLP-40 undergoes calcium-dependent release that is mediated by the calcium sensor, SNT-2/synaptotagmin. We identify AEX-2, the G-protein-coupled receptor on the GABAergic neurons, as the receptor for NLP-40. Functional calcium imaging reveals that NLP-40 and AEX-2/GPCR are both necessary for rhythmic activation of these neurons. Furthermore, acute application of synthetic NLP-40-derived peptide depolarizes the GABAergic neurons in vivo. Our results show that NLP-40 carries the timing information from the pacemaker via calcium-dependent release and delivers it to the GABAergic neurons by instructing their activation. Thus, we propose that rhythmic release of neuropeptides can deliver temporal information from pacemakers to downstream neurons to execute rhythmic behaviors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Neuropeptide Secreted from a Pacemaker Activates Neurons to Control a Rhythmic Behavior

PubMed Central

Wang, Han; Girskis, Kelly; Janssen, Tom; Chan, Jason P.; Dasgupta, Krishnakali; Knowles, James A.; Schoofs, Liliane; Sieburth, Derek

2013-01-01

Summary Background Rhythmic behaviors are driven by endogenous biological clocks in pacemakers, which must reliably transmit timing information to target tissues that execute rhythmic outputs. During the defecation motor program in C. elegans, calcium oscillations in the pacemaker (intestine), which occur about every 50 seconds, trigger rhythmic enteric muscle contractions through downstream GABAergic neurons that innervate enteric muscles. However, the identity of the timing signal released by the pacemaker and the mechanism underlying the delivery of timing information to the GABAergic neurons are unknown. Results Here we show that a neuropeptide-like protein (NLP-40) released by the pacemaker triggers a single rapid calcium transient in the GABAergic neurons during each defecation cycle. We find that mutants lacking nlp-40 have normal pacemaker function, but lack enteric muscle contractions. NLP-40 undergoes calcium-dependent release that is mediated by the calcium sensor, SNT-2/synaptotagmin. We identify AEX-2, the G protein-coupled receptor on the GABAergic neurons, as the receptor of NLP-40. Functional calcium imaging reveals that NLP-40 and AEX-2/GPCR are both necessary for rhythmic activation of these neurons. Furthermore, acute application of synthetic NLP-40-derived peptide depolarizes the GABAergic neurons in vivo. Conclusions Our results show that NLP-40 carries the timing information from the pacemaker via calcium-dependent release and delivers it to the GABAergic neurons by instructing their activation. Thus, we propose that rhythmic release of neuropeptides can deliver temporal information from pacemakers to downstream neurons to execute rhythmic behaviors. PMID:23583549

RIC-7 Promotes Neuropeptide Secretion

PubMed Central

Hao, Yingsong; Hu, Zhitao; Sieburth, Derek; Kaplan, Joshua M.

2012-01-01

Secretion of neurotransmitters and neuropeptides is mediated by exocytosis of distinct secretory organelles, synaptic vesicles (SVs) and dense core vesicles (DCVs) respectively. Relatively little is known about factors that differentially regulate SV and DCV secretion. Here we identify a novel protein RIC-7 that is required for neuropeptide secretion in Caenorhabditis elegans. The RIC-7 protein is expressed in all neurons and is localized to presynaptic terminals. Imaging, electrophysiology, and behavioral analysis of ric-7 mutants indicates that acetylcholine release occurs normally, while neuropeptide release is significantly decreased. These results suggest that RIC-7 promotes DCV–mediated secretion. PMID:22275875

Neuropeptide S overcomes short term memory deficit induced by sleep restriction by increasing prefrontal cortex activity.

PubMed

Thomasson, Julien; Canini, Frédéric; Poly-Thomasson, Betty; Trousselard, Marion; Granon, Sylvie; Chauveau, Frédéric

2017-12-01

Sleep restriction (SR) impairs short term memory (STM) that might be related to different processes. Neuropeptide S (NPS), an endogenous neuropeptide that improves short term memory, activates arousal and decreases anxiety is likely to counteract the SR-induced impairment of STM. The objective of the present study was to find common cerebral pathways in sleep restriction and NPS action in order to ultimately antagonize SR effect on memory. The STM was assessed using a spontaneous spatial alternation task in a T-maze. C57-Bl/6J male mice were distributed in 4 groups according to treatment (0.1nmol of NPS or vehicle intracerebroventricular injection) and to 20h-SR. Immediately after behavioural testing, regional c-fos immunohistochemistry was performed and used as a neural activation marker for spatial short term memory (prefrontal cortex, dorsal hippocampus) and emotional reactivity (basolateral amygdala and ventral hippocampus). Anxiety-like behaviour was assessed using elevated-plus maze task. Results showed that SR impaired short term memory performance and decreased neuronal activation in cingular cortex.NPS injection overcame SR-induced STM deficits and increased neuronal activation in infralimbic cortex. SR spared anxiety-like behavior in the elevated-plus maze. Neural activation in basolateral nucleus of amygdala and ventral hippocampus were not changed after SR.In conclusion, the present study shows that NPS overcomes SR-induced STM deficits by increasing prefrontal cortex activation independently of anxiety-like behaviour. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Diversity of Neuropeptide Cell-Cell Signaling Molecules Generated by Proteolytic Processing Revealed by Neuropeptidomics Mass Spectrometry

NASA Astrophysics Data System (ADS)

Hook, Vivian; Lietz, Christopher B.; Podvin, Sonia; Cajka, Tomas; Fiehn, Oliver

2018-05-01

Neuropeptides are short peptides in the range of 3-40 residues that are secreted for cell-cell communication in neuroendocrine systems. In the nervous system, neuropeptides comprise the largest group of neurotransmitters. In the endocrine system, neuropeptides function as peptide hormones to coordinate intercellular signaling among target physiological systems. The diversity of neuropeptide functions is defined by their distinct primary sequences, peptide lengths, proteolytic processing of pro-neuropeptide precursors, and covalent modifications. Global, untargeted neuropeptidomics mass spectrometry is advantageous for defining the structural features of the thousands to tens of thousands of neuropeptides present in biological systems. Defining neuropeptide structures is the basis for defining the proteolytic processing pathways that convert pro-neuropeptides into active peptides. Neuropeptidomics has revealed that processing of pro-neuropeptides occurs at paired basic residues sites, and at non-basic residue sites. Processing results in neuropeptides with known functions and generates novel peptides representing intervening peptide domains flanked by dibasic residue processing sites, identified by neuropeptidomics. While very short peptide products of 2-4 residues are predicted from pro-neuropeptide dibasic processing sites, such peptides have not been readily identified; therefore, it will be logical to utilize metabolomics to identify very short peptides with neuropeptidomics in future studies. Proteolytic processing is accompanied by covalent post-translational modifications (PTMs) of neuropeptides comprising C-terminal amidation, N-terminal pyroglutamate, disulfide bonds, phosphorylation, sulfation, acetylation, glycosylation, and others. Neuropeptidomics can define PTM features of neuropeptides. In summary, neuropeptidomics for untargeted, global analyses of neuropeptides is essential for elucidation of proteases that generate diverse neuropeptides for cell

Diversity of Neuropeptide Cell-Cell Signaling Molecules Generated by Proteolytic Processing Revealed by Neuropeptidomics Mass Spectrometry

NASA Astrophysics Data System (ADS)

Hook, Vivian; Lietz, Christopher B.; Podvin, Sonia; Cajka, Tomas; Fiehn, Oliver

2018-04-01

Neuropeptides are short peptides in the range of 3-40 residues that are secreted for cell-cell communication in neuroendocrine systems. In the nervous system, neuropeptides comprise the largest group of neurotransmitters. In the endocrine system, neuropeptides function as peptide hormones to coordinate intercellular signaling among target physiological systems. The diversity of neuropeptide functions is defined by their distinct primary sequences, peptide lengths, proteolytic processing of pro-neuropeptide precursors, and covalent modifications. Global, untargeted neuropeptidomics mass spectrometry is advantageous for defining the structural features of the thousands to tens of thousands of neuropeptides present in biological systems. Defining neuropeptide structures is the basis for defining the proteolytic processing pathways that convert pro-neuropeptides into active peptides. Neuropeptidomics has revealed that processing of pro-neuropeptides occurs at paired basic residues sites, and at non-basic residue sites. Processing results in neuropeptides with known functions and generates novel peptides representing intervening peptide domains flanked by dibasic residue processing sites, identified by neuropeptidomics. While very short peptide products of 2-4 residues are predicted from pro-neuropeptide dibasic processing sites, such peptides have not been readily identified; therefore, it will be logical to utilize metabolomics to identify very short peptides with neuropeptidomics in future studies. Proteolytic processing is accompanied by covalent post-translational modifications (PTMs) of neuropeptides comprising C-terminal amidation, N-terminal pyroglutamate, disulfide bonds, phosphorylation, sulfation, acetylation, glycosylation, and others. Neuropeptidomics can define PTM features of neuropeptides. In summary, neuropeptidomics for untargeted, global analyses of neuropeptides is essential for elucidation of proteases that generate diverse neuropeptides for cell

Effects of Organophosphate Esters on Neuropeptide Systems.

DTIC Science & Technology

1986-03-01

pathways for the synthesis and degradation of neuropeptides involve hydrolytic enzyme reactions which may be mechanistically similar to those catalyzed by...neuropeptide processing and degradation in vitro, and to assess the effect of introducing organophosphates into these systems. The methods used for the...weight precursors by proteolytic cleavage and inactivation, in which the mature neuropeptides are hydrolyzed by peptidases . More importantly

Neuropeptide systems and new treatments for nicotine addiction

PubMed Central

Bruijnzeel, Adriaan W.

2017-01-01

RATIONALE The mildly euphoric and cognitive enhancing effects of nicotine play a role in the initiation of smoking, while dysphoria and anxiety associated with smoking cessation contribute to relapse. After the acute withdrawal phase, smoking cues, a few cigarettes (i.e., lapse), and stressors can cause relapse. Human and animal studies have shown that neuropeptides play a critical role in nicotine addiction. OBJECTIVES The goal of this paper is to describe the role of neuropeptide systems in the initiation of nicotine intake, nicotine withdrawal, and the reinstatement of extinguished nicotine seeking. RESULTS The reviewed studies indicate that several drugs that target neuropeptide systems diminish the rewarding effects of nicotine by preventing the activation of dopaminergic systems. Other peptide-based drugs diminish the hyperactivity of brain stress systems and diminish withdrawal-associated symptom severity. Blockade of hypocretin-1 and nociceptin receptors and stimulation of galanin and neurotensin receptors diminishes the rewarding effects of nicotine. Both corticotropin-releasing factor type 1 and kappa-opioid receptor antagonists diminish dysphoria and anxiety-like behavior associated with nicotine withdrawal and inhibit stress-induced reinstatement of nicotine seeking. Furthermore, blockade of vasopressin 1b receptors diminishes dysphoria during nicotine withdrawal and melanocortin 4 receptor blockade prevents stress-induced reinstatement of nicotine seeking. The role of neuropeptide systems in nicotine-primed and cue-induced reinstatement is largely unexplored, but there is evidence for a role of hypocretin-1 receptors in cue-induced reinstatement of nicotine seeking. CONCLUSION Drugs that target neuropeptide systems might decrease the euphoric effects of smoking and improve relapse rates by diminishing withdrawal symptoms and improving stress resilience. PMID:28028605

Sex pheromone in the moth Heliothis virescens is produced as a mixture of two pools: de novo and via precursor storage in glycerolipids.

PubMed

Foster, Stephen P; Anderson, Karin G; Casas, Jérôme

2017-08-01

Most species of moths use a female-produced volatile sex pheromone, typically produced via de novo fatty acid synthesis in a specialized gland, for communication among mates. While de novo biosynthesis of pheromone (DNP) is rapid, suggesting transient precursor acids, substantial amounts of pheromone precursor (and other) acids are stored, predominantly in triacylglycerols in the pheromone gland. Whether these stored acids are converted to pheromone later or not has been the subject of some debate. Using a tracer/tracee approach, in which we fed female Heliothis virescens U- 13 C-glucose, we were able to distinguish two pools of pheromone, in which precursors were temporally separated (after and before feeding on labeled glucose): DNP synthesized from a mixed tracer/tracee acetyl CoA pool after feeding, and pheromone made from precursor acids primarily synthesized before feeding, which we call recycled precursor fat pheromone (RPP). DNP titer varied from high (during scotophase) to low (photophase) and with presence/absence of pheromone biosynthesis activating neuropeptide (PBAN), in accord with native pheromone titer previously observed. By contrast, RPP was constant throughout the photoperiod and did not change with PBAN presence/absence. The amount of RPP (6.3-10.3 ng/female) was typically much lower than that of DNP, especially during the scotophase (peak DNP, 105 ng/female). We propose an integral role for stored fats in pheromone biosynthesis, in which they are hydrolyzed and re-esterified throughout the photoperiod, with a small proportion of liberated precursor acyl CoAs being converted to pheromone. During the sexually active period, release of PBAN results in increased flux of glucose (from trehalose) and hydrolyzed acids entering the mitochondria, producing acetyl CoA precursor for de novo fat and pheromone biosynthesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

The evolution of neuropeptide signalling: insights from echinoderms.

PubMed

Semmens, Dean C; Elphick, Maurice R

2017-09-01

Neuropeptides are evolutionarily ancient mediators of neuronal signalling that regulate a wide range of physiological processes and behaviours in animals. Neuropeptide signalling has been investigated extensively in vertebrates and protostomian invertebrates, which include the ecdysozoans Drosophila melanogaster (Phylum Arthropoda) and Caenorhabditis elegans (Phylum Nematoda). However, until recently, an understanding of evolutionary relationships between neuropeptide signalling systems in vertebrates and protostomes has been impaired by a lack of genome/transcriptome sequence data from non-ecdysozoan invertebrates. The echinoderms-a deuterostomian phylum that includes sea urchins, sea cucumbers and starfish-have been particularly important in providing new insights into neuropeptide evolution. Sequencing of the genome of the sea urchin Strongylocentrotus purpuratus (Class Echinoidea) enabled discovery of (i) the first invertebrate thyrotropin-releasing hormone-type precursor, (ii) the first deuterostomian pedal peptide/orcokinin-type precursors and (iii) NG peptides-the 'missing link' between neuropeptide S in tetrapod vertebrates and crustacean cardioactive peptide in protostomes. More recently, sequencing of the neural transcriptome of the starfish Asterias rubens (Class Asteroidea) enabled identification of 40 neuropeptide precursors, including the first kisspeptin and melanin-concentrating hormone-type precursors to be identified outside of the chordates. Furthermore, the characterization of a corazonin-type neuropeptide signalling system in A. rubens has provided important new insights into the evolution of gonadotropin-releasing hormone-related neuropeptides. Looking forward, the discovery of multiple neuropeptide signalling systems in echinoderms provides opportunities to investigate how these systems are used to regulate physiological and behavioural processes in the unique context of a decentralized, pentaradial bauplan. © The Author 2017. Published by

Neuropeptide Signaling Networks and Brain Circuit Plasticity.

PubMed

McClard, Cynthia K; Arenkiel, Benjamin R

2018-01-01

The brain is a remarkable network of circuits dedicated to sensory integration, perception, and response. The computational power of the brain is estimated to dwarf that of most modern supercomputers, but perhaps its most fascinating capability is to structurally refine itself in response to experience. In the language of computers, the brain is loaded with programs that encode when and how to alter its own hardware. This programmed "plasticity" is a critical mechanism by which the brain shapes behavior to adapt to changing environments. The expansive array of molecular commands that help execute this programming is beginning to emerge. Notably, several neuropeptide transmitters, previously best characterized for their roles in hypothalamic endocrine regulation, have increasingly been recognized for mediating activity-dependent refinement of local brain circuits. Here, we discuss recent discoveries that reveal how local signaling by corticotropin-releasing hormone reshapes mouse olfactory bulb circuits in response to activity and further explore how other local neuropeptide networks may function toward similar ends.

Neuropeptide Signaling in Crustaceans Probed by Mass Spectrometry

NASA Astrophysics Data System (ADS)

Liang, Zhidan

Neuropeptides are one of the most diverse classes of signaling molecules whose identities and functions are not yet fully understood. They have been implicated in the regulation of a wide range of physiological processes, including feeding-related and motivated behaviors, and also environmental adaptations. In this work, improved mass spectrometry-based analytical platforms were developed and applied to the crustacean systems to characterize signaling molecules. This dissertation begins with a review of mass spectrometry-based neuropeptide studies from both temporal- and spatial-domains. This review is then followed by several chapters detailing a few research projects related to the crustacean neuropeptidomic characterization and comparative analysis. The neuropeptidome of crayfish, Orconectes rusticus is characterized for the first time using mass spectrometry-based tools. In vivo microdialysis sampling technique offers the capability of direct sampling from extracellular space in a time-resolved manner. It is used to investigate the secreted neuropeptide and neurotransmitter content in Jonah crab, Cancer borealis, in this work. A new quantitation strategy using alternative mass spectrometry data acquisition approach is developed and applied for the first time to quantify neuropeptides. Coupling of this method with microdialysis enables the study of neuropeptide dynamics concurrent with different behaviors. Proof-of-principle experiments validating this approach have been carried out in Jonah crab, Cancer borealis to study feeding- and circadian rhythm-related neuropeptide changes using micoridialysis in a time-resolved manner. This permits a close correlation between behavioral and neurochemical changes, providing potential candidates for future validation of regulatory roles. In addition to providing spatial information, mass spectrometry imaging (MSI) technique enables the characterization of signaling molecules while preserving the temporal resolution. A

C. elegans Stress-Induced Sleep Emerges from the Collective Action of Multiple Neuropeptides.

PubMed

Nath, Ravi D; Chow, Elly S; Wang, Han; Schwarz, Erich M; Sternberg, Paul W

2016-09-26

The genetic basis of sleep regulation remains poorly understood. In C. elegans, cellular stress induces sleep through epidermal growth factor (EGF)-dependent activation of the EGF receptor in the ALA neuron. The downstream mechanism by which this neuron promotes sleep is unknown. Single-cell RNA sequencing of ALA reveals that the most highly expressed, ALA-enriched genes encode neuropeptides. Here we have systematically investigated the four most highly enriched neuropeptides: flp-7, nlp-8, flp-24, and flp-13. When individually removed by null mutation, these peptides had little or no effect on stress-induced sleep. However, stress-induced sleep was abolished in nlp-8; flp-24; flp-13 triple-mutant animals, indicating that these neuropeptides work collectively in controlling stress-induced sleep. We tested the effect of overexpression of these neuropeptide genes on five behaviors modulated during sleep-pharyngeal pumping, defecation, locomotion, head movement, and avoidance response to an aversive stimulus-and we found that, if individually overexpressed, each of three neuropeptides (nlp-8, flp-24, or flp-13) induced a different suite of sleep-associated behaviors. These overexpression results raise the possibility that individual components of sleep might be specified by individual neuropeptides or combinations of neuropeptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

The pheromone production of female Plodia interpunctella is inhibited by tyraminergic antagonists.

PubMed

Hirashima, Akinori; Kimizu, Megumi; Shigeta, Yoko; Matsugu, Sachiko; Eiraku, Tomohiko; Kuwano, Eiichi; Eto, Morifusa

2004-11-01

Several compounds were found to suppress the calling behavior and in vitro pheromone biosynthesis of the Indian meal moth, Plodia interpunctella. The compounds were screened by means of a calling-behavior bioassay with female P. interpunctella. Five derivatives with activities in the nanomolar range were identified, in order of decreasing pheromonostatic activity: 4-hydroxybenzaldehyde semicarbazone (42) > 5-(4-methoxyphenyl)-1,3-oxazole (38) > 5-[4-(tert-butyl)phenyl]-1,3-oxazole (40) > 5-(3-methoxyphenyl)-1,3-oxazole (35) > 5-(4-cyanophenyl)-1,3-oxazole (36). These compounds also showed in vitro inhibitory activity in intracellular de novo pheromone biosynthesis, as determined with isolated pheromone-gland preparations that incorporated [1-(14)C]sodium acetate in the presence of the so-called pheromone-biosynthesis-activating neuropeptide (PBAN). The non-additive effect of the inhibitor with antagonist (yohimbine) for the tyramine (TA) receptor suggests that it could be a tyraminergic antagonist. Three-dimensional (3D) computer models were built from a set of compounds. Among the common-featured models generated by the program Catalyst/HipHop, aromatic-ring (AR) and H-bond-acceptor-lipophilic (HBAl) features were considered to be essential for inhibitory activity in the calling behavior and in vitro pheromone biosynthesis. Active compounds, including yohimbine, mapped well onto all the AR and HBAl features of the hypothesis. Less-active compounds were shown to be unable to achieve an energetically favorable conformation, consistent with our 3D common-feature pharmacophore models. The present hypothesis demonstrates that calling behavior and PBAN-stimulated incorporation of radioactivity are inhibited by tyraminergic antagonists.

Neuropeptides, via specific receptors, regulate T cell adhesion to fibronectin.

PubMed

Levite, M; Cahalon, L; Hershkoviz, R; Steinman, L; Lider, O

1998-01-15

The ability of T cells to adhere to and interact with components of the blood vessel walls and the extracellular matrix is essential for their extravasation and migration into inflamed sites. We have found that the beta1 integrin-mediated adhesion of resting human T cells to fibronectin, a major glycoprotein component of the extracellular matrix, is induced by physiologic concentrations of three neuropeptides: calcitonin gene-related protein (CGRP), neuropeptide Y, and somatostatin; each acts via its own specific receptor on the T cell membrane. In contrast, substance P (SP), which coexists with CGRP in the majority of peripheral endings of sensory nerves, including those innervating the lymphoid organs, blocks T cell adhesion to fibronectin when induced by CGRP, neuropeptide Y, somatostatin, macrophage inflammatory protein-1beta, and PMA. Inhibition of T cell adhesion was obtained both by the intact SP peptide and by its 1-4 N-terminal and its 4-11, 5-11, and 6-11 C-terminal fragments, used at similar nanomolar concentrations. The inhibitory effects of the parent SP peptide and its fragments were abrogated by an SP NK-1 receptor antagonist, suggesting they all act through the same SP NK-1 receptor. These findings suggest that neuropeptides, by activating their specific T cell-expressed receptors, can provide the T cells with both positive (proadhesive) and negative (antiadhesive) signals and thereby regulate their function. Thus, neuropeptides may influence diverse physiologic processes involving integrins, including leukocyte-mediated migration and inflammation.

Human Cathepsin V Protease Participates in Production of Enkephalin and NPY Neuropeptide Neurotransmitters*

PubMed Central

Funkelstein, Lydiane; Lu, W. Douglas; Koch, Britta; Mosier, Charles; Toneff, Thomas; Taupenot, Laurent; O'Connor, Daniel T.; Reinheckel, Thomas; Peters, Christoph; Hook, Vivian

2012-01-01

Proteases are required for processing precursors into active neuropeptides that function as neurotransmitters for cell-cell communication. This study demonstrates the novel function of human cathepsin V protease for producing the neuropeptides enkephalin and neuropeptide Y (NPY). Cathepsin V is a human-specific cysteine protease gene. Findings here show that expression of cathepsin V in neuroendocrine PC12 cells and human neuronal SK-N-MC cells results in production of (Met)enkephalin from proenkephalin. Gene silencing of cathepsin V by siRNA in human SK-N-MC cells results in reduction of (Met)enkephalin by more than 80%, illustrating the prominent role of cathepsin V for neuropeptide production. In vitro processing of proenkephalin by cathepsin V occurs at dibasic residue sites to generate enkephalin-containing peptides and an ∼24-kDa intermediate present in human brain. Cathepsin V is present in human brain cortex and hippocampus where enkephalin and NPY are produced and is present in purified human neuropeptide secretory vesicles. Colocalization of cathepsin V with enkephalin and NPY in secretory vesicles of human neuroblastoma cells was illustrated by confocal microscopy. Furthermore, expression of cathepsin V with proNPY results in NPY production. These findings indicate the unique function of human cathepsin V for producing enkephalin and NPY neuropeptides required for neurotransmission in health and neurological diseases. PMID:22393040

Autonomic control network active in Aplysia during locomotion includes neurons that express splice variants of R15-neuropeptides.

PubMed

Romanova, Elena V; McKay, Natasha; Weiss, Klaudiusz R; Sweedler, Jonathan V; Koester, John

2007-01-01

Splice-variant products of the R15 neuropeptide gene are differentially expressed within the CNS of Aplysia. The goal of this study was to test whether the neurons in the abdominal ganglion that express the peptides encoded by this gene are part of a common circuit. Expression of R15 peptides had been demonstrated previously in neuron R15. Using a combination of immunocytochemical and analytical methods, this study demonstrated that R15 peptides are also expressed in heart exciter neuron RB(HE), the two L9(G) gill motoneurons, and L40--a newly identified interneuron. Mass spectrometric profiling of individual neurons that exhibit R15 peptide-like immunoreactivity confirmed the mutually exclusive expression of two splice-variant forms of R15 peptides in different neurons. The L9(G) cells were found to co-express pedal peptide in addition to the R15 peptides. The R15 peptide-expressing neurons examined here were shown to be part of an autonomic control circuit that is active during fictive locomotion. Activity in this circuit contributes to implementing a central command that may help to coordinate autonomic activity with escape locomotion. Chronic extracellular nerve recording was used to determine the activity patterns of a subset of neurons of this circuit in vivo. These results demonstrate the potential utility of using shared patterns of neuropeptide expression as a guide for neural circuit identification.

Comparison of Caenorhabditis elegans NLP peptides with arthropod neuropeptides.

PubMed

Husson, Steven J; Lindemans, Marleen; Janssen, Tom; Schoofs, Liliane

2009-04-01

Neuropeptides are small messenger molecules that can be found in all metazoans, where they govern a diverse array of physiological processes. Because neuropeptides seem to be conserved among pest species, selected peptides can be considered as attractive targets for drug discovery. Much can be learned from the model system Caenorhabditis elegans because of the availability of a sequenced genome and state-of-the-art postgenomic technologies that enable characterization of endogenous peptides derived from neuropeptide-like protein (NLP) precursors. Here, we provide an overview of the NLP peptide family in C. elegans and discuss their resemblance with arthropod neuropeptides and their relevance for anthelmintic discovery.

The Drosophila genes CG14593 and CG30106 code for G-protein-coupled receptors specifically activated by the neuropeptides CCHamide-1 and CCHamide-2.

PubMed

Hansen, Karina K; Hauser, Frank; Williamson, Michael; Weber, Stine B; Grimmelikhuijzen, Cornelis J P

2011-01-07

Recently, a novel neuropeptide, CCHamide, was discovered in the silkworm Bombyx mori (L. Roller et al., Insect Biochem. Mol. Biol. 38 (2008) 1147-1157). We have now found that all insects with a sequenced genome have two genes, each coding for a different CCHamide, CCHamide-1 and -2. We have also cloned and deorphanized two Drosophila G-protein-coupled receptors (GPCRs) coded for by genes CG14593 and CG30106 that are selectively activated by Drosophila CCH-amide-1 (EC(50), 2×10(-9) M) and CCH-amide-2 (EC(50), 5×10(-9) M), respectively. Gene CG30106 (symbol synonym CG14484) has in a previous publication (E.C. Johnson et al., J. Biol. Chem. 278 (2003) 52172-52178) been wrongly assigned to code for an allatostatin-B receptor. This conclusion is based on our findings that the allatostatins-B do not activate the CG30106 receptor and on the recent findings from other research groups that the allatostatins-B activate an unrelated GPCR coded for by gene CG16752. Comparative genomics suggests that a duplication of the CCHamide neuropeptide signalling system occurred after the split of crustaceans and insects, about 410 million years ago, because only one CCHamide neuropeptide gene is found in the water flea Daphnia pulex (Crustacea) and the tick Ixodes scapularis (Chelicerata). Copyright © 2010 Elsevier Inc. All rights reserved.

Phosphopeptidomics Reveals Differential Phosphorylation States and Novel SxE Phosphosite Motifs of Neuropeptides in Dense Core Secretory Vesicles

NASA Astrophysics Data System (ADS)

Lietz, Christopher B.; Toneff, Thomas; Mosier, Charles; Podvin, Sonia; O'Donoghue, Anthony J.; Hook, Vivian

2018-05-01

Neuropeptides are vital for cell-cell communication and function in the regulation of the nervous and endocrine systems. They are generated by post-translational modification (PTM) steps resulting in small active peptides generated from prohormone precursors. Phosphorylation is a significant PTM for the bioactivity of neuropeptides. From the known diversity of distinct neuropeptide functions, it is hypothesized that the extent of phosphorylation varies among different neuropeptides. To assess this hypothesis, neuropeptide-containing dense core secretory vesicles from bovine adrenal medullary chromaffin cells were subjected to global phosphopeptidomics analyses by liquid chromatography (LC)-mass spectrometry (MS/MS). Phosphopeptides were identified directly by LC-MS/MS and indirectly by phosphatase treatment followed by LC-MS/MS. The data identified numerous phosphorylated peptides derived from neuropeptide precursors such as chromogranins, secretogranins, proenkephalin and pro-NPY. Phosphosite occupancies were observed at high and low levels among identified peptides and many of the high occupancy phosphopeptides represent prohormone-derived peptides with currently unknown bioactivities. Peptide sequence analyses demonstrated SxE as the most prevalent phosphorylation site motif, corresponding to phosphorylation sites of the Fam20C protein kinase known to be present in the secretory pathway. The range of high to low phosphosite occupancies for neuropeptides demonstrates cellular regulation of neuropeptide phosphorylation. [Figure not available: see fulltext.

Phosphopeptidomics Reveals Differential Phosphorylation States and Novel SxE Phosphosite Motifs of Neuropeptides in Dense Core Secretory Vesicles

NASA Astrophysics Data System (ADS)

Lietz, Christopher B.; Toneff, Thomas; Mosier, Charles; Podvin, Sonia; O'Donoghue, Anthony J.; Hook, Vivian

2018-03-01

Neuropeptides are vital for cell-cell communication and function in the regulation of the nervous and endocrine systems. They are generated by post-translational modification (PTM) steps resulting in small active peptides generated from prohormone precursors. Phosphorylation is a significant PTM for the bioactivity of neuropeptides. From the known diversity of distinct neuropeptide functions, it is hypothesized that the extent of phosphorylation varies among different neuropeptides. To assess this hypothesis, neuropeptide-containing dense core secretory vesicles from bovine adrenal medullary chromaffin cells were subjected to global phosphopeptidomics analyses by liquid chromatography (LC)-mass spectrometry (MS/MS). Phosphopeptides were identified directly by LC-MS/MS and indirectly by phosphatase treatment followed by LC-MS/MS. The data identified numerous phosphorylated peptides derived from neuropeptide precursors such as chromogranins, secretogranins, proenkephalin and pro-NPY. Phosphosite occupancies were observed at high and low levels among identified peptides and many of the high occupancy phosphopeptides represent prohormone-derived peptides with currently unknown bioactivities. Peptide sequence analyses demonstrated SxE as the most prevalent phosphorylation site motif, corresponding to phosphorylation sites of the Fam20C protein kinase known to be present in the secretory pathway. The range of high to low phosphosite occupancies for neuropeptides demonstrates cellular regulation of neuropeptide phosphorylation. [Figure not available: see fulltext.

Vesicle capture, not delivery, scales up neuropeptide storage in neuroendocrine terminals.

PubMed

Bulgari, Dinara; Zhou, Chaoming; Hewes, Randall S; Deitcher, David L; Levitan, Edwin S

2014-03-04

Neurons vary in their capacity to produce, store, and release neuropeptides packaged in dense-core vesicles (DCVs). Specifically, neurons used for cotransmission have terminals that contain few DCVs and many small synaptic vesicles, whereas neuroendocrine neuron terminals contain many DCVs. Although the mechanistic basis for presynaptic variation is unknown, past research demonstrated transcriptional control of neuropeptide synthesis suggesting that supply from the soma limits presynaptic neuropeptide accumulation. Here neuropeptide release is shown to scale with presynaptic neuropeptide stores in identified Drosophila cotransmitting and neuroendocrine terminals. However, the dramatic difference in DCV number in these terminals occurs with similar anterograde axonal transport and DCV half-lives. Thus, differences in presynaptic neuropeptide stores are not explained by DCV delivery from the soma or turnover. Instead, greater neuropeptide accumulation in neuroendocrine terminals is promoted by dramatically more efficient presynaptic DCV capture. Greater capture comes with tradeoffs, however, as fewer uncaptured DCVs are available to populate distal boutons and replenish neuropeptide stores following release. Finally, expression of the Dimmed transcription factor in cotransmitting neurons increases presynaptic DCV capture. Therefore, DCV capture in the terminal is genetically controlled and determines neuron-specific variation in peptidergic function.

Vesicle capture, not delivery, scales up neuropeptide storage in neuroendocrine terminals

PubMed Central

Bulgari, Dinara; Zhou, Chaoming; Hewes, Randall S.; Deitcher, David L.; Levitan, Edwin S.

2014-01-01

Neurons vary in their capacity to produce, store, and release neuropeptides packaged in dense-core vesicles (DCVs). Specifically, neurons used for cotransmission have terminals that contain few DCVs and many small synaptic vesicles, whereas neuroendocrine neuron terminals contain many DCVs. Although the mechanistic basis for presynaptic variation is unknown, past research demonstrated transcriptional control of neuropeptide synthesis suggesting that supply from the soma limits presynaptic neuropeptide accumulation. Here neuropeptide release is shown to scale with presynaptic neuropeptide stores in identified Drosophila cotransmitting and neuroendocrine terminals. However, the dramatic difference in DCV number in these terminals occurs with similar anterograde axonal transport and DCV half-lives. Thus, differences in presynaptic neuropeptide stores are not explained by DCV delivery from the soma or turnover. Instead, greater neuropeptide accumulation in neuroendocrine terminals is promoted by dramatically more efficient presynaptic DCV capture. Greater capture comes with tradeoffs, however, as fewer uncaptured DCVs are available to populate distal boutons and replenish neuropeptide stores following release. Finally, expression of the Dimmed transcription factor in cotransmitting neurons increases presynaptic DCV capture. Therefore, DCV capture in the terminal is genetically controlled and determines neuron-specific variation in peptidergic function. PMID:24550480

Expression and bioactivity of allatostatin-like neuropeptides in helminths.

PubMed

Mousley, Angela; Moffett, Christy L; Duve, Hanne; Thorpe, Alan; Halton, David W; Geary, Timothy G; Thompson, David P; Maule, Aaron G; Marks, Nikki J

2005-12-01

Allatostatins are the largest family of known arthropod neuropeptides. To date more than 150 different arthropod type-A allatostatins have been identified and are characterized by the C-terminal signature, (Y/F)XFG(L/I)amide. Using specific allatostatin antisera, positive immunoreactivity has been identified within the central and peripheral nervous systems of the flatworm (platyhelminth) Procerodes littoralis and the roundworm (nematode) Panagrellus redivivus. Comparative analyses of the allatostatin-like immunoreactivity and that of other known helminth neuropeptides (FMRFamide-like peptides [FLPs]) indicate differences in the distribution of these peptide families. Specific differences in neuropeptide distribution have been noted within the pharyngeal innervation of flatworms and in the cephalic papillary neurons of nematodes. In arthropods, type-A allatostatins have functions that include potent myoactivity. In this study, seven members of the allatostatin superfamily induced concentration-dependent contractions of flatworm muscle fibres. Pharmacological studies indicate that these peptides do not interact with muscle-based FLP receptors. The type-A allatostatins, therefore, represent the second family of neuropeptides that induce muscle contraction in flatworms. Although the majority of arthropod type-A allatostatins examined did not affect the somatic body wall muscle or the ovijector of the pig nematode, Ascaris suum, two type-A allatostatins (GDGRLYAFGLamide and DRLYSFGLamide) exhibited significant inhibitory effects on the A. suum ovijector at 10 microM. These data suggest that allatostatin-like peptides and receptors occur in helminths. Further, although arthropod type-A allatostatins display inter-phyla activities, their receptors are less compelling as potential targets for broad-spectrum parasiticides (endectocides) than FLP receptors.

Identification of specific sites in the third intracellular loop and carboxyl terminus of the Bombyx mori PBAN receptor crucial for ligand-induced internalization

USDA-ARS?s Scientific Manuscript database

Sex pheromone production in most moths is mediated by the pheromone biosynthesis activating neuropeptide receptor (PBANR). Similar to other rhodopsin-like G protein-coupled receptors, the silkmoth Bombyx mori PBANR (BmPBANR) undergoes agonist-induced internalization. Despite interest in developing...

Measurement of Neuropeptides in Crustacean Hemolymph via MALDI Mass Spectrometry

PubMed Central

Chen, Ruibing; Ma, Mingming; Hui, Limei; Zhang, Jiang; Li, Lingjun

2009-01-01

Neuropeptides are often released into circulatory fluid (hemolymph) to act as circulating hormones and regulate many physiological processes. However, the detection of these low-level peptide hormones in circulation is often complicated by high salt interference and rapid degradation of proteins and peptides in crude hemolymph extracts. In this study, we systematically evaluated three different neuropeptide extraction protocols and developed a simple and effective hemolymph preparation method suitable for MALDI MS profiling of neuropeptides by combining acid-induced abundant protein precipitation/depletion, ultrafiltration, and C18 micro-column desalting. In hemolymph samples collected from crab Cancer borealis several secreted neuropeptides have been detected, including members from at least five neuropeptide families, such as RFamide, allatostatin, orcokinin, tachykinin-related peptide (TRP), and crustacean cardioactive peptide (CCAP). Furthermore, two TRPs were detected in the hemolymph collected from food-deprived animals, suggesting the potential role of these neuropeptides in feeding regulation. In addition, a novel peptide with a Lys-Phe-amide C-terminus was identified and de novo sequenced directly from the Cancer borealis hemolymph sample. To better characterize the hemolymph peptidome, we also identified several abundant peptide signals in C. borealis hemolymph that were assigned to protein degradation products. Collectively, our study describes a simple and effective sample preparation method for neuropeptide analysis directly from crude crustacean hemolymph. Numerous endogenous neuropeptides were detected including both known ones and new peptides whose functions remain to be characterized. PMID:19185513

Peptidase modulation of airway effects of neuropeptides.

PubMed

Lilly, C M; Drazen, J M; Shore, S A

1993-09-01

SP and NKA are potent endogenous bronchoconstrictors, whereas VIP is a potent endogenous bronchodilator. There is abundant evidence that these neuropeptides are released in the lung in a variety of conditions and that they have the capacity to modulate the bronchoactivity of the same stimuli that release them. On many occasions, their bronchoactive effects are masked by their degradation at or near the site of their release. However, when the microenvironment is modified to decrease their cleavage, they can express enhanced physiologic effects. Although it appears that the human asthmatic lung may be an environment in which the effects of neuropeptides can be amplified, the role of neuropeptides in the pathogenesis of airway obstruction remains speculative.

Primary structure of an adipokinetic neuropeptide from the rhinoceros beetle, Oryctes rhinoceros L (Coleoptera: Dynastidae).

PubMed

Ajay Kumar, A P; Gokuldas, M

2011-07-01

Neuropeptides play an important role in cellular communication in vertebrates. This is also true for insects in which many physiological, developmental and behavioral processes are affected by neuropeptides produced in neurosecretory cells of the retrocerebral complex. Small neuropeptides of the adipokinetic hormone/red pigment concentrating hormone family (AKH/RPCH) are one of the important groups of peptides that regulate physiological homeostasis. The present investigation was carried out to elucidate the primary structure of adipokinetic neuropeptides in the rhinoceros beetle, O. rhinoceros. In the present investigation, an adipokinetic neuropeptide from the coconut pest, Oryctes rhinoceros was isolated from corpora cardiaca by HPLC; the chromatographic fractions were tested for adipokinetic activity in the plant bug, Iphita limbata in vivo. Two UV absorbance peaks were found to be significantly active in elevating haemolymph lipid levels. MALDI-MS analysis of the extract indicated that the molecular mass, 1003.70 Da is similar to the already known AKH from another beetle, Melolontha melolontha. MALDI-MS/MS analysis confirmed that its primary structure is exactly similar to the structure reported for the Melme-AKH (pE-L-N-Y-S-P-D-W-NH2). The findings suggest that the distribution of AKH peptides has shown that there exists a taxonomic order or family specificity. This data can be used as additional information to aid in the construction of phylogenetic trees by means of computer programme and protein parsimony algorithms.

Modulation of Vasomotive Activity in Rabbit External Ophthalmic Artery by Neuropeptides

PubMed Central

Delgado, Esmeralda Sofia Costa; Marques-Neves, Carlos; Rocha, Maria Isabel Sousa; Sales-Luís, José Paulo Pacheco; Silva-Carvalho, Luís Filipe

2012-01-01

Purpose. To investigate the vasomotive activity upon the external ophthalmic artery of vasointestinal peptide (VIP) and neuropeptide Y (NPY) using a previously developed model. Methods. Isolated rabbit eyes (n = 12) were perfused in situ with tyrode through the external ophthalmic artery. Effects of intra-arterial injections of NPY 200 μg/ml (Group A; n = 6) and VIP 200 μg/ml (Group B; n = 6) on the recorded pressure were obtained. For statistical analysis, Student's paired t-test and Fast Fourier Transform were used. Results. Spontaneous oscillations were observed before any drug administration in the 12 rabbit models. NPY produced an increase in total vascular resistance and a higher frequency and amplitude of oscillations, while VIP evoked the opposite effects. Conclusions. This study provides evidence of vasomotion in basal conditions in rabbit external ophthalmic artery. Concerning drug effects, NPY increased arterial resistance and enhanced vasomotion while VIP produced opposite effects which demonstrates their profound influence in arterial vasomotion. PMID:22496962

The Drosophila neuropeptides PDF and sNPF have opposing electrophysiological and molecular effects on central neurons.

PubMed

Vecsey, Christopher G; Pírez, Nicolás; Griffith, Leslie C

2014-03-01

Neuropeptides have widespread effects on behavior, but how these molecules alter the activity of their target cells is poorly understood. We employed a new model system in Drosophila melanogaster to assess the electrophysiological and molecular effects of neuropeptides, recording in situ from larval motor neurons, which transgenically express a receptor of choice. We focused on two neuropeptides, pigment-dispersing factor (PDF) and small neuropeptide F (sNPF), which play important roles in sleep/rhythms and feeding/metabolism. PDF treatment depolarized motor neurons expressing the PDF receptor (PDFR), increasing excitability. sNPF treatment had the opposite effect, hyperpolarizing neurons expressing the sNPF receptor (sNPFR). Live optical imaging using a genetically encoded fluorescence resonance energy transfer (FRET)-based sensor for cyclic AMP (cAMP) showed that PDF induced a large increase in cAMP, whereas sNPF caused a small but significant decrease in cAMP. Coexpression of pertussis toxin or RNAi interference to disrupt the G-protein Gαo blocked the electrophysiological responses to sNPF, showing that sNPFR acts via Gαo signaling. Using a fluorescent sensor for intracellular calcium, we observed that sNPF-induced hyperpolarization blocked spontaneous waves of activity propagating along the ventral nerve cord, demonstrating that the electrical effects of sNPF can cause profound changes in natural network activity in the brain. This new model system provides a platform for mechanistic analysis of how neuropeptides can affect target cells at the electrical and molecular level, allowing for predictions of how they regulate brain circuits that control behaviors such as sleep and feeding.

The Drosophila neuropeptides PDF and sNPF have opposing electrophysiological and molecular effects on central neurons

PubMed Central

Vecsey, Christopher G.; Pírez, Nicolás

2013-01-01

Neuropeptides have widespread effects on behavior, but how these molecules alter the activity of their target cells is poorly understood. We employed a new model system in Drosophila melanogaster to assess the electrophysiological and molecular effects of neuropeptides, recording in situ from larval motor neurons, which transgenically express a receptor of choice. We focused on two neuropeptides, pigment-dispersing factor (PDF) and small neuropeptide F (sNPF), which play important roles in sleep/rhythms and feeding/metabolism. PDF treatment depolarized motor neurons expressing the PDF receptor (PDFR), increasing excitability. sNPF treatment had the opposite effect, hyperpolarizing neurons expressing the sNPF receptor (sNPFR). Live optical imaging using a genetically encoded fluorescence resonance energy transfer (FRET)-based sensor for cyclic AMP (cAMP) showed that PDF induced a large increase in cAMP, whereas sNPF caused a small but significant decrease in cAMP. Coexpression of pertussis toxin or RNAi interference to disrupt the G-protein Gαo blocked the electrophysiological responses to sNPF, showing that sNPFR acts via Gαo signaling. Using a fluorescent sensor for intracellular calcium, we observed that sNPF-induced hyperpolarization blocked spontaneous waves of activity propagating along the ventral nerve cord, demonstrating that the electrical effects of sNPF can cause profound changes in natural network activity in the brain. This new model system provides a platform for mechanistic analysis of how neuropeptides can affect target cells at the electrical and molecular level, allowing for predictions of how they regulate brain circuits that control behaviors such as sleep and feeding. PMID:24353297

Neuropeptide S Receptor Induces Neuropeptide Expression and Associates with Intermediate Phenotypes of Functional Gastrointestinal Disorders

PubMed Central

Camilleri, Michael; Carlson, Paula; Zinsmeister, Alan R.; McKinzie, Sanna; Busciglio, Irene; Burton, Duane; Zucchelli, Marco; D’Amato, Mauro

2009-01-01

Background & Aims NPSR1, the receptor for neuropeptide S (NPS), is expressed by gastrointestinal (GI) enteroendocrine (EE) cells, and is involved in inflammation, anxiety and nociception. NPSR1 polymorphisms are associated with asthma and inflammatory bowel disease. We aimed to determine whether NPS induces expression of GI neuropeptides; and to associate NPSR1 single nucleotide polymorphisms (SNPs) with symptom phenotype and GI functions in health and functional GI disorders (FGID). Methods The effect of NPS on mRNA expression of neuropeptides was assessed using real-time PCR in NPSR1-tranfected HEK293 cells. Seventeen NPSR1 SNPs were successfully genotyped in 699 subjects from a regional cohort of 466 FGID patients and 233 healthy controls. Associations were sought using sex-adjusted regression analysis and false discovery rate (FDR) correction. Results NPS-NPSR1 signaling induced increased expression of CCK, VIP, PYY, and somatostatin. There were no significant associations with phenotypes of FGID symptoms. There were several NPSR1 SNPs associated with individual motor or sensory functions; the associations of SNPs rs2609234, rs6972158 and rs1379928 with colonic transit rate remained significant after FDR correction. The rs1379928 polymorphism was also associated with pain, gas and urgency sensory ratings at 36 mm Hg distension, the level pre-specified for formal testing. Associations with rectal sensory ratings were not significant after FDR correction. Conclusions Expression of several neuropeptides is induced upon NPS-NPSR1 signaling; NPSR1 variants are associated with colonic transit in FGID. The role of the NPS system in FGID deserves further study. PMID:19732772

Neuropeptides activate human mast cell degranulation and chemokine production

PubMed Central

Kulka, Marianna; Sheen, Cecilia H; Tancowny, Brian P; Grammer, Leslie C; Schleimer, Robert P

2008-01-01

During neuronal-induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcεRI-independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti-IgE and compound 48/80. Primary cultured mast cells, generated from CD34+ progenitors in the presence of stem cell factor and interleukin-6 (IL-6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti-IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein-1, inducible protein-10, monokine induced by interferon-γ (MIG), RANTES (regulated on activation, normal, T-cell expressed, and secreted) and IL-8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL-3 and granulocyte–macrophage colony-stimulating factor, but not IL-4, interferon-γ or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti-IgE up-regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G-protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases. PMID

Mass Spectrometric Assignment of Leu/Ile in Neuropeptides From Single Neurohemal Organ Preparations of Insets

DTIC Science & Technology

2005-01-01

spectrometry has been applied for the first time on an insect/arthropod target, focusing on PVK/CAP2b neuropeptides in the housefly Musca domestica and...critical physiological processes in insects. The unnatural Ile analog is 4.5 times more active than the native Leu sequence in a housefly Malpighian...periviscerokinin/cardioacceleratory peptide 2b) neuropeptides from single neurohemal organ preparations of adults of the housefly Musca domestica and flesh fly

Neuropeptides: Developmental Signals in Placode Progenitor Formation

PubMed Central

Lleras-Forero, Laura; Tambalo, Monica; Christophorou, Nicolas; Chambers, David; Houart, Corinne; Streit, Andrea

2013-01-01

Summary Few families of signaling factors have been implicated in the control of development. Here, we identify the neuropeptides nociceptin and somatostatin, a neurotransmitter and neuroendocrine hormone, as a class of developmental signals in both chick and zebrafish. We show that signals from the anterior mesendoderm are required for the formation of anterior placode progenitors, with one of the signals being somatostatin. Somatostatin controls ectodermal expression of nociceptin, and both peptides regulate Pax6 in lens and olfactory progenitors. Consequently, loss of somatostatin and nociceptin signaling leads to severe reduction of lens formation. Our findings not only uncover these neuropeptides as developmental signals but also identify a long-sought-after mechanism that initiates Pax6 in placode progenitors and may explain the ancient evolutionary origin of neuropeptides, predating a complex nervous system. PMID:23906067

Neuropeptide Mapping of Dimmed Cells of Adult Drosophila Brain

NASA Astrophysics Data System (ADS)

Diesner, Max; Predel, Reinhard; Neupert, Susanne

2018-05-01

Neuropeptides are structurally highly diverse messenger molecules that act as regulators of many physiological processes such as development, metabolism, reproduction or behavior in general. Differentiation of neuropeptidergic cells often corresponds with the presence of the transcription factor DIMMED. In the central nervous system of the fruit fly Drosophila melanogaster, DIMMED commonly occurs in neuroendocrine neurons that release peptides as neurohormones but also in interneurons with complex branching patterns. Fly strains with green fluorescence protein (GFP)-expressing dimmed cells make it possible to systematically analyze the processed neuropeptides in these cells. In this study, we mapped individual GFP-expressing neurons of adult D. melanogaster from the dimmed ( c929)>GFP line. Using single cell mass spectrometry, we analyzed 10 types of dimmed neurons from the brain/gnathal ganglion. These cells included neuroendocrine cells with projection into the retrocerebral complex but also a number of large interneurons. Resulting mass spectra not only provided comprehensive data regarding mature products from 13 neuropeptide precursors but also evidence for the cellular co-localization of neuropeptides from different neuropeptide genes. The results can be implemented in a neuroanatomical map of the D. melanogaster brain. [Figure not available: see fulltext.

Neuropeptide Mapping of Dimmed Cells of Adult Drosophila Brain

NASA Astrophysics Data System (ADS)

Diesner, Max; Predel, Reinhard; Neupert, Susanne

2018-01-01

Neuropeptides are structurally highly diverse messenger molecules that act as regulators of many physiological processes such as development, metabolism, reproduction or behavior in general. Differentiation of neuropeptidergic cells often corresponds with the presence of the transcription factor DIMMED. In the central nervous system of the fruit fly Drosophila melanogaster, DIMMED commonly occurs in neuroendocrine neurons that release peptides as neurohormones but also in interneurons with complex branching patterns. Fly strains with green fluorescence protein (GFP)-expressing dimmed cells make it possible to systematically analyze the processed neuropeptides in these cells. In this study, we mapped individual GFP-expressing neurons of adult D. melanogaster from the dimmed (c929)>GFP line. Using single cell mass spectrometry, we analyzed 10 types of dimmed neurons from the brain/gnathal ganglion. These cells included neuroendocrine cells with projection into the retrocerebral complex but also a number of large interneurons. Resulting mass spectra not only provided comprehensive data regarding mature products from 13 neuropeptide precursors but also evidence for the cellular co-localization of neuropeptides from different neuropeptide genes. The results can be implemented in a neuroanatomical map of the D. melanogaster brain. [Figure not available: see fulltext.

Neuropeptide Mapping of Dimmed Cells of Adult Drosophila Brain.

PubMed

Diesner, Max; Predel, Reinhard; Neupert, Susanne

2018-05-01

Neuropeptides are structurally highly diverse messenger molecules that act as regulators of many physiological processes such as development, metabolism, reproduction or behavior in general. Differentiation of neuropeptidergic cells often corresponds with the presence of the transcription factor DIMMED. In the central nervous system of the fruit fly Drosophila melanogaster, DIMMED commonly occurs in neuroendocrine neurons that release peptides as neurohormones but also in interneurons with complex branching patterns. Fly strains with green fluorescence protein (GFP)-expressing dimmed cells make it possible to systematically analyze the processed neuropeptides in these cells. In this study, we mapped individual GFP-expressing neurons of adult D. melanogaster from the dimmed (c929)>GFP line. Using single cell mass spectrometry, we analyzed 10 types of dimmed neurons from the brain/gnathal ganglion. These cells included neuroendocrine cells with projection into the retrocerebral complex but also a number of large interneurons. Resulting mass spectra not only provided comprehensive data regarding mature products from 13 neuropeptide precursors but also evidence for the cellular co-localization of neuropeptides from different neuropeptide genes. The results can be implemented in a neuroanatomical map of the D. melanogaster brain. Graphical Abstract ᅟ.

Loss of Huntingtin stimulates capture of retrograde dense-core vesicles to increase synaptic neuropeptide stores.

PubMed

Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

2017-08-01

The Huntington's disease protein Huntingtin (Htt) regulates axonal transport of dense-core vesicles (DCVs) containing neurotrophins and neuropeptides. DCVs travel down axons to reach nerve terminals where they are either captured in synaptic boutons to support later release or reverse direction to reenter the axon as part of vesicle circulation. Currently, the impact of Htt on DCV dynamics in the terminal is unknown. Here we report that knockout of Drosophila Htt selectively reduces retrograde DCV flux at proximal boutons of motoneuron terminals. However, initiation of retrograde transport at the most distal bouton and transport velocity are unaffected suggesting that synaptic capture rate of these retrograde DCVs could be altered. In fact, tracking DCVs shows that retrograde synaptic capture efficiency is significantly elevated by Htt knockout or knockdown. Furthermore, synaptic boutons contain more neuropeptide in Htt knockout larvae even though bouton size, single DCV fluorescence intensity, neuropeptide release in response to electrical stimulation and subsequent activity-dependent capture are unaffected. Thus, loss of Htt increases synaptic capture as DCVs travel by retrograde transport through boutons resulting in reduced transport toward the axon and increased neuropeptide in the terminal. These results therefore identify native Htt as a regulator of synaptic capture and neuropeptide storage. Copyright © 2017 Elsevier GmbH. All rights reserved.

[Advances in mass spectrometry-based approaches for neuropeptide analysis].

PubMed

Ji, Qianyue; Ma, Min; Peng, Xin; Jia, Chenxi; Ji, Qianyue

2017-07-25

Neuropeptides are an important class of endogenous bioactive substances involved in the function of the nervous system, and connect the brain and other neural and peripheral organs. Mass spectrometry-based neuropeptidomics are designed to study neuropeptides in a large-scale manner and obtain important molecular information to further understand the mechanism of nervous system regulation and the pathogenesis of neurological diseases. This review summarizes the basic strategies for the study of neuropeptides using mass spectrometry, including sample preparation and processing, qualitative and quantitative methods, and mass spectrometry imagining.

An evaluation of neuropeptide Y status in subacute sclerosing panencephalitis patients.

PubMed

Abuhandan, M; Calik, M; Almaz, V; Taskın, A; Cakmak, A; Selek, S

2013-01-01

This study aimed to evaluate the neuropeptide Y values of patients with subacute sclerosing panencephalitis. The study comprised 38 patients diagnosed with subacute sclerosing panencephalitis at our clinic, who were being routinely followed-up, together with a control group of 36. Using the Risk and Haddad classification for clinical staging, 16 patients were determined as Stage II and 22 patients as Stage III. Neuropeptide Y values were measured by Enzyme Immunoassay methods. The neuropeptide Y values of the all patients with subacute sclerosing panencephalitis were found to be significantly high compared to the control group (p<0.01). The neuropeptide Y values of the Stage III group were found to be significantly high compared to the Stage II and control groups (p<0.05). The neuropeptide Y values of the Stage II group were not determined to be significant compared to the control group (p≤0.05). Neuropeptide Y can be considered a useful parameter to confirm diagnosis at advanced stages and to establish differences between stages in patients with subacute sclerosing panencephalitis.

From a marine neuropeptide to antimicrobial pseudopeptides containing aza-β(3)-amino acids: structure and activity

PubMed Central

Laurencin, Mathieu; Legrand, Baptiste; Duval, Emilie; Henry, Joël; Baudy-Floc'H, Michèle; Zatylny-Gaudin, Céline; Bondon, Arnaud

2012-01-01

Incorporation of aza-β3-amino acids into endogenous neuropeptide from mollusks (ALSGDAFLRF-NH2) with weak antimicrobial activities allows us to design new AMPs sequences. We find that, depending on the nature of the substitution, these could result either in inactive pseudopeptides or in a drastic enhancement of the antimicrobial activity without high cytotoxicity resulted. Structural studies perform by NMR and circular dichroism on the pseudopeptides show the impact of aza-β3-amino acids on the peptide structures. We obtain the first three-dimensional structures of pseudopeptides containing aza-β3-amino acids in aqueous micellar SDS and demonstrate that hydrazino turn can be formed in aqueous solution. Overall, these results demonstrate the ability to modulate AMPs activities through structural modifications induced by the nature and the position of these amino acid analogs in the peptide sequences. PMID:22320306

Selective expression of neuropeptides in the rat mammary gland: somatostatin gene is expressed during lactation.

PubMed

Chen, A; Laskar-Levy, O; Koch, Y

1999-12-01

, examined by RT-PCR, are not expressed by the mammary gland suggest that these neuropeptides are actively concentrated by the mammary glands from the general circulation. The GnRH gene has been previously demonstrated to be expressed in the mammary gland, and in this study somatostatin was the only neuropeptide that was found to be produced by the mammary gland. The observation that only a small portion of the neuropeptides that are present in milk are being produced by the lactating mammary gland suggest that these neuropeptides have important functions in the biology of the suckling neonate and probably also in the development and function of the breast.

Nematode neuropeptides as transgenic nematicides

PubMed Central

Patten, Cheryl; Fleming, Colin C.; Maule, Aaron G.

2017-01-01

Plant parasitic nematodes (PPNs) seriously threaten global food security. Conventionally an integrated approach to PPN management has relied heavily on carbamate, organophosphate and fumigant nematicides which are now being withdrawn over environmental health and safety concerns. This progressive withdrawal has left a significant shortcoming in our ability to manage these economically important parasites, and highlights the need for novel and robust control methods. Nematodes can assimilate exogenous peptides through retrograde transport along the chemosensory amphid neurons. Peptides can accumulate within cells of the central nerve ring and can elicit physiological effects when released to interact with receptors on adjoining cells. We have profiled bioactive neuropeptides from the neuropeptide-like protein (NLP) family of PPNs as novel nematicides, and have identified numerous discrete NLPs that negatively impact chemosensation, host invasion and stylet thrusting of the root knot nematode Meloidogyne incognita and the potato cyst nematode Globodera pallida. Transgenic secretion of these peptides from the rhizobacterium, Bacillus subtilis, and the terrestrial microalgae Chlamydomonas reinhardtii reduce tomato infection levels by up to 90% when compared with controls. These data pave the way for the exploitation of nematode neuropeptides as a novel class of plant protective nematicide, using novel non-food transgenic delivery systems which could be deployed on farmer-preferred cultivars. PMID:28241060

Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation.

PubMed

Fernø, Johan; Varela, Luis; Skrede, Silje; Vázquez, María Jesús; Nogueiras, Rubén; Diéguez, Carlos; Vidal-Puig, Antonio; Steen, Vidar M; López, Miguel

2011-01-01

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.

Olanzapine-Induced Hyperphagia and Weight Gain Associate with Orexigenic Hypothalamic Neuropeptide Signaling without Concomitant AMPK Phosphorylation

PubMed Central

Fernø, Johan; Vázquez, María Jesús; Nogueiras, Rubén; Diéguez, Carlos; Vidal-Puig, Antonio; Steen, Vidar M.; López, Miguel

2011-01-01

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance. PMID:21695181

Incorporation of monodisperse oligoethyleneglycol amino acids into anticonvulsant analogues of galanin and neuropeptide y provides peripherally acting analgesics.

PubMed

Zhang, Liuyin; Klein, Brian D; Metcalf, Cameron S; Smith, Misty D; McDougle, Daniel R; Lee, Hee-Kyoung; White, H Steve; Bulaj, Grzegorz

2013-02-04

Delivery of neuropeptides into the central and/or peripheral nervous systems supports development of novel neurotherapeutics for the treatment of pain, epilepsy and other neurological diseases. Our previous work showed that the combination of lipidization and cationization applied to anticonvulsant neuropeptides galanin (GAL) and neuropeptide Y (NPY) improved their penetration across the blood-brain barrier yielding potent antiepileptic lead compounds, such as Gal-B2 (NAX 5055) or NPY-B2. To dissect peripheral and central actions of anticonvulsant neuropeptides, we rationally designed, synthesized and characterized GAL and NPY analogues containing monodisperse (discrete) oligoethyleneglycol-lysine (dPEG-Lys). The dPEGylated analogues Gal-B2-dPEG(24), Gal-R2-dPEG(24) and NPY-dPEG(24) displayed analgesic activities following systemic administration, while avoiding penetration into the brain. Gal-B2-dPEG(24) was synthesized by a stepwise deprotection of orthogonal 4-methoxytrityl and allyloxycarbonyl groups, and subsequent on-resin conjugations of dPEG(24) and palmitic acids, respectively. All the dPEGylated analogues exhibited substantially decreased hydrophobicity (expressed as logD values), increased in vitro serum stabilities and pronounced analgesia in the formalin and carrageenan inflammatory pain assays following systemic administration, while lacking apparent antiseizure activities. These results suggest that discrete PEGylation of neuropeptides offers an attractive strategy for developing neurotherapeutics with restricted penetration into the central nervous system.

Alterations in neuropeptides in aging and disease. Pathophysiology and potential for clinical intervention.

PubMed

Leake, A; Ferrier, I N

1993-01-01

Marked specific and selective changes in the levels of some neuropeptides in age-related diseases, such as senile dementia of the Alzheimer (SDAT) or Lewy body (SDLT) types, Parkinson's disease, Huntington's disease and major depressive disorder, versus normal aging have been noted. However, the levels of most neuropeptides are normal. The only 2 peptides consistently altered in SDAT are somatostatin and corticotrophin-releasing hormone both of which are reduced. In Huntington's disease, the level of substance P in the basal ganglia is reduced suggesting a preferential vulnerability of spiny neurones in this disease. In Parkinson's disease, substance P is attenuated in the basal ganglia while somatostatin is reduced in the neocortex. These and other results suggest that substance P deficits are related to movement disorders while somatostatin deficits are related to cognitive impairment. SDLT is a type of dementia with features common to both SDAT and Parkinson's disease, although the changes in neuropeptides suggest that neurochemically the disease is more closely related to SDAT. In major depressive disorder, the level of corticotrophin-releasing hormone is reduced while there is a reciprocal increase in corticotrophin-releasing hormone receptors suggesting that the neurones remain functional. Potential clinical intervention has been limited by problems such as poor penetration of agents into the brain and the short half-lives of neuropeptide agonists and antagonists. However, some currently available agents may act, at least in part, through modulation of neuropeptide pathways, e.g. carbamazepine and alprazolam both modulate the corticotrophin-releasing hormone system in animals, and both have clinically proven antidepressant activity.

Neuropeptide modulation of addiction: focus on galanin.

PubMed

Genders, Shannyn G; Scheller, Karlene J; Djouma, Elvan

2018-06-24

Addiction is a chronic, relapsing disorder characterised by the use of a substance or act to the point of compulsion. There are a number of medical treatments available for the intervention of these disorders, however, the effectiveness of current therapeutics is far from adequate. Neuropeptides are known to modulate addictive behaviours and may provide new therapeutic targets for the treatment of substance abuse. Accumulating evidence has suggested galanin as a potential important neuromodulator of addiction. Both human genetic studies and animal models have highlighted a role for this neuropeptide in affective disorders, as well as alcohol, nicotine, and opiate dependence. This review highlights the role of galanin and other primary neuropeptides implicated in modulating addiction to different drugs of abuse. Orexin, relaxin-3, corticotrophin-releasing factor, dynorphin and enkephalin, are also discussed given their involvement in mediating reward-seeking behaviour. Copyright © 2018. Published by Elsevier Ltd.

Reproductive neuropeptides that stimulate spawning in the Sydney Rock Oyster (Saccostrea glomerata).

PubMed

In, Vu Van; Ntalamagka, Nikoleta; O'Connor, Wayne; Wang, Tianfang; Powell, Daniel; Cummins, Scott F; Elizur, Abigail

2016-08-01

The Sydney Rock Oyster, Saccostrea glomerata, is a socioeconomically important species in Australia, yet little is known about the molecular mechanism that regulates its reproduction. To address this gap, we have performed a combination of high throughput transcriptomic and peptidomic analysis, to identify genes and neuropeptides that are expressed in the key regulatory tissues of S. glomerata; the visceral ganglia and gonads. Neuropeptides are known to encompass a diverse class of peptide messengers that play functional roles in many aspects of an animal's life, including reproduction. Approximately 28 neuropeptide genes were identified, primarily within the visceral ganglia transcriptome, that encode precursor proteins containing numerous neuropeptides; some were confirmed through mass spectral peptidomics analysis of the visceral ganglia. Of those, 28 bioactive neuropeptides were synthesized, and then tested for their capacity to induce gonad development and spawning in S. glomerata. Egg laying hormone, gonadotropin-releasing hormone, APGWamide, buccalin, CCAP and LFRFamide were neuropeptides found to trigger spawning in ripe animals. Additional testing of APGWa and buccalin demonstrated their capacity to advance conditioning and gonadal maturation. In summary, our analysis of S. glomerata has identified neuropeptides that can influence the reproductive cycle of this species, specifically by accelerating gonadal maturation and triggering spawning. Other molluscan neuropeptides identified in this study will enable further research into understanding the neuroendocrinology of oysters, which may benefit their cultivation. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits

PubMed Central

Baribeau, Danielle A.; Anagnostou, Evdokia

2015-01-01

Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders. PMID:26441508

Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits.

PubMed

Baribeau, Danielle A; Anagnostou, Evdokia

2015-01-01

Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.

Multiple Neuropeptide-Coding Genes Involved in Planarian Pharynx Extension.

PubMed

Shimoyama, Seira; Inoue, Takeshi; Kashima, Makoto; Agata, Kiyokazu

2016-06-01

Planarian feeding behavior involves three steps: moving toward food, extending the pharynx from their planarian's ventral side after arriving at the food, and ingesting the food through the pharynx. Although pharynx extension is a remarkable behavior, it remains unknown what neuronal cell types are involved in its regulation. To identify neurons involved in regulating pharynx extension, we quantitatively analyzed pharynx extension and sought to identify these neurons by RNA interference (RNAi) and in situ hybridization. This assay, when performed using planarians with amputation of various body parts, clearly showed that the head portion is indispensable for inducing pharynx extension. We thus tested the effects of knockdown of brain neurons such as serotonergic, GABAergic, and dopaminergic neurons by RNAi, but did not observe any effects on pharynx extension behavior. However, animals with RNAi of the Prohormone Convertase 2 (PC2, a neuropeptide processing enzyme) gene did not perform the pharynx extension behavior, suggesting the possible involvement of neuropeptide(s in the regulation of pharynx extension. We screened 24 neuropeptide-coding genes, analyzed their functions by RNAi using the pharynx extension assay system, and identified at least five neuropeptide genes involved in pharynx extension. These was expressed in different cells or neurons, and some of them were expressed in the brain, suggesting complex regulation of planarian feeding behavior by the nervous system.

More than two decades of research on insect neuropeptide GPCRs: an overview

PubMed Central

Caers, Jelle; Verlinden, Heleen; Zels, Sven; Vandersmissen, Hans Peter; Vuerinckx, Kristel; Schoofs, Liliane

2012-01-01

This review focuses on the state of the art on neuropeptide receptors in insects. Most of these receptors are G protein-coupled receptors (GPCRs) and are involved in the regulation of virtually all physiological processes during an insect's life. More than 20 years ago a milestone in invertebrate endocrinology was achieved with the characterization of the first insect neuropeptide receptor, i.e., the Drosophila tachykinin-like receptor. However, it took until the release of the Drosophila genome in 2000 that research on neuropeptide receptors boosted. In the last decade a plethora of genomic information of other insect species also became available, leading to a better insight in the functions and evolution of the neuropeptide signaling systems and their intracellular pathways. It became clear that some of these systems are conserved among all insect species, indicating that they fulfill crucial roles in their physiological processes. Meanwhile, other signaling systems seem to be lost in several insect orders or species, suggesting that their actions were superfluous in those insects, or that other neuropeptides have taken over their functions. It is striking that the deorphanization of neuropeptide GPCRs gets much attention, but the subsequent unraveling of the intracellular pathways they elicit, or their physiological functions are often hardly examined. Especially in insects besides Drosophila this information is scarce if not absent. And although great progress made in characterizing neuropeptide signaling systems, even in Drosophila several predicted neuropeptide receptors remain orphan, awaiting for their endogenous ligand to be determined. The present review gives a précis of the insect neuropeptide receptor research of the last two decades. But it has to be emphasized that the work done so far is only the tip of the iceberg and our comprehensive understanding of these important signaling systems will still increase substantially in the coming years. PMID

Pedal peptide/orcokinin-type neuropeptide signaling in a deuterostome: The anatomy and pharmacology of starfish myorelaxant peptide in Asterias rubens.

PubMed

Lin, Ming; Egertová, Michaela; Zampronio, Cleidiane G; Jones, Alexandra M; Elphick, Maurice R

2017-12-15

Pedal peptide (PP) and orcokinin (OK) are related neuropeptides that were discovered in protostomian invertebrates (mollusks, arthropods). However, analysis of genome/transcriptome sequence data has revealed that PP/OK-type neuropeptides also occur in a deuterostomian phylum-the echinoderms. Furthermore, a PP/OK-type neuropeptide (starfish myorelaxant peptide, SMP) was recently identified as a muscle relaxant in the starfish Patiria pectinifera. Here mass spectrometry was used to identify five neuropeptides (ArPPLN1a-e) derived from the SMP precursor (PP-like neuropeptide precursor 1; ArPPLNP1) in the starfish Asterias rubens. Analysis of the expression of ArPPLNP1 and neuropeptides derived from this precursor in A. rubens using mRNA in situ hybridization and immunohistochemistry revealed a widespread pattern of expression, with labeled cells and/or processes present in the radial nerve cords, circumoral nerve ring, digestive system (e.g., cardiac stomach) and body wall-associated muscles (e.g., apical muscle) and appendages (e.g., tube feet and papulae). Furthermore, our data provide the first evidence that neuropeptides are present in the lateral motor nerves and in nerve processes innervating interossicular muscles. In vitro pharmacological tests with SMP (ArPPLN1b) revealed that it causes dose-dependent relaxation of apical muscle, tube foot and cardiac stomach preparations from A. rubens. Collectively, these anatomical and pharmacological data indicate that neuropeptides derived from ArPPLNP1 act as inhibitory neuromuscular transmitters in starfish, which contrasts with the myoexcitatory actions of PP/OK-type neuropeptides in protostomian invertebrates. Thus, the divergence of deuterostomes and protostomes may have been accompanied by an inhibitory-excitatory transition in the roles of PP/OK-type neuropeptides as regulators of muscle activity. © 2017 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Pedal peptide/orcokinin‐type neuropeptide signaling in a deuterostome: The anatomy and pharmacology of starfish myorelaxant peptide in Asterias rubens

PubMed Central

Lin, Ming; Egertová, Michaela; Zampronio, Cleidiane G.; Jones, Alexandra M.

2017-01-01

Abstract Pedal peptide (PP) and orcokinin (OK) are related neuropeptides that were discovered in protostomian invertebrates (mollusks, arthropods). However, analysis of genome/transcriptome sequence data has revealed that PP/OK‐type neuropeptides also occur in a deuterostomian phylum—the echinoderms. Furthermore, a PP/OK‐type neuropeptide (starfish myorelaxant peptide, SMP) was recently identified as a muscle relaxant in the starfish Patiria pectinifera. Here mass spectrometry was used to identify five neuropeptides (ArPPLN1a‐e) derived from the SMP precursor (PP‐like neuropeptide precursor 1; ArPPLNP1) in the starfish Asterias rubens. Analysis of the expression of ArPPLNP1 and neuropeptides derived from this precursor in A. rubens using mRNA in situ hybridization and immunohistochemistry revealed a widespread pattern of expression, with labeled cells and/or processes present in the radial nerve cords, circumoral nerve ring, digestive system (e.g., cardiac stomach) and body wall‐associated muscles (e.g., apical muscle) and appendages (e.g., tube feet and papulae). Furthermore, our data provide the first evidence that neuropeptides are present in the lateral motor nerves and in nerve processes innervating interossicular muscles. In vitro pharmacological tests with SMP (ArPPLN1b) revealed that it causes dose‐dependent relaxation of apical muscle, tube foot and cardiac stomach preparations from A. rubens. Collectively, these anatomical and pharmacological data indicate that neuropeptides derived from ArPPLNP1 act as inhibitory neuromuscular transmitters in starfish, which contrasts with the myoexcitatory actions of PP/OK‐type neuropeptides in protostomian invertebrates. Thus, the divergence of deuterostomes and protostomes may have been accompanied by an inhibitory–excitatory transition in the roles of PP/OK‐type neuropeptides as regulators of muscle activity. PMID:28880392

Crypteins derived from the mouse neuropeptide FF (NPFF)A precursor display NPFF-like effects in nociceptive tests in mice.

PubMed

Kotlinska, Jolanta H; Gibula-Bruzda, Ewa; Suder, Piotr; Wasielak, Magdalena; Bray, Lauriane; Raoof, Hana; Bodzon-Kulakowska, Anna; Silberring, Jerzy

2012-07-01

NPFF precursor, pro-NPFF(A) contains three known bioactive sequences: NPFF (FLFQPQRF-NH(2)), neuropeptide AF (NPAF; AGEGLSSPFWSLAAPQRF-NH(2)) and neuropeptide SF (NPSF; SLAAPQRF-NH(2)). The key-feature of these fragments is their common PQRF-amidated sequence at their C termini. Here, we evaluated the biological activity of two other sequences derived from the mouse NPFF(A) precursor, that does not have PQRF-amidated C-terminus. One peptide was residing between positions 85 and 99 in the mice pro-NPFF(A). This peptide was referred to as neuropeptide SA (NPSA; SAWGSWSKEQLNPQA), assigned due to its flanking amino acids. Another sequence used in the experiments was N-terminal fragment of NPSA, here referred to as neuropeptide SS (NPSS; SAWGSWS). These two peptides, classified as crypteins, were synthesized and tested in the hot-plate and tail immersion tests in mice for their pharmacological activity in morphine-induced antinociception. The effects of both crypteins were compared to NPFF. Our experiments indicated that both crypteins inhibited morphine antinociception and their effects were reversed by RF9, an antagonist of NPFF receptors. These data show that NPSA and NPSS possess NPFF-like anti-opioid activity in these behavioral tests. Copyright © 2012 Elsevier Inc. All rights reserved.

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?

PubMed

Staines, Donald R

2004-01-01

Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All

Can neuropeptides treat obesity? A review of neuropeptides and their potential role in the treatment of obesity

PubMed Central

Boughton, C K; Murphy, K G

2013-01-01

Obesity is a major worldwide public health issue. The physiological systems that regulate body weight are thus of great interest as targets for anti-obesity agents. Peptidergic systems are critical to the regulation of energy homeostasis by key regions in the hypothalamus and brainstem. A number of neuropeptide systems have therefore been investigated as potential treatments for obesity. Blocking orexigenic peptide signals such as neuropeptide Y, melanin-concentrating hormone, orexins, relaxin-3 and galanin-like peptide or stimulating anorectic signalling pathways used by peptides such as the melanocortins, ciliary neurotrophic factor and brain-derived neurotrophic factor, are approaches that have shown some promise, but which have also highlighted possible concerns. Manipulation of central peptidergic systems poses a number of therapeutic problems, including brain access and side effects. Given that the homeostatic defence of body weight may limit the effectiveness of any single-target therapy developed, a combination therapy approach may offer the best hope for the effective prevention and treatment of obesity. LINKED ARTICLES This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7 PMID:23121386

Synthesis and binding affinity of neuropeptide Y at opiate receptors.

PubMed

Kiddle, James J; McCreery, Heather J; Soles, Sonia

2003-03-24

Neuropeptide Y and several metabolic fragments were synthesized and evaluated for binding affinity at non-selective opiate receptors. Neuropeptide Y and several C-terminal fragments were shown to bind to non-selective opiate receptors with an affinity similar to that of Leu-enkephalin.

Parasitic peptides! The structure and function of neuropeptides in parasitic worms.

PubMed

Day, T A; Maule, A G

1999-01-01

Parasitic worms come from two very different phyla-Platyhelminthes (flatworms) and Nematoda (roundworms). Although both phyla possess nervous systems with highly developed peptidergic components, there are key differences in the structure and action of native neuropeptides in the two groups. For example, the most abundant neuropeptide known in platyhelminths is the pancreatic polypeptide-like neuropeptide F, whereas the most prevalent neuropeptides in nematodes are FMRFamide-related peptides (FaRPs), which are also present in platyhelminths. With respect to neuropeptide diversity, platyhelminth species possess only one or two distinct FaRPs, whereas nematodes have upwards of 50 unique FaRPs. FaRP bioactivity in platyhelminths appears to be restricted to myoexcitation, whereas both excitatory and inhibitory effects have been reported in nematodes. Recently interest has focused on the peptidergic signaling systems of both phyla because elucidation of these systems will do much to clarify the basic biology of the worms and because the peptidergic systems hold the promise of yielding novel targets for a new generation of antiparasitic drugs.

Sensory Neurons Arouse C. elegans Locomotion via Both Glutamate and Neuropeptide Release

PubMed Central

Chatzigeorgiou, Marios; Hu, Zhitao; Schafer, William R.; Kaplan, Joshua M.

2015-01-01

C. elegans undergoes periods of behavioral quiescence during larval molts (termed lethargus) and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Lethargus and adult locomotion quiescence is dramatically reduced in mutants lacking the neuropeptide receptor NPR-1. Here, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH), touch sensitive (ALM and PLM), and stretch sensing (DVA) neurons. These sensory neurons accelerate locomotion via both neuropeptide and glutamate release. The relative contribution of these sensory neurons to arousal differs between larval molts and adults. Our results suggest that a broad network of sensory neurons dictates transitions between aroused and quiescent behavioral states. PMID:26154367

The neuropeptide NLP-22 regulates a sleep-like state in Caenorhabditis elegans

PubMed Central

Nelson, MD; Trojanowski, NF; George-Raizen, JB; Smith, CJ; Yu, C-C; Fang-Yen, C; Raizen, DM

2013-01-01

Neuropeptides play central roles in the regulation of homeostatic behaviors such as sleep and feeding. Caenorhabditis elegans displays sleep-like quiescence of locomotion and feeding during a larval transition stage called lethargus and feeds during active larval and adult stages. Here we show that the neuropeptide NLP-22 is a regulator of Caenorhabditis elegans sleep-like quiescence observed during lethargus. nlp-22 shows cyclical mRNA expression in synchrony with lethargus; it is regulated by LIN-42, an orthologue of the core circadian protein PERIOD; and it is expressed solely in the two RIA interneurons. nlp-22 and the RIA interneurons are required for normal lethargus quiescence, and forced expression of nlp-22 during active stages causes anachronistic locomotion and feeding quiescence. Optogenetic stimulation of RIA interneurons has a movement-promoting effect, demonstrating functional complexity in a single neuron type. Our work defines a quiescence-regulating role for NLP-22 and expands our knowledge of the neural circuitry controlling Caenorhabditis elegans behavioral quiescence. PMID:24301180

The neuropeptide NLP-22 regulates a sleep-like state in Caenorhabditis elegans.

PubMed

Nelson, M D; Trojanowski, N F; George-Raizen, J B; Smith, C J; Yu, C-C; Fang-Yen, C; Raizen, D M

2013-01-01

Neuropeptides have central roles in the regulation of homoeostatic behaviours such as sleep and feeding. Caenorhabditis elegans displays sleep-like quiescence of locomotion and feeding during a larval transition stage called lethargus and feeds during active larval and adult stages. Here we show that the neuropeptide NLP-22 is a regulator of Caenorhabditis elegans sleep-like quiescence observed during lethargus. nlp-22 shows cyclical mRNA expression in synchrony with lethargus; it is regulated by LIN-42, an orthologue of the core circadian protein PERIOD; and it is expressed solely in the two RIA interneurons. nlp-22 and the RIA interneurons are required for normal lethargus quiescence, and forced expression of nlp-22 during active stages causes anachronistic locomotion and feeding quiescence. Optogenetic stimulation of the RIA interneurons has a movement-promoting effect, demonstrating functional complexity in a single-neuron type. Our work defines a quiescence-regulating role for NLP-22 and expands our knowledge of the neural circuitry controlling Caenorhabditis elegans behavioural quiescence.

Doxycycline exerted neuroprotective activity by enhancing the activation of neuropeptide GPCR PAC1.

PubMed

Yu, Rongjie; Zheng, Lijun; Cui, Yue; Zhang, Huahua; Ye, Heng

2016-04-01

Doxycycline has significant neuroprotective effect with anti-inflammatory and anti-apoptotic activity. We found for the first time that doxycycline specially promoted the proliferation of Chinese hamster ovary (CHO) cells with high expression of neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) preferring G protein-coupled receptor (GPCR), PACAP receptor 1(PAC1) and induced the internalization of PAC1 tagged with yellow fluorescent protein (YFP) indicating doxycycline interacted with PAC1. The homology modeling of PAC1 and molecular docking of doxycycline with PAC1 showed the theoretical binding of doxycycline to PAC1 at the site where PACAP(30-37) recognized. The competition binding assay and PAC1 site-specific mutation of Asp116, which formed two hydrogen bonds with Dox, confirmed the binding of doxycycline to PAC1 imitating PACAP(30-37). Doxycycline (100 ng/mL) significantly promoted the proliferative activities of vasoactive intestinal polypeptide (VIP) and oligopeptide HSDGIF responsible for the activation of PAC1 in PAC1-CHO cells, indicating that doxycycline facilitated the binding and the activation of PAC1 imitating PACAP(28-38). In Neuro2a cells with endogenous expression of PAC1 and its ligands, doxycycline not only promoted the proliferation of Neuro2a cells but also protected the cells from scopolamine induced apoptosis, which was inhibited by cAMP-PKA signal pathway inhibitor H-89, PAC1 shRNA or PACAP antagonist PACAP(6-38). The in vivo study showed long-term treatment with doxycycline (100ug/kg) had significant effect against scopolamine induced amnesia, and the synergetic anti-apoptotic, anti-oxidative and neuroprotective effect of doxycycline with VIP was more efficient than doxycycline alone or VIP alone, indicating doxycycline enhanced the activation of PAC1 in vivo effectively. Furthermore, doxycycline analogue minocycline also had similar theoretically binding site on PAC1 to doxycycline and displayed corresponding

Can neuropeptides treat obesity? A review of neuropeptides and their potential role in the treatment of obesity.

PubMed

Boughton, C K; Murphy, K G

2013-12-01

Obesity is a major worldwide public health issue. The physiological systems that regulate body weight are thus of great interest as targets for anti-obesity agents. Peptidergic systems are critical to the regulation of energy homeostasis by key regions in the hypothalamus and brainstem. A number of neuropeptide systems have therefore been investigated as potential treatments for obesity. Blocking orexigenic peptide signals such as neuropeptide Y, melanin-concentrating hormone, orexins, relaxin-3 and galanin-like peptide or stimulating anorectic signalling pathways used by peptides such as the melanocortins, ciliary neurotrophic factor and brain-derived neurotrophic factor, are approaches that have shown some promise, but which have also highlighted possible concerns. Manipulation of central peptidergic systems poses a number of therapeutic problems, including brain access and side effects. Given that the homeostatic defence of body weight may limit the effectiveness of any single-target therapy developed, a combination therapy approach may offer the best hope for the effective prevention and treatment of obesity. This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Monoamines differentially modulate neuropeptide release from distinct sites within a single neuron pair.

PubMed

Clark, Tobias; Hapiak, Vera; Oakes, Mitchell; Mills, Holly; Komuniecki, Richard

2018-01-01

Monoamines and neuropeptides often modulate the same behavior, but monoaminergic-peptidergic crosstalk remains poorly understood. In Caenorhabditis elegans, the adrenergic-like ligands, tyramine (TA) and octopamine (OA) require distinct subsets of neuropeptides in the two ASI sensory neurons to inhibit nociception. TA selectively increases the release of ASI neuropeptides encoded by nlp-14 or nlp-18 from either synaptic/perisynaptic regions of ASI axons or the ASI soma, respectively, and OA selectively increases the release of ASI neuropeptides encoded by nlp-9 asymmetrically, from only the synaptic/perisynaptic region of the right ASI axon. The predicted amino acid preprosequences of genes encoding either TA- or OA-dependent neuropeptides differed markedly. However, these distinct preprosequences were not sufficient to confer monoamine-specificity and additional N-terminal peptide-encoding sequence was required. Collectively, our results demonstrate that TA and OA specifically and differentially modulate the release of distinct subsets of neuropeptides from different subcellular sites within the ASIs, highlighting the complexity of monoaminergic/peptidergic modulation, even in animals with a relatively simple nervous system.

Monoamines differentially modulate neuropeptide release from distinct sites within a single neuron pair

PubMed Central

Oakes, Mitchell; Mills, Holly; Komuniecki, Richard

2018-01-01

Monoamines and neuropeptides often modulate the same behavior, but monoaminergic-peptidergic crosstalk remains poorly understood. In Caenorhabditis elegans, the adrenergic-like ligands, tyramine (TA) and octopamine (OA) require distinct subsets of neuropeptides in the two ASI sensory neurons to inhibit nociception. TA selectively increases the release of ASI neuropeptides encoded by nlp-14 or nlp-18 from either synaptic/perisynaptic regions of ASI axons or the ASI soma, respectively, and OA selectively increases the release of ASI neuropeptides encoded by nlp-9 asymmetrically, from only the synaptic/perisynaptic region of the right ASI axon. The predicted amino acid preprosequences of genes encoding either TA- or OA-dependent neuropeptides differed markedly. However, these distinct preprosequences were not sufficient to confer monoamine-specificity and additional N-terminal peptide-encoding sequence was required. Collectively, our results demonstrate that TA and OA specifically and differentially modulate the release of distinct subsets of neuropeptides from different subcellular sites within the ASIs, highlighting the complexity of monoaminergic/peptidergic modulation, even in animals with a relatively simple nervous system. PMID:29723289

Discovery and functional characterisation of a luqin-type neuropeptide signalling system in a deuterostome.

PubMed

Yañez-Guerra, Luis Alfonso; Delroisse, Jérôme; Barreiro-Iglesias, Antón; Slade, Susan E; Scrivens, James H; Elphick, Maurice R

2018-05-08

Neuropeptides are diverse and evolutionarily ancient regulators of physiological/behavioural processes in animals. Here we have investigated the evolution and comparative physiology of luqin-type neuropeptide signalling, which has been characterised previously in protostomian invertebrates. Phylogenetic analysis indicates that luqin-type receptors and tachykinin-type receptors are paralogous and probably originated in a common ancestor of the Bilateria. In the deuterostomian lineage, luqin-type signalling has been lost in chordates but interestingly it has been retained in ambulacrarians. Therefore, here we characterised luqin-type signalling for the first time in an ambulacrarian - the starfish Asterias rubens (phylum Echinodermata). A luqin-like neuropeptide with a C-terminal RWamide motif (ArLQ; EEKTRFPKFMRW-NH 2 ) was identified as the ligand for two luqin-type receptors in A. rubens, ArLQR1 and ArLQR2. Furthermore, analysis of the expression of the ArLQ precursor using mRNA in situ hybridisation revealed expression in the nervous system, digestive system and locomotory organs (tube feet) and in vitro pharmacology revealed that ArLQ causes dose-dependent relaxation of tube feet. Accordingly, previous studies have revealed that luqin-type signalling regulates feeding and locomotor activity in protostomes. In conclusion, our phylogenetic analysis combined with characterisation of luqin-type signalling in a deuterostome has provided new insights into neuropeptide evolution and function in the animal kingdom.

A PDF/NPF neuropeptide signaling circuitry of male Drosophila melanogaster controls rival-induced prolonged mating.

PubMed

Kim, Woo Jae; Jan, Lily Yeh; Jan, Yuh Nung

2013-12-04

A primary function of males for many species involves mating with females for reproduction. Drosophila melanogaster males respond to the presence of other males by prolonging mating duration to increase the chance of passing on their genes. To understand the basis of such complex behaviors, we examine the genetic network and neural circuits that regulate rival-induced Longer-Mating-Duration (LMD). Here, we identify a small subset of clock neurons in the male brain that regulate LMD via neuropeptide signaling. LMD requires the function of pigment-dispersing factor (PDF) in four s-LNv neurons and its receptor PDFR in two LNd neurons per hemisphere, as well as the function of neuropeptide F (NPF) in two neurons within the sexually dimorphic LNd region and its receptor NPFR1 in four s-LNv neurons per hemisphere. Moreover, rival exposure modifies the neuronal activities of a subset of clock neurons involved in neuropeptide signaling for LMD. Copyright © 2013 Elsevier Inc. All rights reserved.

A PDF/NPF neuropeptide signaling circuitry of male Drosophila melanogaster controls rival-induced prolonged mating

PubMed Central

Kim, Woo Jae; Jan, Lily Yeh; Jan, Yuh Nung

2013-01-01

SUMMARY A primary function of males for many species involves mating with females for reproduction. Drosophila melanogaster males respond to the presence of other males by prolonging mating duration to increase the chance of passing on their genes. To understand the basis of such complex behaviors, we examine the genetic network and neural circuits that regulate rival-induced longer mating duration (LMD). Here we identify a small subset of clock neurons in the male brain that regulate LMD via neuropeptide signaling. LMD requires the function of pigment-dispersing factor (PDF) in four s-LNv neurons and its receptor PDFR in two LNd neurons per hemisphere, as well as the function of neuropeptide F (NPF) in two neurons within the sexually dimorphic LNd region and its receptor NPFR1 in four s-LNv neurons per hemisphere. Moreover, rival exposure modifies the neuronal activities of a subset of clock neurons involved in neuropeptide signaling for LMD. PMID:24314729

Study of the Role of CREB, BDNF, and VGF Neuropeptide in Long Term Antidepressant Activity of Crocin in the Rat Cerebellum

PubMed Central

Razavi, Bibi Marjan; Sadeghi, Mahdieh; Abnous, Khalil; Vahdati Hasani, Faezeh; Hosseinzadeh, Hossein

2017-01-01

Antidepressant activity of crocin, saffron main component, has been established before. Based on previous study, it is suggested that elevation in the levels of BDNF (brain-derived neurotrophic factor), CREB (cAMP response element binding) and VGF neuropeptide could be considered as one probable molecular mechanisms involved in antidepressant activity of long term crocin administration in the rat hippocampus. In this study we further investigated whether the antidepressant activity of crocin in long term administration was associated with alteration in these factors in the rat cerebellum. Crocin (12.5, 25 and 50 mg/kg/day) and imipramine (10 mg/kg/day) were administered interaperitoneally for 21 days to rats. At the end of experiment, animals were sacrificed and cerebellums were dissected. BDNF, VGF, CREB, and phospho-CREB (P-CREB) protein and mRNA levels in the rat cerebellum were evaluated using Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In the current study significant increases in mRNA and protein levels of VGF, CREB and (BDNF) in long term crocin treatment were not observed in the rat cerebellum. Although a slight increase was observed in protein level of P-CREB compared to normal saline, but it was not significant. It is concluded that antidepressant activity of crocin might be partially mediated to CREB. Moreover, other factors rather than BDNF and VGF neuropeptides may alter following long term crocin treatment in the cerebellum. To understand the precise mechanism of crocin antidepressant effects in the cerebellum, longer duration of crocin treatment in further studies is recommended. PMID:29552054

Dipeptidylpeptidase-IV, a key enzyme for the degradation of incretins and neuropeptides: activity and expression in the liver of lean and obese rats

PubMed Central

Tarantola, E.; Bertone, V.; Milanesi, G.; Capelli, E.; Ferrigno, A.; Neri, D.; Vairetti, M.; Barni, S.; Freitas, I.

2012-01-01

Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns

Dipeptidylpeptidase--IV, a key enzyme for the degradation of incretins and neuropeptides: activity and expression in the liver of lean and obese rats.

PubMed

Tarantola, E; Bertone, V; Milanesi, G; Capelli, E; Ferrigno, A; Neri, D; Vairetti, M; Barni, S; Freitas, I

2012-10-08

Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns

Functional Characterization of Paralogous Gonadotropin-Releasing Hormone-Type and Corazonin-Type Neuropeptides in an Echinoderm

PubMed Central

Tian, Shi; Egertová, Michaela; Elphick, Maurice R.

2017-01-01

Homologs of the vertebrate neuropeptide gonadotropin-releasing hormone (GnRH) have been identified in invertebrates, including the insect neuropeptide corazonin (CRZ). Recently, we reported the discovery of GnRH-type and CRZ-type signaling systems in an echinoderm, the starfish Asterias rubens, demonstrating that the evolutionary origin of paralogous GnRH-type and CRZ-type neuropeptides can be traced back to the common ancestor of protostomes and deuterostomes. Here, we have investigated the physiological roles of the GnRH-type (ArGnRH) and the CRZ-type (ArCRZ) neuropeptides in A. rubens, using mRNA in situ hybridization, immunohistochemistry and in vitro pharmacology. ArGnRH precursor (ArGnRHP)-expressing cells and ArGnRH-immunoreactive cells and/or processes are present in the radial nerve cords, circumoral nerve ring, digestive system (e.g., cardiac stomach and pyloric stomach), body wall-associated muscle (apical muscle), and appendages (tube feet, terminal tentacle). The general distribution of ArCRZ precursor (ArCRZP)-expressing cells is similar to that of ArGnRHP, but with specific local differences. For example, cells expressing ArGnRHP are present in both the ectoneural and hyponeural regions of the radial nerve cords and circumoral nerve ring, whereas cells expressing ArCRZP were only observed in the ectoneural region. In vitro pharmacological experiments revealed that both ArGnRH and ArCRZ cause contraction of cardiac stomach, apical muscle, and tube foot preparations. However, ArGnRH was more potent/effective than ArCRZ as a contractant of the cardiac stomach, whereas ArCRZ was more potent/effective than ArGnRH as a contractant of the apical muscle. These findings demonstrate that both ArGnRH and ArCRZ are myoexcitatory neuropeptides in starfish, but differences in their expression patterns and pharmacological activities are indicative of distinct physiological roles. This is the first study to investigate the physiological roles of both GnRH-type and

Characterization of impaired processing of neuropeptides in the brains of endoprotease knockout mice.

PubMed

Beinfeld, Margery C

2011-01-01

With the development of mice in which individual proteolytic enzymes have been inactivated, it has been of great interest to see how loss of these enzymes alters the processing of neuropeptides. In the course of studying changes in the peptide cholecystokinin (CCK) and other neuropeptides in several of these knockout mice, it has become clear that neuropeptide processing is complex and regionally specific. The enzyme responsible for processing in one part of the brain may not be involved in other parts of the brain. It is essential to do a detailed dissection of the brain and analyze peptide levels in many brain regions to fully understand the role of the enzymes. Because loss of these proteases may trigger compensatory mechanisms which involve expression of the neuropeptides being studied or other proteases or accessory proteins, it is also important to examine how loss of an enzyme alters expression of the neuropeptides being studied as well as other proteins thought to be involved in neuropeptide processing. By determining how loss of an enzyme alters the molecular form(s) of the peptide that are made, additional mechanistic information can be obtained. This review will describe established methods to achieve these research goals.

Zinc Regulation of Aminopeptidase B Involved in Neuropeptide Production

PubMed Central

Hwang, Shin-Rong; Hook, Vivian

2009-01-01

Aminopeptidase B (AP-B) is a metallopeptidase that removes basic residues from the N-termini of neuropeptide substrates in secretory vesicles. This study assessed zinc regulation of AP-B activity, since secretory vesicles contain endogenous zinc. AP-B was inhibited by zinc at concentrations typically present in secretory vesicles. Zinc effects were dependent on concentration, incubation time, and the molar ratio of zinc to enzyme. AP-B activity was recovered upon removal of zinc. AP-B with zinc became susceptible to degradation by trypsin, suggesting that zinc alters enzyme conformation. Zinc regulation demonstrates the metallopeptidase property of AP-B. PMID:18571504

Effects of neuropeptides and capsaicin on the canine tracheal vasculature in vivo.

PubMed

Salonen, R O; Webber, S E; Widdicombe, J G

1988-12-01

1. The nonadrenergic, noncholinergic nervous system may control the airway vasculature via various neuropeptides. We have perfused the cranial tracheal arteries of the anaesthetized dog and investigated the effects of neuropeptides and capsaicin (which is supposed to release neuropeptides from sensory nerve endings) on the tracheal vasculature by injecting them locally into the perfusion system. 2. Neurokinin A (NKA, 0.02-20 pmol), calcitonin gene-related peptide (CGRP, 2-200 pmol) and peptide histidine isoleucine (PHI, 0.02-2 nmol) dose-dependently decreased tracheal vascular resistance (Rtv). NKA was 10 and 100 times more potent than CGRP and PHI, respectively. The duration of the response to CGRP was greatly prolonged with larger doses. Galanin (0.2-2 nmol) had no appreciable effect on Rtv. 3. Neuropeptide Y (NPY 0.02-2 nmol) and bombesin (0.02-10 nmol) dose-dependently increased Rtv. However, the dose-response curve for bombesin was bell-shaped suggesting the development of tachyphylaxis with larger doses. In smaller doses, bombesin was twice as potent as NPY. The duration of the response to NPY was prolonged with larger doses. 4. With the exception of PHI no neuropeptide altered tracheal smooth muscle tone; PHI (1 and 2 nmol) caused small dilatations of the trachea. 5. The effects of capsaicin (2-100 nmol) were complex. Usually, the vascular response had two dose-dependent phases: a rapid vasoconstriction followed by a small, longer-lasting vasodilatation. The tracheal smooth muscle response was usually biphasic, a contraction followed by a relaxation. 6. According to previous and present data, the order of potency of the neuropeptides on the canine tracheal vasculature is for the vasodilators : NKA > vasoactive intestinal peptide (VIP) > CGRP > substance P > PHI, and for the vasoconstrictors: bombesin > NPY. The longer-acting neuropeptides (VIP, CGRP and NPY) may be more important than the shorter-acting neuropeptides (substance P, NKA, PHI and bombesin) as

Ghrelin-induced stimulation of colonic propulsion is dependent on hypothalamic neuropeptide Y1- and corticotrophin-releasing factor 1 receptor activation.

PubMed

Tebbe, J J; Mronga, S; Tebbe, C G; Ortmann, E; Arnold, R; Schäfer, M K-H

2005-09-01

Peptides participating in the hypothalamic control of feeding behaviour are also involved in the central autonomic control of gastrointestinal functions, such as secretion and motility. An anatomical interaction and functional relationship in the central nervous system between the feeding-related peptides neuropeptide Y and ghrelin is well documented. Furthermore, it has been shown that feeding-related peptides can influence digestive function via central corticotrophin-releasing factor (CRF) pathways. In the present study, we investigated the role of ghrelin in the central autonomic control of colonic motility. Furthermore, we addressed the hypothesis that ghrelin is involved in the hypothalamic control of colonic motor function, utilizing central neuropeptide Y receptors and hypothalamic CRF pathways. Ghrelin (0.03, 0.06 and 0.12 nmol) bilaterally microinjected into the paraventricular nucleus (PVN) induced a significant stimulation of colonic propulsion. In particular, the colonic transit time decreased from 312+/-7 min to 198+/-12 min. Microinjection of the neuropeptide Y1 receptor antagonist, BIBP-3226 (200 pmol), or the nonselective CRF receptor antagonist, astressin (30 pmol), into the PVN abolished the stimulatory effect of ghrelin injected into the PVN on colonic transit time, whereas pretreatment with the selective CRF2 receptor, antisauvagine-30 (28 pmol), failed to affect the effect of PVN-ghrelin injection on colonic propulsion. These results suggest that ghrelin can act as central modulator of gastrointestinal motor functions at the level of the PVN via neuropeptide Y1- and CRF1 receptor-dependent mechanisms.

The neuropeptide substance P stimulates the effector functions of platelets.

PubMed Central

Damonneville, M; Monté, D; Auriault, C; Capron, A

1990-01-01

Sensory neuropeptides, such as substance P, appear as potent mediators of various immunological reactions, and inhibit or stimulate a wide range of functions of immune inflammatory cells. Platelets were recently shown to participate as effector cells in an IgE or lymphokine-dependent killing of parasites. Substance P and its carboxy-terminal fragment SP (4-11) induce the cytotoxic activity of platelets towards the larvae of Schistosoma mansoni, respectively, by 90% and 40%, whereas the modified C terminal SP, the SP-free acid, exhibits no effect on the platelets. The neuropeptide effects occur at low doses (10(-8) M), are specific as shown by inhibition studies with a substance P antagonist, the D-SP. Binding data obtained after flow cytofluorometry with FITC-SP lead to the conclusion that SP binds specifically to about 20% of the homogenous population of platelets. Moreover, IgE could modulate the SP-dependent functions of platelets since the pre-incubation with myeloma human IgE or with AP2 monoclonal antibodies--known to inhibit the IgE-dependent killing of these cells-leads to a dramatic decrease of the SP dependent cytotoxic activity of platelets towards the larvae. These findings identify a potent mechanism for nervous system regulation of host defence responses. PMID:1696868

Neuropeptide Y in the adult and fetal human pineal gland.

PubMed

Møller, Morten; Phansuwan-Pujito, Pansiri; Badiu, Corin

2014-01-01

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be colocalized with noradrenaline in sympathetic nerve terminals. The peptide has been demonstrated to be present in sympathetic nerve fibers innervating the pineal gland in many mammalian species. In this investigation, we show by use of immunohistochemistry that neuropeptide Y is present in nerve fibers of the adult human pineal gland. The fibers are classical neuropeptidergic fibers endowed with large boutons en passage and primarily located in a perifollicular position with some fibers entering the pineal parenchyma inside the follicle. The distance from the immunoreactive terminals to the pinealocytes indicates a modulatory function of neuropeptide Y for pineal physiology. Some of the immunoreactive fibers might originate from neurons located in the brain and be a part of the central innervation of the pineal gland. In a series of human fetuses, neuropeptide Y-containing nerve fibers was present and could be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is different from most rodents, where the innervation starts postnatally.

Neuropeptide Y in the Adult and Fetal Human Pineal Gland

PubMed Central

Møller, Morten; Phansuwan-Pujito, Pansiri

2014-01-01

Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be colocalized with noradrenaline in sympathetic nerve terminals. The peptide has been demonstrated to be present in sympathetic nerve fibers innervating the pineal gland in many mammalian species. In this investigation, we show by use of immunohistochemistry that neuropeptide Y is present in nerve fibers of the adult human pineal gland. The fibers are classical neuropeptidergic fibers endowed with large boutons en passage and primarily located in a perifollicular position with some fibers entering the pineal parenchyma inside the follicle. The distance from the immunoreactive terminals to the pinealocytes indicates a modulatory function of neuropeptide Y for pineal physiology. Some of the immunoreactive fibers might originate from neurons located in the brain and be a part of the central innervation of the pineal gland. In a series of human fetuses, neuropeptide Y-containing nerve fibers was present and could be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is different from most rodents, where the innervation starts postnatally. PMID:24757681

Neuropeptide tyrosine (NPY)--a major cardiac neuropeptide.

PubMed

Gu, J; Polak, J M; Adrian, T E; Allen, J M; Tatemoto, K; Bloom, S R

1983-05-07

A newly discovered bioactive peptide, neuropeptide tyrosine (NPY), has been found in the human cardiac nervous system. Dense concentrations of NPY-immunoreactive nerve fibres were found in association with nodal tissue (atrioventricular node 22.1 +/- 3.7 pmol/g). NPY nerve fibres were seen in close contact with cardiac muscle fibres and were also found around the coronary vessels (19.6 +/- 6.2 pmol/g). Analysis of the peptide by high-performance liquid chromatography demonstrated that it was present in a single molecular form, closely similar or identical to that of the isolated bioactive peptide. Cardiac function in man has long been known to be influenced by cholinergic and adrenergic nerves. There now appears to be a further component of the nervous system in the human heart, involving peptidergic nerves containing NPY.

Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase.

PubMed

Zheng, R; Iwase, A; Shen, R; Goodman, O B; Sugimoto, N; Takuwa, Y; Lerner, D J; Nanus, D M

2006-09-28

The neuropeptides bombesin and endothelin-1 stimulate prostate cancer (PC) cell migration and invasion (J Clin Invest, 2000; 106: 1399-1407). The intracellular signaling pathways that direct this cell movement are not well delineated. The monomeric GTPase RhoA is required for migration in several cell types including neutrophils, monocytes and fibroblasts. We demonstrate that bombesin-stimulated PC cell migration occurs via the heterotrimeric G-protein-coupled receptors (G-protein) G alpha 13 subunit leading to activation of RhoA, and Rho-associated coiled-coil forming protein kinase (ROCK). Using siRNA to suppress expression of the three known G-protein alpha-subunit-associated RhoA guanine nucleotide exchange factors (GEFs), we also show that two of these RhoA GEFs, PDZ-RhoGEF and leukemia-associated RhoGEF (LARG), link bombesin receptors to RhoA in a non-redundant manner in PC cells. We next show that focal adhesion kinase, which activates PDZ-RhoGEF and LARG, is required for bombesin-stimulated RhoA activation. Neutral endopeptidase (NEP) is expressed on normal prostate epithelium whereas loss of NEP expression contributes to PC progression. We also demonstrate that NEP inhibits neuropeptide activation of RhoA. Together, these results establish a contiguous signaling pathway from the bombesin receptor to ROCK in PC cells, and they implicate NEP as a major regulator of neuropeptide-stimulated RhoA in these cells. This work also identifies members of this signaling pathway as potential targets for rational pharmacologic manipulation of neuropeptide-stimulated migration of PC cells.

Drosophila DH31 Neuropeptide and PDF Receptor Regulate Night-Onset Temperature Preference

PubMed Central

Goda, Tadahiro; Tang, Xin; Umezaki, Yujiro; Chu, Michelle L.

2016-01-01

Body temperature exhibits rhythmic fluctuations over a 24 h period (Refinetti and Menaker, 1992) and decreases during the night, which is associated with sleep initiation (Gilbert et al., 2004; Kräuchi, 2007a,b). However, the underlying mechanism of this temperature decrease is largely unknown. We have previously shown that Drosophila exhibit a daily temperature preference rhythm (TPR), in which their preferred temperatures increase during the daytime and then decrease at the transition from day to night (night-onset) (Kaneko et al., 2012). Because Drosophila are small ectotherms, their body temperature is very close to that of the ambient temperature (Stevenson, 1985), suggesting that their TPR generates their body temperature rhythm. Here, we demonstrate that the neuropeptide diuretic hormone 31 (DH31) and pigment-dispersing factor receptor (PDFR) contribute to regulate the preferred temperature decrease at night-onset. We show that PDFR and tethered-DH31 expression in dorsal neurons 2 (DN2s) restore the preferred temperature decrease at night-onset, suggesting that DH31 acts on PDFR in DN2s. Notably, we previously showed that the molecular clock in DN2s is important for TPR. Although PDF (another ligand of PDFR) is a critical factor for locomotor activity rhythms, Pdf mutants exhibit normal preferred temperature decreases at night-onset. This suggests that DH31-PDFR signaling specifically regulates a preferred temperature decrease at night-onset. Thus, we propose that night-onset TPR and locomotor activity rhythms are differentially controlled not only by clock neurons but also by neuropeptide signaling in the brain. SIGNIFICANCE STATEMENT Body temperature rhythm (BTR) is fundamental for the maintenance of functions essential for homeostasis, such as generating metabolic energy and sleep. One major unsolved question is how body temperature decreases dramatically during the night. Previously, we demonstrated that a BTR-like mechanism, referred to as temperature

Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in Drosophila

PubMed Central

Nässel, Dick R.

2018-01-01

It has been known for more than 40 years that individual neurons can produce more than one neurotransmitter and that neuropeptides often are colocalized with small molecule neurotransmitters (SMNs). Over the years much progress has been made in understanding the functional consequences of cotransmission in the nervous system of mammals. There are also some excellent invertebrate models that have revealed roles of coexpressed neuropeptides and SMNs in increasing complexity, flexibility, and dynamics in neuronal signaling. However, for the fly Drosophila there are surprisingly few functional studies on cotransmission, although there is ample evidence for colocalization of neuroactive compounds in neurons of the CNS, based both on traditional techniques and novel single cell transcriptome analysis. With the hope to trigger interest in initiating cotransmission studies, this review summarizes what is known about Drosophila neurons and neuronal circuits where different neuropeptides and SMNs are colocalized. Coexistence of neuroactive substances has been recorded in different neuron types such as neuroendocrine cells, interneurons, sensory cells and motor neurons. Some of the circuits highlighted here are well established in the analysis of learning and memory, circadian clock networks regulating rhythmic activity and sleep, as well as neurons and neuroendocrine cells regulating olfaction, nociception, feeding, metabolic homeostasis, diuretic functions, reproduction, and developmental processes. One emerging trait is the broad role of short neuropeptide F in cotransmission and presynaptic facilitation in a number of different neuronal circuits. This review also discusses the functional relevance of coexisting peptides in the intestine. Based on recent single cell transcriptomics data, it is likely that the neuronal systems discussed in this review are just a fraction of the total set of circuits where cotransmission occurs in Drosophila. Thus, a systematic search for

Exploring the Sea Urchin Neuropeptide Landscape by Mass Spectrometry.

PubMed

Monroe, Eric B; Annangudi, Suresh P; Wadhams, Andinet A; Richmond, Timothy A; Yang, Ning; Southey, Bruce R; Romanova, Elena V; Schoofs, Liliane; Baggerman, Geert; Sweedler, Jonathan V

2018-05-01

Neuropeptides are essential cell-to-cell signaling messengers and serve important regulatory roles in animals. Although remarkable progress has been made in peptide identification across the Metazoa, for some phyla such as Echinodermata, limited neuropeptides are known and even fewer have been verified on the protein level. We employed peptidomic approaches using bioinformatics and mass spectrometry (MS) to experimentally confirm 23 prohormones and to characterize a new prohormone in nervous system tissue from Strongylocentrotus purpuratus, the purple sea urchin. Ninety-three distinct peptides from known and novel prohormones were detected with MS from extracts of the radial nerves, many of which are reported or experimentally confirmed here for the first time, representing a large-scale study of neuropeptides from the phylum Echinodermata. Many of the identified peptides and their precursor proteins have low homology to known prohormones from other species/phyla and are unique to the sea urchin. By pairing bioinformatics with MS, the capacity to characterize novel peptides and annotate prohormone genes is enhanced. Graphical Abstract.

The cellular localization of the neuropeptides substance P, neurokinin A, calcitonin gene-related peptide and neuropeptide Y in guinea-pig vestibular sensory organs: a high-resolution confocal microscopy study.

PubMed

Scarfone, E; Ulfendahl, M; Lundeberg, T

1996-11-01

Four neuropeptides, substance P, neurokinin A, calcitonin gene-related peptide and neuropeptide Y, were detected by radioimmunoassay in guinea-pig vestibular end-organs. High-resolution confocal microscopy visualization of immunofluorescence staining was used to determine the cellular localization of these peptides. Substance P- and neurokinin A-like immunoreactivities were found to co-exist in afferent fibers innervating the peripheral regions of both the utricular and ampullar sensory organs. The immunoreactivity was more concentrated in the distal ends of the calyceal-shaped nerve endings that innervate type I sensory cells. While in the guinea-pig, nerve calyces and type I cells are distributed in both the central and peripheral regions of the sensory epithelia, immunoreactive calyces were found only in the peripheral regions. Calcitonin gene-related peptide-like immunoreactivity was localized in small bouton endings situated at the level of the base of the hair cells. These boutons were in a position to make axosomatic contacts with type II sensory cells and axodendritic contacts with afferent nerve endings. Calcitonin gene-related peptide immunoreactivity co-existed with choline acetyltransferase immunoreactivity. The localization and shape of these boutons identified them as the axonal endings of efferent vestibular fibers. Neuropeptide Y-like immunoreactivity was not observed in the actual sensory epithelium but in the underlying connective tissue, where it was located in varicose fibers along blood vessels. The synaptic position of the tachykinins is clearly distinct from that of calcitonin gene-related peptide. This segregation distinguishes the vestibular end-organs from most peripheral tissues where these peptides are co-localized. The tachykinin-immunoreactive afferent fibers are postsynaptic to the hair cells. If, as in somatic sensory endings, these fibers can be triggered to release the neuropeptides by an axon reflex type of activation, then the

Insight into the Molecular and Functional Diversity of Cnidarian Neuropeptides

PubMed Central

Takahashi, Toshio; Takeda, Noriyo

2015-01-01

Cnidarians are the most primitive animals to possess a nervous system. This phylum is composed of the classes Scyphozoa (jellyfish), Cubozoa (box jellyfish), and Hydrozoa (e.g., Hydra, Hydractinia), which make up the subphylum Medusozoa, as well as the class Anthozoa (sea anemones and corals). Neuropeptides have an early evolutionary origin and are already abundant in cnidarians. For example, from the cnidarian Hydra, a key model system for studying the peptides involved in developmental and physiological processes, we identified a wide variety of novel neuropeptides from Hydra magnipapillata (the Hydra Peptide Project). Most of these peptides act directly on muscle cells and induce contraction and relaxation. Some peptides are involved in cell differentiation and morphogenesis. In this review, we describe FMRFamide-like peptides (FLPs), GLWamide-family peptides, and the neuropeptide Hym-355; FPQSFLPRGamide. Several hundred FLPs have been isolated from invertebrate animals such as cnidarians. GLWamide-family peptides function as signaling molecules in muscle contraction, metamorphosis, and settlement in cnidarians. Hym-355; FPQSFLPRGamide enhances neuronal differentiation in Hydra. Recently, GLWamide-family peptides and Hym-355; FPQSFLPRGamide were shown to trigger oocyte maturation and subsequent spawning in the hydrozoan jellyfish Cytaeis uchidae. These findings suggest the importance of these neuropeptides in both developmental and physiological processes. PMID:25625515

Insight into the molecular and functional diversity of cnidarian neuropeptides.

PubMed

Takahashi, Toshio; Takeda, Noriyo

2015-01-23

Cnidarians are the most primitive animals to possess a nervous system. This phylum is composed of the classes Scyphozoa (jellyfish), Cubozoa (box jellyfish), and Hydrozoa (e.g., Hydra, Hydractinia), which make up the subphylum Medusozoa, as well as the class Anthozoa (sea anemones and corals). Neuropeptides have an early evolutionary origin and are already abundant in cnidarians. For example, from the cnidarian Hydra, a key model system for studying the peptides involved in developmental and physiological processes, we identified a wide variety of novel neuropeptides from Hydra magnipapillata (the Hydra Peptide Project). Most of these peptides act directly on muscle cells and induce contraction and relaxation. Some peptides are involved in cell differentiation and morphogenesis. In this review, we describe FMRFamide-like peptides (FLPs), GLWamide-family peptides, and the neuropeptide Hym-355; FPQSFLPRGamide. Several hundred FLPs have been isolated from invertebrate animals such as cnidarians. GLWamide-family peptides function as signaling molecules in muscle contraction, metamorphosis, and settlement in cnidarians. Hym-355; FPQSFLPRGamide enhances neuronal differentiation in Hydra. Recently, GLWamide-family peptides and Hym-355; FPQSFLPRGamide were shown to trigger oocyte maturation and subsequent spawning in the hydrozoan jellyfish Cytaeis uchidae. These findings suggest the importance of these neuropeptides in both developmental and physiological processes.

Immunohistochemical localization of cardio-active neuropeptides in the heart of a living fossil, Nautilus pompilius L. (Cephalopoda, Tetrabranchiata).

PubMed

Springer, J; Ruth, P; Beuerlein, K; Westermann, B; Schipp, R

2004-01-01

Neuropeptides play an important role in modulating the effects of neurotransmitters such as acetylcholine and noradrenaline in the heart and the vascular system of vertebrates and invertebrates. Various neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP) and FMRFamide, have been localized in the brain in cephalopods and the neurosecretory system of the vena cava. Previous studies involving cephalopods have mainly focussed on the modern, coleoid cephalopods, whereas little attention was paid to the living fossil Nautilus. In this study, the distributions of the peptides related to tachykinins (TKs) and the high affinity receptor for the best characterized TK substance P (tachykinin NK-1), VIP, as well as FMRFamide were investigated in the heart of Nautilus pompilius L. by immunohistochemistry. TK-like immunoreactivity (TK-LI) was seen associated to a sub-population of hemocytes, VIP-LI glial cells in larger nerves entering the heart, whereas FMRFamide immunoreactivity was distributed throughout the entire heart, including the semilunar atrioventricular valves. The pattern of FMRFamide immunoreactivity matched that of Bodian silver staining for nervous tissue. The NK-1-LI receptor was located on endothelial cells, which were also positive for endothelial nitric oxide synthase-LI (eNOS). The results indicate that neuropeptides may be involved in the regulation of the Nautilus heart via different mechanisms, (1) by direct interaction with myocardial receptors (FMRFamide), (2) by interacting with the nervus cardiacus (VIP-related peptides) and (3) indirectly by stimulating eNOS in the endothelium throughout the heart (TK-related peptides).

Exploring the Sea Urchin Neuropeptide Landscape by Mass Spectrometry

NASA Astrophysics Data System (ADS)

Monroe, Eric B.; Annangudi, Suresh P.; Wadhams, Andinet A.; Richmond, Timothy A.; Yang, Ning; Southey, Bruce R.; Romanova, Elena V.; Schoofs, Liliane; Baggerman, Geert; Sweedler, Jonathan V.

2018-05-01

Neuropeptides are essential cell-to-cell signaling messengers and serve important regulatory roles in animals. Although remarkable progress has been made in peptide identification across the Metazoa, for some phyla such as Echinodermata, limited neuropeptides are known and even fewer have been verified on the protein level. We employed peptidomic approaches using bioinformatics and mass spectrometry (MS) to experimentally confirm 23 prohormones and to characterize a new prohormone in nervous system tissue from Strongylocentrotus purpuratus, the purple sea urchin. Ninety-three distinct peptides from known and novel prohormones were detected with MS from extracts of the radial nerves, many of which are reported or experimentally confirmed here for the first time, representing a large-scale study of neuropeptides from the phylum Echinodermata. Many of the identified peptides and their precursor proteins have low homology to known prohormones from other species/phyla and are unique to the sea urchin. By pairing bioinformatics with MS, the capacity to characterize novel peptides and annotate prohormone genes is enhanced. [Figure not available: see fulltext.

Exploring the Sea Urchin Neuropeptide Landscape by Mass Spectrometry

NASA Astrophysics Data System (ADS)

Monroe, Eric B.; Annangudi, Suresh P.; Wadhams, Andinet A.; Richmond, Timothy A.; Yang, Ning; Southey, Bruce R.; Romanova, Elena V.; Schoofs, Liliane; Baggerman, Geert; Sweedler, Jonathan V.

2018-04-01

Neuropeptides are essential cell-to-cell signaling messengers and serve important regulatory roles in animals. Although remarkable progress has been made in peptide identification across the Metazoa, for some phyla such as Echinodermata, limited neuropeptides are known and even fewer have been verified on the protein level. We employed peptidomic approaches using bioinformatics and mass spectrometry (MS) to experimentally confirm 23 prohormones and to characterize a new prohormone in nervous system tissue from Strongylocentrotus purpuratus, the purple sea urchin. Ninety-three distinct peptides from known and novel prohormones were detected with MS from extracts of the radial nerves, many of which are reported or experimentally confirmed here for the first time, representing a large-scale study of neuropeptides from the phylum Echinodermata. Many of the identified peptides and their precursor proteins have low homology to known prohormones from other species/phyla and are unique to the sea urchin. By pairing bioinformatics with MS, the capacity to characterize novel peptides and annotate prohormone genes is enhanced. [Figure not available: see fulltext.

An indirect action contributes to c-fos induction in paraventricular hypothalamic nucleus by neuropeptide Y

USDA-ARS?s Scientific Manuscript database

Neuropeptide Y (NPY) is a well-established orexigenic peptide and hypothalamic paraventricular nucleus (PVH) is one major brain site that mediates the orexigenic action of NPY. NPY induces abundant expression of C-Fos, an indicator for neuronal activation, in the PVH, which has been used extensively...

Drosophila DH31 Neuropeptide and PDF Receptor Regulate Night-Onset Temperature Preference.

PubMed

Goda, Tadahiro; Tang, Xin; Umezaki, Yujiro; Chu, Michelle L; Kunst, Michael; Nitabach, Michael N; Hamada, Fumika N

2016-11-16

Body temperature exhibits rhythmic fluctuations over a 24 h period (Refinetti and Menaker, 1992) and decreases during the night, which is associated with sleep initiation (Gilbert et al., 2004; Kräuchi, 2007a,b). However, the underlying mechanism of this temperature decrease is largely unknown. We have previously shown that Drosophila exhibit a daily temperature preference rhythm (TPR), in which their preferred temperatures increase during the daytime and then decrease at the transition from day to night (night-onset) (Kaneko et al., 2012). Because Drosophila are small ectotherms, their body temperature is very close to that of the ambient temperature (Stevenson, 1985), suggesting that their TPR generates their body temperature rhythm. Here, we demonstrate that the neuropeptide diuretic hormone 31 (DH31) and pigment-dispersing factor receptor (PDFR) contribute to regulate the preferred temperature decrease at night-onset. We show that PDFR and tethered-DH31 expression in dorsal neurons 2 (DN2s) restore the preferred temperature decrease at night-onset, suggesting that DH31 acts on PDFR in DN2s. Notably, we previously showed that the molecular clock in DN2s is important for TPR. Although PDF (another ligand of PDFR) is a critical factor for locomotor activity rhythms, Pdf mutants exhibit normal preferred temperature decreases at night-onset. This suggests that DH31-PDFR signaling specifically regulates a preferred temperature decrease at night-onset. Thus, we propose that night-onset TPR and locomotor activity rhythms are differentially controlled not only by clock neurons but also by neuropeptide signaling in the brain. Body temperature rhythm (BTR) is fundamental for the maintenance of functions essential for homeostasis, such as generating metabolic energy and sleep. One major unsolved question is how body temperature decreases dramatically during the night. Previously, we demonstrated that a BTR-like mechanism, referred to as temperature preference rhythm (TPR

Endopeptidases 24.16 and 24.15 are responsible for the degradation of somatostatin, neurotensin, and other neuropeptides by cultivated rat cortical astrocytes.

PubMed

Mentlein, R; Dahms, P

1994-01-01

Several neuropeptides, including neurotensin, somatostatin, bradykinin, angiotensin II, substance P, and luteinizing hormone-releasing hormone but not vasopressin and oxytocin, were actively metabolized through proteolytic degradation by cultivated astrocytes obtained from rat cerebral cortex. Because phenanthroline was an effective degradation inhibitor, metalloproteases were responsible for neuropeptide fragmentation. Neurotensin was cleaved by astrocytes at the Pro10-Tyr11 and Arg8-Arg9 bonds, whereas somatostatin was cleaved at the Phe6-Phe7 and Thr10-Phe11 bonds. These cleavage sites have been found previously with endopeptidases 24.16 and 24.15 purified from rat brain. Addition of specific inhibitors of these proteases, the dipeptide Pro-Ile and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-4-aminobenzoate, significantly reduced the generation of the above neuropeptide fragments by astrocytes. The presence of endopeptidases 24.16 and 24.15 in homogenates of astrocytes could also be demonstrated by chromatographic separations of supernatant solubilized cell preparations. Proteolytic activity for neurotensin eluted after both gel and hydroxyapatite chromatography at the same positions as found for purified endopeptidase 24.16 or 24.15. In incubation experiments or in chromatographic separations no phosphoramidon-sensitive endopeptidase 24.11 (enkephalinase) or captopril-sensitive peptidyl dipeptidase A (angiotensin-converting enzyme) could be detected in cultivated astrocytes. Because astrocytes embrace the neuronal synapses where neuropeptides are released, we presume that the endopeptidases 24.16 and 24.15 on astrocytes are strategically located to contribute significantly to the inactivation of neurotensin, somatostatin, and other neuropeptides in the brain.

Isolation and structure elucidation of neuropeptides of the AKH/RPCH family in long-horned grasshoppers (Ensifera).

PubMed

Gäde, G

1992-11-01

An identical neuropeptide was isolated by reversed-phase high-performance liquid chromatography from the corpora cardiaca of the king cricket, Libanasidus vittatus, and the two armoured ground crickets, Heterodes namaqua and Acanthoproctus cervinus. The crude gland extracts had adipokinetic activity in migratory locusts, hypertrehalosaemic activity in American cockroaches and a slight hypertrehalosaemic, but no adipokinetic, effect in armoured ground crickets. The primary structure of this neuropeptide was determined by pulsed-liquid phase sequencing employing Edman chemistry after enzymically deblocking the N-terminal 5-oxopyrrolidine-2-carboxylic acid residue. The C-terminus was also blocked, as indicated by the lack of digestion by carboxypeptidase A. The peptide was assigned the structure [symbol: see text]Glu-Leu-Asn-Phe-Ser-Thr-Gly-TrpNH2, previously designated Scg-AKH-II. The corpora cardiaca of the cricket Gryllodes sigillatus contained a neuropeptide which differed in retention time from the one isolated from the king and armoured ground crickets. The structure was assigned as [symbol: see text]Glu-Val-Asn-Phe-Ser-Thr-Gly-TrpNH2, previously designated Grb-AKH. This octapeptide caused hyperlipaemia in its donor species. The presence of the same peptide, Scg-AKH-II, in the two primitive infraorders of Ensifera, and the different peptide, Grb-AKH, in the most advanced infraorder of Ensifera, supports the evolutionary trends assigned formerly from morphological and physiological evidence.

Habituation as an adaptive shift in response strategy mediated by neuropeptides

NASA Astrophysics Data System (ADS)

Ardiel, Evan L.; Yu, Alex J.; Giles, Andrew C.; Rankin, Catharine H.

2017-08-01

Habituation is a non-associative form of learning characterized by a decremented response to repeated stimulation. It is typically framed as a process of selective attention, allowing animals to ignore irrelevant stimuli in order to free up limited cognitive resources. However, habituation can also occur to threatening and toxic stimuli, suggesting that habituation may serve other functions. Here we took advantage of a high-throughput Caenorhabditis elegans learning assay to investigate habituation to noxious stimuli. Using real-time computer vision software for automated behavioral tracking and optogenetics for controlled activation of a polymodal nociceptor, ASH, we found that neuropeptides mediated habituation and performed an RNAi screen to identify candidate receptors. Through subsequent mutant analysis and cell-type-specific gene expression, we found that pigment-dispersing factor (PDF) neuropeptides function redundantly to promote habituation via PDFR-1-mediated cAMP signaling in both neurons and muscles. Behavioral analysis during learning acquisition suggests that response habituation and sensitization of locomotion are parts of a shifting behavioral strategy orchestrated by pigment dispersing factor signaling to promote dispersal away from repeated aversive stimuli.

Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model.

PubMed

Ahmed, M M; Hoshino, H; Chikuma, T; Yamada, M; Kato, T

2004-01-01

It has been implicated that glia activation plays a critical role in the progression of Alzheimer's disease (AD). However, the precise mechanism of glia activation is not clearly understood yet. In our present studies, we confirmed our previous results where change the levels of neuropeptides and peptidases in ibotenic acid (IBO) infusion into the rat nucleus basalis magnocellularis, an animal model of AD. Furthermore, we extended our study to investigate a possible protection effect of co-administration on the changes of neuropeptides, and neuronal and glial cells in IBO-infused rat brain by memantine treatment. The levels of substance P and somatostatin were decreased in the striatum and frontal cortex 1 week after IBO infusion, and recovered to the control level by memantine treatment, indicating the involvement of neuropeptides in AD pathology. Furthermore, the immunohistochemical and enzymatic studies of GFAP and CD 11b, and peptidylarginine deiminase, markers of glia, in the striatum and frontal cortex showed the increase in IBO-treated rat brain as compared with controls, while co-administration of memantine and IBO no increase of astrocytes and microglia activation was observed. The present biochemical and immunohistochemical results suggest that glia activation might play an important role to the pathology of AD, and correlate with the changes of neuropeptide levels in AD brain that is recovered by memantine treatment.

Modulation of methamphetamine-induced nitric oxide production by neuropeptide Y in the murine striatum.

PubMed

Yarosh, Haley L; Angulo, Jesus A

2012-11-05

Methamphetamine (METH) is a potent stimulant that induces both acute and long-lasting neurochemical changes in the brain including neuronal cell loss. Our laboratory demonstrated that the neuropeptide substance P enhances the striatal METH-induced production of nitric oxide (NO). In order to better understand the role of the striatal neuropeptides on the METH-induced production of NO, we used agonists and antagonists of the NPY (Y1R and Y2R) receptors infused via intrastriatal microinjection followed by a bolus of METH (30 mg/kg, ip) and measured 3-NT immunofluorescence, an indirect index of NO production. One striatum received pharmacological agent while the contralateral striatum received aCSF and served as control. NPY receptor agonists dose dependently attenuated the METH-induced production of striatal 3-NT. Conversely, NPY receptor antagonists had the opposite effect. Moreover, METH induced the accumulation of cyclic GMP and activated caspase-3 in approximately 18% of striatal neurons, a phenomenon that was attenuated by pre-treatment with NPY2 receptor agonist. Lastly, METH increased the levels of striatal preproneuropeptide Y mRNA nearly five-fold 16 h after injection as determined by RT-PCR, suggesting increased utilization of the neuropeptide. In conclusion, NPY inhibits the METH-induced production of NO in striatal tissue. Consequently, production of this second messenger induces the accumulation of cyclic GMP and activated caspase-3 in some striatal neurons, an event that may precede the apoptosis of some striatal neurons. Copyright © 2012 Elsevier B.V. All rights reserved.

Macrophage Resistance to HIV-1 Infection Is Enhanced by the Neuropeptides VIP and PACAP

PubMed Central

Temerozo, Jairo R.; Joaquim, Rafael; Regis, Eduardo G.; Savino, Wilson; Bou-Habib, Dumith Chequer

2013-01-01

It is well established that host factors can modulate HIV-1 replication in macrophages, critical cells in the pathogenesis of HIV-1 infection due to their ability to continuously produce virus. The neuropeptides VIP and PACAP induce well-characterized effects on macrophages through binding to the G protein-coupled receptors VPAC1, VPAC2 and PAC1, but their influence on HIV-1 production by these cells has not been established. Here, we describe that VIP and PACAP reduce macrophage production of HIV-1, acting in a synergistic or additive manner to decrease viral growth. Using receptor antagonists, we detected that the HIV-1 inhibition promoted by VIP is dependent on its ligation to VPAC1/2, whereas PACAP decreases HIV-1 growth via activation of the VPAC1/2 and PAC1 receptors. Specific agonists of VPAC2 or PAC1 decrease macrophage production of HIV-1, whereas sole activation of VPAC1 enhances viral growth. However, the combination of specific agonists mimicking the receptor preference of the natural neuropeptides reproduces the ability of VIP and PACAP to increase macrophage resistance to HIV-1 replication. VIP and PACAP up-regulated macrophage secretion of the β-chemokines CCL3 and CCL5 and the cytokine IL-10, whose neutralization reversed the neuropeptide-induced inhibition of HIV-1 replication. Our results suggest that VIP and PACAP and the receptors VPAC2 and PAC1 could be used as targets for developing alternative therapeutic strategies for HIV-1 infection. PMID:23818986

Insect capa neuropeptides impact desiccation and cold tolerance

PubMed Central

Terhzaz, Selim; Teets, Nicholas M.; Cabrero, Pablo; Henderson, Louise; Ritchie, Michael G.; Nachman, Ronald J.; Dow, Julian A. T.; Denlinger, David L.; Davies, Shireen-A.

2015-01-01

The success of insects is linked to their impressive tolerance to environmental stress, but little is known about how such responses are mediated by the neuroendocrine system. Here we show that the capability (capa) neuropeptide gene is a desiccation- and cold stress-responsive gene in diverse dipteran species. Using targeted in vivo gene silencing, physiological manipulations, stress-tolerance assays, and rationally designed neuropeptide analogs, we demonstrate that the Drosophila melanogaster capa neuropeptide gene and its encoded peptides alter desiccation and cold tolerance. Knockdown of the capa gene increases desiccation tolerance but lengthens chill coma recovery time, and injection of capa peptide analogs can reverse both phenotypes. Immunohistochemical staining suggests that capa accumulates in the capa-expressing Va neurons during desiccation and nonlethal cold stress but is not released until recovery from each stress. Our results also suggest that regulation of cellular ion and water homeostasis mediated by capa peptide signaling in the insect Malpighian (renal) tubules is a key physiological mechanism during recovery from desiccation and cold stress. This work augments our understanding of how stress tolerance is mediated by neuroendocrine signaling and illustrates the use of rationally designed peptide analogs as agents for disrupting protective stress tolerance. PMID:25730885

Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1.

PubMed

Manorak, Wichayapha; Idahosa, Chizobam; Gupta, Kshitij; Roy, Saptarshi; Panettieri, Reynold; Ali, Hydar

2018-01-03

Hemokinin-1 (HK-1) is a novel neuropeptide produced by human bronchial cells and macrophages and causes contraction of human bronchi ex vivo. It is also generated by antigen/IgE-activated murine mast cells (MCs) and contributes to experimental chronic allergic airway inflammation via the activation of the neurokinin receptor-1 (NK-1R) expressed on murine MCs. We found elevated MC numbers in the lungs of individuals who died from asthma (asthma) when compared to lungs of individuals who died from other causes (non-asthma). Mas-related G Protein coupled receptor X2 (MRGPRX2) is a novel G-protein coupled receptor (GPCR) that is expressed predominantly on human MCs. We detected low level of MRGPRX2 in non-asthma lung MCs but its expression was significantly upregulated in asthma lung MCs. HK-1 caused degranulation in a human MC line (LAD2) and RBL-2H3 cells stably expressing MRGPRX2 and this response was resistant to inhibition by an NK-1R antagonist. However, knockdown of MRGPRX2 in LAD2 cells resulted in substantial inhibition of HK-1-induced degranulation. These findings suggest that while HK-1 contributes to the development of experimental asthma in mice via NK-1R on murine MCs the effect of this neuropeptide on human bronchoconstriction likely reflects the activation of MRGPRX2 on lung MCs. Thus, development of selective MRGPRX2 antagonists could serve as novel target for the modulation of asthma.

Evaluation of molecular chaperons Hsp72 and neuropeptide Y as characteristic markers of adaptogenic activity of plant extracts.

PubMed

Asea, Alexzander; Kaur, Punit; Panossian, Alexander; Wikman, Karl Georg

2013-11-15

We have previously demonstrated that ADAPT-232, a fixed combination of adaptogenic substances derived from Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract stimulated the expression and release of neuropeptide Y (NPY) and molecular chaperone Hsp72 from isolated human neurolgia cells. Both of these mediators of stress response are known to play an important role in regulation of neuroendocrine system and immune response. We further demonstrated that ADAPT-232 induced release of Hsp70 is mediated by NPY, suggesting an existence of NPY-mediated pathway of activation of Hsp72 release into the blood circulation system. The objective of this study was to determine whether this pathway is common for adaptogens and whether NPY and/or Hsp72 can be considered as necessary specific biomarkers for adaptogenic activity. The release of NPY and Hsp72 from neuroglia cells in response to treatment with various plant extracts (n=23) including selected validated adaptogens, partly validated adaptogens, claimed but negligibly validated adaptogens and some other plant extracts affecting neuroendocrine and immune systems but never considered as adaptogens was measured using high throughput ELISA techniques. We demonstrated that adaptogens, e.g. R. rosea, S. chinensis and E. senticosus stimulate both NPY and Hsp70 release from neuroblastoma cells, while tonics and stimulants have no significant effect on NPY in this in vitro test. In the groups of partly validated adaptogens the effect of Panax ginseng and Withania somnifera was not statistically significant both on NPY and Hsp70 release, while the activating effect of Bryonia alba and Rhaponticum cartamoides was significant only on Hsp70. In contrast, all tested non-adaptogens, such as antiinflammatoty plant extracts Matricaria recutita, Pelargonium sidoides, Hedera helix and Vitis vinifera significantly inhibit Hsp70 release and have no influence on NPY release from neuroblastoma

Comparison of the activation of somatostatin- and neuropeptide Y-containing neuronal populations of the rat amygdala following two different anxiogenic stressors

PubMed Central

Butler, Ryan K.; White, L. Casey; Frederick-Duus, Dani; Kaigler, Kris F.; Fadel, Jim R.; Wilson, Marlene A.

2012-01-01

Rats exposed to the odor of a predator or to the elevated plus maze express fear behaviors without a prior exposure to either stimulus. The expression of innate fear provides for an ideal model of anxiety which can aid in the elucidation of brain circuits involved in anxiety-related behaviors. The current experiments compared activation of neuropeptide-containing neuronal populations in the amygdala of rats exposed to either the elevated plus maze (EPM; 5 minutes) versus home cage controls, or predator ferret odor versus butyric acid, or no odor (30 minutes). Sections of the brains were prepared for dual-labeled immunohistochemistry and counts of c-Fos co-localized with somatostatin (SOM) or neuropeptide Y (NPY) were made in the basolateral (BLA), central (CEA), medial (MEA) nucleus of the amygdala. Ferret odor and butyric acid exposure significantly decreased the percentage of SOM–positive neurons also immunoreactive for c-Fos in the anterior BLA compared to controls, whereas EPM exposure yielded a significant increase in the activation of SOM-positive neurons versus home cage controls. In the CEA, ferret odor and butyric exposure significantly decreased the percentage of SOM-positive neurons also immunoreactive for c-Fos compared to no-odor controls whereas EPM exposure yielded no change versus controls. In the MEA, both ferret odor exposure and EPM exposure resulted in increased SOM co-localized with c-Fos compared to control groups whereas NPY co-localized with c-Fos occurred following ferret odor exposure, but not EPM exposure. These results indicate that phenotypically distinct neuronal populations of the amygdala are differentially activated following exposure to different anxiogenic stimuli. These studies further elucidate the fundamental neurocircuitry of anxiety and could possibly explain the differential behavioral effects of predator versus novelty-induced stress. PMID:22917777

A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder.

PubMed

Sayed, Sehrish; Van Dam, Nicholas T; Horn, Sarah R; Kautz, Marin M; Parides, Michael; Costi, Sara; Collins, Katherine A; Iacoviello, Brian; Iosifescu, Dan V; Mathé, Aleksander A; Southwick, Steven M; Feder, Adriana; Charney, Dennis S; Murrough, James W

2018-01-01

Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519). © The Author(s) 2017. Published by Oxford University Press on behalf of CINP.

Select Neuropeptides and their G-Protein Coupled Receptors in Caenorhabditis Elegans and Drosophila Melanogaster

PubMed Central

Bendena, William G.; Campbell, Jason; Zara, Lian; Tobe, Stephen S.; Chin-Sang, Ian D.

2012-01-01

The G-protein coupled receptor (GPCR) family is comprised of seven transmembrane domain proteins and play important roles in nerve transmission, locomotion, proliferation and development, sensory perception, metabolism, and neuromodulation. GPCR research has been targeted by drug developers as a consequence of the wide variety of critical physiological functions regulated by this protein family. Neuropeptide GPCRs are the least characterized of the GPCR family as genetic systems to characterize their functions have lagged behind GPCR gene discovery. Drosophila melanogaster and Caenorhabditis elegans are genetic model organisms that have proved useful in characterizing neuropeptide GPCRs. The strength of a genetic approach leads to an appreciation of the behavioral plasticity that can result from subtle alterations in GPCRs or regulatory proteins in the pathways that GPCRs control. Many of these invertebrate neuropeptides, GPCRs, and signaling pathway components serve as models for mammalian counterparts as they have conserved sequences and function. This review provides an overview of the methods to match neuropeptides to their cognate receptor and a state of the art account of neuropeptide GPCRs that have been characterized in D. melanogaster and C. elegans and the behaviors that have been uncovered through genetic manipulation. PMID:22908006

Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS).

PubMed

Birklein, Frank; Schmelz, Martin

2008-06-06

This review explains symptoms and nature of neuropeptide signaling and its importance for clinical symptoms of CRPS. Neurogenic inflammation regularly accompanies excitation of primary afferent nociceptors. It has two major components-plasma extravasation and vasodilatation. The most important mediators are the calcitonin gene-related peptide (CGRP) and substance P (SP). After peripheral trauma immune reaction (e.g. cytokines) and the attempts of the tissue to regenerate (e.g. growth factors) sensitize nociceptors and amplify neurogenic inflammation. This cascade of events has been demonstrated in rat models of CRPS. Clinical findings in these animals strongly resemble clinical findings in CRPS, and can be prevented by anti-cytokine and anti-neuropeptide treatment. In CRPS patients, there is meanwhile also plenty of evidence that neurogenic inflammation contributes to clinical presentation. Increased cytokine production was demonstrated, as well as facilitated neurogenic inflammation. Very recently even "non-inflammatory" signs of CRPS (hyperhidrosis, cold skin) have been linked to neuropeptide signaling. Surprisingly, there was even moderately increased neurogenic inflammation in unaffected body regions. This favors the possibility that CRPS patients share genetic similarities. The future search for genetic commonalities will help us to further unravel the "mystery" CRPS.

Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal

PubMed Central

Núnez, Cristina; Zelei, Edina; Polyák, Ágnes; Milanés, M. Victoria

2013-01-01

Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH), urocortin 2 (UCN2) and proopiomelanocortin (POMC) compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15–30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY) and arginine vasopressin (AVP) mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls. PMID:23805290

The neuropeptides CCK and NPY and the changing view of cell-to-cell communication in the taste bud.

PubMed

Herness, Scott; Zhao, Fang-Li

2009-07-14

The evolving view of the taste bud increasingly suggests that it operates as a complex signal processing unit. A number of neurotransmitters and neuropeptides and their corresponding receptors are now known to be expressed in subsets of taste receptor cells in the mammalian bud. These expression patterns set up hard-wired cell-to-cell communication pathways whose exact physiological roles still remain obscure. As occurs in other cellular systems, it is likely that neuropeptides are co-expressed with neurotransmitters and function as neuromodulators. Several neuropeptides have been identified in taste receptor cells including cholecystokinin (CCK), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and glucagon-like peptide 1 (GLP-1). Of these, CCK and NPY are the best studied. These two peptides are co-expressed in the same presynaptic cells; however, their postsynaptic actions are both divergent and antagonistic. CCK and its receptor, the CCK-1 subtype, are expressed in the same subset of taste receptor cells and the autocrine activation of these cells produces a number of excitatory physiological actions. Further, most of these cells are responsive to bitter stimuli. On the other hand, NPY and its receptor, the NPY-1 subtype, are expressed in different cells. NPY, acting in a paracrine fashion on NPY-1 receptors, results in inhibitory actions on the cell. Preliminary evidence suggests the NPY-1 receptor expressing cell co-expresses T1R3, a member of the T1R family of G-protein coupled receptors thought to be important in detection of sweet and umami stimuli. Thus the neuropeptide expressing cells co-express CCK, NPY, and CCK-1 receptor. Neuropeptides released from these cells during bitter stimulation may work in concert to both modulate the excitation of bitter-sensitive taste receptor cells while concurrently inhibiting sweet-sensitive cells. This modulatory process is similar to the phenomenon of lateral inhibition that occurs in other sensory systems.

Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides.

PubMed

Do Rego, Jean Luc; Seong, Jae Young; Burel, Delphine; Leprince, Jerôme; Luu-The, Van; Tsutsui, Kazuyoshi; Tonon, Marie-Christine; Pelletier, Georges; Vaudry, Hubert

2009-08-01

Neuroactive steroids synthesized in neuronal tissue, referred to as neurosteroids, are implicated in proliferation, differentiation, activity and survival of nerve cells. Neurosteroids are also involved in the control of a number of behavioral, neuroendocrine and metabolic processes such as regulation of food intake, locomotor activity, sexual activity, aggressiveness, anxiety, depression, body temperature and blood pressure. In this article, we summarize the current knowledge regarding the existence, neuroanatomical distribution and biological activity of the enzymes responsible for the biosynthesis of neurosteroids in the brain of vertebrates, and we review the neuronal mechanisms that control the activity of these enzymes. The observation that the activity of key steroidogenic enzymes is finely tuned by various neurotransmitters and neuropeptides strongly suggests that some of the central effects of these neuromodulators may be mediated via the regulation of neurosteroid production.

Neuropeptide gene expression in brain is differentially regulated by midbrain dopamine neurons.

PubMed

Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H

1990-01-01

In situ hybridization was used to study the expression of prepro-neuropeptide Y (NPY), preprosomatostatin (SOM), preprotachykinin (PPT) and preprocholecystokinin (CCK) mRNA in caudate-putamen and frontoparietal cortex of rat brain with unilateral lesion of midbrain dopamine neurons. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a dopamine deafferentation, the numerical density of both NPY and SOM mRNA producing neurons almost doubled in the lesioned caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to suppress expression of these two neuropeptide genes leading to an activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons when the level of dopamine is decreased. In the fronto-parietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. Thus, in the absence of dopamine about half of the NPY positive neurons disappeared. However, for SOM the number of positive neurons did not change, but rather most positive neurons appeared to have down-regulated their SOM mRNA expression. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions.

Functional characterization of a second pedal peptide/orcokinin‐type neuropeptide signaling system in the starfish Asterias rubens

PubMed Central

Lin, Ming; Egertová, Michaela; Zampronio, Cleidiane G.; Jones, Alexandra M.

2017-01-01

Abstract Molluscan pedal peptides (PPs) and arthropod orcokinins (OKs) are prototypes of a family of neuropeptides that have been identified in several phyla. Recently, starfish myorelaxant peptide (SMP) was identified as a PP/OK‐type neuropeptide in the starfish Patiria pectinifera (phylum Echinodermata). Furthermore, analysis of transcriptome sequence data from the starfish Asterias rubens revealed two PP/OK‐type precursors: an SMP‐type precursor (A. rubens PP‐like neuropeptide precursor 1; ArPPLNP1) and a second precursor (ArPPLNP2). We reported previously a detailed analysis of ArPPLNP1 expression in A. rubens and here we report the first functional characterization ArPPLNP2‐derived neuropeptides. Sequencing of a cDNA encoding ArPPLNP2 revealed that it comprises eleven related neuropeptides (ArPPLN2a‐k), the structures of several of which were confirmed using mass spectrometry. Analysis of the expression of ArPPLNP2 and neuropeptides derived from this precursor using mRNA in situ hybridization and immunohistochemistry revealed a widespread distribution, including expression in radial nerve cords, circumoral nerve ring, digestive system, tube feet and innervation of interossicular muscles. In vitro pharmacology revealed that the ArPPLNP2‐derived neuropeptide ArPPLN2h has no effect on the contractility of tube feet or the body wall‐associated apical muscle, contrasting with the relaxing effect of ArPPLN1b (ArSMP) on these preparations. ArPPLN2h does, however, cause dose‐dependent relaxation of cardiac stomach preparations, with greater potency/efficacy than ArPPLN1b and with similar potency/efficacy to the SALMFamide neuropeptide S2. In conclusion, there are similarities in the expression patterns of ArPPLNP1 and ArPPLNP2 but our data also indicate specialization in the roles of neuropeptides derived from these two PP/OK‐type precursors in starfish. PMID:29218721

THE NEUROPEPTIDE BURSICON ACTS IN CUTICLE METABOLISM

USDA-ARS?s Scientific Manuscript database

Bursicon is a neuropeptide composed of two cysteine knot proteins, bursicon a (burs a) and bursicon b (burs b), responsible for cuticle tanning (melanization and sclerotization) and for wing expansion in newly-eclosed adult Drosophila melanogaster, and probably most insect species. Aside from formin...

Hyperthyroidism differentially regulates neuropeptide S system in the rat brain.

PubMed

González, Carmen R; Martínez de Morentin, Pablo B; Martínez-Sánchez, Noelia; Gómez-Díaz, Consuelo; Lage, Ricardo; Varela, Luis; Diéguez, Carlos; Nogueiras, Rubén; Castaño, Justo P; López, Miguel

2012-04-23

Thyroid hormones play an important role in the regulation of energy balance, sleep and emotional behaviors. Neuropeptide S (NPS) is a recently discovered neuropeptide, regulating feeding, sleep and anxiety. Here, we examined the effect of hyperthyroidism on the gene and protein expression of neuropeptide S and its receptor (NPS-R) in the hypothalamus, brainstem and amygdala of rats. Our results showed that the expression of NPS and NPS-R was differentially modulated by hyperthyroidism in the rat brain. NPS and NPS-R mRNA and protein levels were decreased in the hypothalamus of hyperthyroid rats. Conversely NPS-R expression was highly increased in the brainstem and NPS and NPS-R expression were unchanged in the amygdala of these rats. These data suggest that changes in anxiety and food intake patterns observed in hyperthyroidism could be associated with changes in the expression of NPS and NPS-R. Thus, the NPS/NPS-R system may be involved in several hyperthyroidism-associated comorbidities. Copyright © 2012 Elsevier B.V. All rights reserved.

Mimicking of Arginine by Functionalized N(ω)-Carbamoylated Arginine As a New Broadly Applicable Approach to Labeled Bioactive Peptides: High Affinity Angiotensin, Neuropeptide Y, Neuropeptide FF, and Neurotensin Receptor Ligands As Examples.

PubMed

Keller, Max; Kuhn, Kilian K; Einsiedel, Jürgen; Hübner, Harald; Biselli, Sabrina; Mollereau, Catherine; Wifling, David; Svobodová, Jaroslava; Bernhardt, Günther; Cabrele, Chiara; Vanderheyden, Patrick M L; Gmeiner, Peter; Buschauer, Armin

2016-03-10

Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an effective and commonly used approach to prepare molecular tools and diagnostic agents. Whereas lysine, cysteine, and N-terminal amino acids have been mostly used for peptide conjugation, we describe a new, widely applicable approach to peptide conjugation based on the nonclassical bioisosteric replacement of the guanidine group in arginine by a functionalized carbamoylguanidine moiety. Four arginine-containing peptide receptor ligands (angiotensin II, neurotensin(8-13), an analogue of the C-terminal pentapeptide of neuropeptide Y, and a neuropeptide FF analogue) were subject of this proof-of-concept study. The N(ω)-carbamoylated arginines, bearing spacers with a terminal amino group, were incorporated into the peptides by standard Fmoc solid phase peptide synthesis. The synthesized chemically stable peptide derivatives showed high receptor affinities with Ki values in the low nanomolar range, even when bulky fluorophores had been attached. Two new tritiated tracers for angiotensin and neurotensin receptors are described.

A C. elegans Thermosensory Circuit Regulates Longevity through crh-1/CREB-Dependent flp-6 Neuropeptide Signaling.

PubMed

Chen, Yen-Chih; Chen, Hung-Jhen; Tseng, Wei-Chin; Hsu, Jiun-Min; Huang, Tzu-Ting; Chen, Chun-Hao; Pan, Chun-Liang

2016-10-24

Sensory perception, including thermosensation, shapes longevity in diverse organisms, but longevity-modulating signals from the sensory neurons are largely obscure. Here we show that CRH-1/CREB activation by CMK-1/CaMKI in the AFD thermosensory neuron is a key mechanism that maintains lifespan at warm temperatures in C. elegans. In response to temperature rise and crh-1 activation, the AFD neurons produce and secrete the FMRFamide neuropeptide FLP-6. Both CRH-1 and FLP-6 are necessary and sufficient for longevity at warm temperatures. Our data suggest that FLP-6 targets the AIY interneurons and engages DAF-9 sterol hormone signaling. Moreover, we show that FLP-6 signaling downregulates ins-7/insulin-like peptide and several insulin pathway genes, whose activity compromises lifespan. Our work illustrates how temperature experience is integrated by the thermosensory circuit to generate neuropeptide signals that remodel insulin and sterol hormone signaling and reveals a neuronal-endocrine circuit driven by thermosensation to promote temperature-specific longevity. Copyright © 2016 Elsevier Inc. All rights reserved.

Kinetic study of the processing by dipeptidyl-peptidase IV/CD26 of neuropeptides involved in pancreatic insulin secretion.

PubMed

Lambeir, A M; Durinx, C; Proost, P; Van Damme, J; Scharpé, S; De Meester, I

2001-11-02

Dipeptidyl-peptidase IV (DPPIV/CD26) metabolizes neuropeptides regulating insulin secretion. We studied the in vitro steady-state kinetics of DPPIV/CD26-mediated truncation of vasoactive intestinal peptide (VIP), pituitary adenylyl cyclase-activating peptide (PACAP27 and PACAP38), gastrin-releasing peptide (GRP) and neuropeptide Y (NPY). DPPIV/CD26 sequentially cleaves off two dipeptides of VIP, PACAP27, PACAP38 and GRP. GRP situates between the best DPPIV/CD26 substrates reported, comparable to NPY. Surprisingly, the C-terminal extension of PACAP38, distant from the scissile bond, improves both PACAP38 binding and turnover. Therefore, residues remote from the scissile bond can modulate DPPIV/CD26 substrate selectivity as well as residues flanking it.

Neuropeptide imaging on an LTQ with vMALDI source: The complete `all-in-one' peptidome analysis

NASA Astrophysics Data System (ADS)

Verhaert, Peter D.; Conaway, Maria C. Prieto; Pekar, Tonya M.; Miller, Ken

2007-02-01

Direct tissue imaging was performed on dissected insect tissue using a MALDI ion trap to visualize endogenous neuropeptides. Coupling tissue imaging to tandem MSn allows for the identification of previously known species and the ability to identify new ones by de novo sequencing, as searchable databases for insects are sparse. Direct tissue imaging is an attractive technique for the study of neuropeptides as minimal sample preparation is required prior to mass spectrometry. We successfully identified neuropeptides present in the corpora cardiaca and allata of Acheta domesticus (the house cricket). Diagnostic fragments at low m/z were used to distinguish between lipids and neuropeptides. The distribution of peptides appears to be more differentially localized than that of phospholipids, which seem to be more evenly distributed within the tissue.

Functional characterization of a second pedal peptide/orcokinin-type neuropeptide signaling system in the starfish Asterias rubens.

PubMed

Lin, Ming; Egertová, Michaela; Zampronio, Cleidiane G; Jones, Alexandra M; Elphick, Maurice R

2018-04-01

Molluscan pedal peptides (PPs) and arthropod orcokinins (OKs) are prototypes of a family of neuropeptides that have been identified in several phyla. Recently, starfish myorelaxant peptide (SMP) was identified as a PP/OK-type neuropeptide in the starfish Patiria pectinifera (phylum Echinodermata). Furthermore, analysis of transcriptome sequence data from the starfish Asterias rubens revealed two PP/OK-type precursors: an SMP-type precursor (A. rubens PP-like neuropeptide precursor 1; ArPPLNP1) and a second precursor (ArPPLNP2). We reported previously a detailed analysis of ArPPLNP1 expression in A. rubens and here we report the first functional characterization ArPPLNP2-derived neuropeptides. Sequencing of a cDNA encoding ArPPLNP2 revealed that it comprises eleven related neuropeptides (ArPPLN2a-k), the structures of several of which were confirmed using mass spectrometry. Analysis of the expression of ArPPLNP2 and neuropeptides derived from this precursor using mRNA in situ hybridization and immunohistochemistry revealed a widespread distribution, including expression in radial nerve cords, circumoral nerve ring, digestive system, tube feet and innervation of interossicular muscles. In vitro pharmacology revealed that the ArPPLNP2-derived neuropeptide ArPPLN2h has no effect on the contractility of tube feet or the body wall-associated apical muscle, contrasting with the relaxing effect of ArPPLN1b (ArSMP) on these preparations. ArPPLN2h does, however, cause dose-dependent relaxation of cardiac stomach preparations, with greater potency/efficacy than ArPPLN1b and with similar potency/efficacy to the SALMFamide neuropeptide S2. In conclusion, there are similarities in the expression patterns of ArPPLNP1 and ArPPLNP2 but our data also indicate specialization in the roles of neuropeptides derived from these two PP/OK-type precursors in starfish. © 2017 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Non-monoaminergic targets for the development of antidepressants: focus on neuropeptides.

PubMed

Catena-Dell'Osso, Mario; Fagiolini, Andrea; Marazziti, Donatella; Baroni, Stefano; Bellantuono, Cesario

2013-01-01

In the last decades, no significant paradigm shifts in the psychopharmacology of major depressive disorder (MDD) have occurred. In fact, after the serendipitous discovery of the first antidepressant, the poor understanding of the pathophysiology of the illness has deeply limited the development of novel antidepressant agents. Although the discovery of the selective serotonin reuptake inhibitors and the dual-acting serotonin/norepinephrine reuptake inhibitors allowed to improve the treatment of MDD, there are still important unmet clinical needs, as the long latency of antidepressant action, the presence of relevant side effects and the lack of efficacy. In fact, even though the available antidepressants have consistently improved the prognosis of the disorder, the pharmacological treatment of MDD is far from being satisfactory and the disorder remains one of the major causes of morbidity and disability worldwide. Recently, besides the classical research involving the monoamines, other non-monoaminergic molecular mechanisms have been explored in search of new antidepressants. Amongst them, the investigation of the central neuropeptides, including substance P, corticotropin-releasing factor, neuropeptide Y, vasopressin and oxytocin, galanin and melanin-concentrating hormone, is increasingly attracting the attention of researchers worldwide. A number of novel compounds acting on neuropeptide receptors have been developed and tested in both animals and humans with different results. In this review, we provided a synthetic overview of the main neuropeptides, going through biochemical and molecular aspects up to preclinical and clinical evidence which link these molecules to the presence of MDD.

Degradation of airway neuropeptides by human lung tryptase.

PubMed

Tam, E K; Caughey, G H

1990-07-01

Several lines of evidence suggest a possible role for mast cell proteases in modulating the biologic effects of neuropeptides. To explore the potential of such interactions in human airway, we examined the activity of human tryptase, the major secretory protease of human lung mast cells, against several neuropeptides with proposed regulatory functions in human airway. Using highly purified tryptase obtained from extracts of human lung, we determined the sites and rats of hydrolysis of vasoactive intestinal peptide (VIP), peptide histidine-methionine (PHM), calcitonin gene-related peptide (CGRP), and the tachykinins substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). Tryptase hydrolyzes VIP rapidly at several sites (Arg12, Arg14, Lys20, and Lys21) with an overall kcat/Km of 1.5 x 10(5) M-1 s-1 and hydrolyzes PHM primarily at a single site (Lys20) with a kcat/Km of 1.9 x 10(4) M-1 s-1. Tryptase also rapidly hydrolyzes CGRP at two sites (Arg18 and Lys24) with a kcat/Km of 2.7 x 10(5) M-1 s-1. The tachykinins are not hydrolyzed by tryptase. These observations raise the possibility that tryptase-mediated degradation of the bronchodilators VIP and PHM combined with exaggerated mast cell release of tryptase may contribute to the increase in bronchial responsiveness and the decrease in immunoreactive VIP in airway nerves associated with asthma. The favorable rates of hydrolysis of CGRP suggest that tryptase may also terminate the effects of CGRP on bronchial and vascular smooth muscle tone and permeability.

The neuropeptide bursicon acts in cuticle metabolism

USDA-ARS?s Scientific Manuscript database

Bursicon is a heterodimeric neuropeptide formed of bursicon a (burs a) and bursicon B (burs B) that controls cuticle tanning and wing expansion in insects. Burs a-a and burs B-B homodimers are also formed; they act via an unknown receptor to induce expression of prophylactic immune and stress genes ...

Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis

NASA Astrophysics Data System (ADS)

Davis, Shaun M.; Thomas, Amanda L.; Nomie, Krystle J.; Huang, Longwen; Dierick, Herman A.

2014-02-01

Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour.

Expression of Neuropeptides and Cytokines in a Rabbit Model of Diabetic Neuroischemic Wound-Healing

PubMed Central

Nabzdyk, Leena Pradhan; Kuchibhotla, Sarada; Guthrie, Patrick; Chun, Maggie; Auster, Michael E; Nabzdyk, Christoph; Deso, Steven; Andersen, Nicholas; LoGerfo, Frank W.; Veves, Aristidis

2013-01-01

Objective The present study is designed to understand the contribution of peripheral vascular disease and peripheral neuropathy to the wound-healing impairment associated with diabetes. Using a rabbit model of diabetic neuroischemic wound-healing we investigated rate of healing, leukocyte infiltration and expression of cytokines, Interleukin (IL)-8 and IL-6, and, neuropeptides, Substance P (SP) and Neuropeptide Y (NPY). Design of study Diabetes was induced in White New Zealand rabbits by administering alloxan while control rabbits received saline. Ten days later animals in both groups underwent surgery. One ear served as a sham and the other was made ischemic (ligation of central+rostral arteries), or neuroischemic (ischemia+ resection of central+rostral nerves). Four, 6mm punch biopsy wounds were created in both ears and wound-healing was followed for ten days using computerized planimetry. Results Non-diabetic sham and ischemic wounds healed significantly more rapidly than diabetic sham and ischemic wounds. Healing was slowest in neuroischemic wounds, irrespective of diabetic status. A high M1/M2 macrophage ratio and a high pro-inflammatory cytokine expression, both indicators of chronic-proinflammatory state, and low neuropeptide expression were seen in pre-injury diabetic skin. Post-injury, in diabetic wounds M1/M2 ratio remained high, the reactive increase in cytokine expression was low and neuropeptide expression was further decreased in neuroischemic wounds. Conclusion This rabbit model illustrates how a combination of a high M1/M2 ratio, a failure to mount post-injury cytokine response as well as a diminished neuropeptide expression contribute to wound-healing impairment in diabetes. The addition of neuropathy to ischemia leads to equivalently severe impaired wound-healing irrespective of diabetes status, suggesting that in the presence of ischemia, loss of neuropeptide function contributes to the impaired healing associated with diabetes. PMID:23755976

Asymmetric localization of natural antisense RNA of neuropeptide sensorin in Aplysia sensory neurons during aging and activity.

PubMed

Kadakkuzha, Beena M; Liu, Xin-An; Narvaez, Maria; Kaye, Alexandra; Akhmedov, Komolitdin; Puthanveettil, Sathyanarayanan V

2014-01-01

Despite the advances in our understanding of transcriptome, regulation and function of its non-coding components continue to be poorly understood. Here we searched for natural antisense transcript for sensorin (NAT-SRN), a neuropeptide expressed in the presynaptic sensory neurons of gill-withdrawal reflex of the marine snail Aplysia californica. Sensorin (SRN) has a key role in learning and long-term memory storage in Aplysia. We have now identified NAT-SRN in the central nervous system (CNS) and have confirmed its expression by northern blotting and fluorescent RNA in situ hybridization. Quantitative analysis of NAT-SRN in micro-dissected cell bodies and processes of sensory neurons suggest that NAT-SRN is present in the distal neuronal processes along with sense transcripts. Importantly, aging is associated with reduction in levels of NAT-SRN in sensory neuron processes. Furthermore, we find that forskolin, an activator of CREB signaling, differentially alters the distribution of SRN and NAT-SRN. These studies reveal novel insights into physiological regulation of natural antisense RNAs.

MICELLAR NANOMEDICINE OF HUMAN NEUROPEPTIDE Y

PubMed Central

Kuzmis, Antonina; Lim, Sok Bee; Desai, Esha; Jeon, Eunjung; Lee, Bao-Shiang; Rubinstein, Israel; Önyüksel, Hayat

2011-01-01

Human neuropeptide Y (NPY) is an important biologics that regulates multitude of physiological functions and could be amenable to therapeutic manipulations in certain disease states. However, rapid (minutes) enzymatic degradation and inactivation of NPY precludes its development as a drug. Accordingly, we determined whether self-association of NPY with biocompatible and biodegradable sterically stabilized phospholipid micelles (SSM) improves its stability and bioactivity. We found that in saline NPY spontaneously aggregates whereas in the presence of SSM it self-associates with the micelles as monomers. Three NPY molecules self-associate with one SSM at saturation. This process stabilizes the peptide in α-helix conformation, abrogates its degradation by dipeptidyl peptidase-4 and potentiates NPY-induced inhibition of cAMP elaboration in SK-N-MC cells. Collectively, these data indicate that self-association of NPY with SSM stabilizes and protects the peptide in active monomeric conformation, thereby amplifying its bioactivity in vitro. We propose further development of NPY in SSM as a novel, long-acting nanomedicine. PMID:21272667

A neuropeptide-mediated stretch response links muscle contraction to changes in neurotransmitter release

PubMed Central

Hu, Zhitao; Pym, Edward C.G.; Babu, Kavita; Vashlishan Murray, Amy B.; Kaplan, Joshua M.

2011-01-01

Although C. elegans has been utilized extensively to study synapse formation and function, relatively little is known about synaptic plasticity in C. elegans. We show that a brief treatment with the cholinesterase inhibitor aldicarb induces a form of presynaptic potentiation whereby ACh release at neuromuscular junctions (NMJs) is doubled. Aldicarb-induced potentiation was eliminated by mutations that block processing of pro-neuropeptides, by mutations inactivating a single pro-neuropeptide (NLP-12), and by those inactivating an NLP-12 receptor (CKR-2). NLP-12 expression is limited to a single stretch-activated neuron, DVA. Analysis of a YFP-tagged NLP-12 suggests that aldicarb stimulates DVA secretion of NLP-12. Mutations disrupting the DVA mechanoreceptor (TRP-4) decreased aldicarb-induced NLP-12 secretion and blocked aldicarb-induced synaptic potentiation. Mutants lacking NLP-12 or CKR-2 have decreased locomotion rates. Collectively, these results suggest that NLP-12 mediates a mechanosensory feedback loop that couples muscle contraction to changes in presynaptic release, thereby providing a mechanism for proprioceptive control of locomotion. PMID:21745640

Hyperphagia of hyperthyroidism: is neuropeptide Y involved?

PubMed

Pétervári, Erika; Balaskó, Márta; Jech-Mihálffy, Andrea; Székely, Miklós

2005-11-01

The possible role of neuropeptide Y (NPY) was studied in rats with hypermetabolism and hyperphagia induced by thyroxine (50-100-200 microg/day s.c. for 3-4 weeks). Both metabolic rate and body temperature increased quickly with thyroxine treatment, while hyperphagia started to develop only after 2 weeks of treatment. The weight gain rate progressively decreased or stopped. The NPY-induced hyperphagia was not altered significantly during thyroxine treatment (in severe thyrotoxicosis it was rather suppressed); the fasting-induced hyperphagia was smaller than in controls following 1 week of treatment, and it became enhanced only after 3 weeks, when the deficit in body weight indicated a certain level of starvation already prior to the food deprivation. The NPY-antagonist D-Tyr27,36,D-Thr32-NPY27,36 suppressed this fasting-induced hyperphagia, suggesting that endogenous NPY is involved in this late phase. In conclusion, hyperthyroidism per se does not increase the NPY activity, instead the quickly developing hyperthermia may inhibit the NPY actions; NPY may, however, be activated by a concurrent hypermetabolism-induced starvation.

Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α.

PubMed

Keane, Fiona M; Nadvi, Naveed A; Yao, Tsun-Wen; Gorrell, Mark D

2011-04-01

Fibroblast activation protein-α (FAP) is a cell surface-expressed and soluble enzyme of the prolyl oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4). FAP is not generally expressed in normal adult tissues, but is found at high levels in activated myofibroblasts and hepatic stellate cells in fibrosis and in stromal fibroblasts of epithelial tumours. FAP possesses a rare catalytic activity, hydrolysis of the post-proline bond two or more residues from the N-terminus of target substrates. α(2)-antiplasmin is an important physiological substrate of FAP endopeptidase activity. This study reports the first natural substrates of FAP dipeptidyl peptidase activity. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY were the most efficiently hydrolysed substrates and the first hormone substrates of FAP to be identified. In addition, FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are efficient DPP4 substrates. FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4. This novel identification of FAP substrates furthers our understanding of this unique protease by indicating potential roles in cardiac function and neurobiology. © 2011 The Authors Journal compilation © 2011 FEBS.

Peptidomics of Cpefat/fat mouse brain regions: Implications for neuropeptide processing

PubMed Central

Zhang, Xin; Che, Fa-Yun; Berezniuk, Iryna; Sonmez, Kemal; Toll, Lawrence; Fricker, Lloyd D.

2009-01-01

SUMMARY Quantitative peptidomics was used to compare levels of peptides in wild type and Cpefat/fat mice, which lack carboxypeptidase E (CPE) activity due to a point mutation. Six different brain regions were analyzed: amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, and thalamus. Altogether, 111 neuropeptides or other peptides derived from secretory pathway proteins were identified in wild type mouse brain extracts by tandem mass spectrometry, and another 47 peptides were tentatively identified based on mass and other criteria. Most secretory pathway peptides were much lower in Cpefat/fat mouse brain, relative to wild type mouse brain, indicating that CPE plays a major role in their biosynthesis. Other peptides were only partially reduced in the Cpefat/fat mice, indicating that another enzyme (presumably carboxypeptidase D) contributes to their biosynthesis. Approximately 10% of the secretory pathway peptides were present in the Cpefat/fat mouse brain at levels similar to those in wild type mouse brain. Many peptides were greatly elevated in the Cpefat/fat mice; these peptide processing intermediates with C-terminal Lys and/or Arg were generally not detectable in wild type mice. Taken together, these results indicate that CPE contributes, either directly or indirectly, to the production of the majority of neuropeptides. PMID:19014391

Two neuropeptides colocalized in a command-like neuron use distinct mechanisms to enhance its fast synaptic connection.

PubMed

Koh, H Y; Vilim, F S; Jing, J; Weiss, K R

2003-09-01

In many neurons more than one peptide is colocalized with a classical neurotransmitter. The functional consequence of such an arrangement has been rarely investigated. Here, within the feeding circuit of Aplysia, we investigate at a single synapse the actions of two modulatory neuropeptides that are present in a cholinergic interneuron. In combination with previous work, our study shows that the command-like neuron for feeding, CBI-2, contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that high-frequency prestimulation or repeated stimulation of CBI-2 increases the size of CBI-2 to B61/62 excitatory postsynaptic potentials (EPSPs) and shortens the latency of firing of neuron B61/62 in response to CBI-2 stimulation. We find that both FCAP and CP2 mimic these two effects. The variance method of quantal analysis indicates that FCAP increases the calculated quantal size (q) and CP2 increases the calculated quantal content (m) of EPSPs. Since the PSP amplitude represents the product of q and m, the joint action of the two peptides is expected to be cooperative. This observation suggests a possible functional implication for multiple neuropeptides colocalized with a classical neurotransmitter in one neuron.

Members of the neuropeptide transcriptional network in Helicoverpa armigera and their expression in response to light stress.

PubMed

Wang, Lijun; Liu, Xinhui; Liu, Zhengxing; Wang, Xiaoping; Lei, Chaoliang; Zhu, Fen

2018-05-19

Neuropeptides and peptide hormones play central roles in the regulation of various types of insect physiology and behavior. Artificial light at night, a form of environmental stress, has recently been regarded as a source of light stress on nocturnal insects. Because related genomic information is not available, molecular biological studies on the response of neuropeptides in nocturnal insects to light stress are limited. Based on the de novo sequencing of the Helicoverpa armigera head transcriptome, we obtained 124,960 unigenes. Of these, the number of unigenes annotated as neuropeptides and peptide hormones, neurotransmitter precursor processing enzymes, and neurotransmitter receptors were 34, 17, and 58, respectively. Under light stress, there were sex-specific differences in gene expression measured by qRT-PCR. The IMFamide, leucokinin and sNPF genes were differentially expressed at the mRNA level in males but not in females in response to light stress. The results provide new insights on the diversity of the neuropeptide transcriptional network of H. armigera. In addition, some neuropeptides exhibited sex-specific differential expression in response to light stress. Taken collectively, these results not only expand the catalog of known insect neuropeptides but also provide a framework for future functional studies on the physiological roles they play in the light stress response behavior of nocturnal moths. Copyright © 2017. Published by Elsevier B.V.

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides.

PubMed

Yoshimura, Mitsuhiro; Uezono, Yasuhito; Ueta, Yoichi

2015-09-01

Anorexia, a loss of appetite for food, can be caused by various physiological and pathophysiological conditions. In this review, firstly, clinical aspects of anorexia nervosa are summarized in brief. Secondly, hypothalamic neuropeptides responsible for feeding regulation in each hypothalamic nucleus are discussed. Finally, three different types of anorexigenic animal models; dehydration-induced anorexia, cisplatin-induced anorexia and cancer anorexia-cachexia, are introduced. In conclusion, hypothalamic neuropeptides may give us novel insight to understand and find effective therapeutics strategy essential for various kinds of anorexia.

Transcriptomic Analysis of Neuropeptides and Peptide Hormones in the Barnacle Balanus amphitrite: Evidence of Roles in Larval Settlement

PubMed Central

Yan, Xing-Cheng; Chen, Zhang-Fan; Sun, Jin; Matsumura, Kiyotaka; Wu, Rudolf S. S.; Qian, Pei-Yuan

2012-01-01

The barnacle Balanus amphitrite is a globally distributed marine crustacean and has been used as a model species for intertidal ecology and biofouling studies. Its life cycle consists of seven planktonic larval stages followed by a sessile juvenile/adult stage. The transitional processes between larval stages and juveniles are crucial for barnacle development and recruitment. Although some studies have been conducted on the neuroanatomy and neuroactive substances of the barnacle, a comprehensive understanding of neuropeptides and peptide hormones remains lacking. To better characterize barnacle neuropeptidome and its potential roles in larval settlement, an in silico identification of putative transcripts encoding neuropeptides/peptide hormones was performed, based on transcriptome of the barnacle B. amphitrite that has been recently sequenced. Potential cleavage sites andstructure of mature peptides were predicted through homology search of known arthropod peptides. In total, 16 neuropeptide families/subfamilies were predicted from the barnacle transcriptome, and 14 of them were confirmed as genuine neuropeptides by Rapid Amplification of cDNA Ends. Analysis of peptide precursor structures and mature sequences showed that some neuropeptides of B. amphitrite are novel isoforms and shared similar characteristics with their homologs from insects. The expression profiling of predicted neuropeptide genes revealed that pigment dispersing hormone, SIFamide, calcitonin, and B-type allatostatin had the highest expression level in cypris stage, while tachykinin-related peptide was down regulated in both cyprids and juveniles. Furthermore, an inhibitor of proprotein convertase related to peptide maturation effectively delayed larval metamorphosis. Combination of real-time PCR results and bioassay indicated that certain neuropeptides may play an important role in cypris settlement. Overall, new insight into neuropeptides/peptide hormones characterized in this study shall

The Role of Neuropeptides in Persistent Virus Infections of the Central Nervous System

DTIC Science & Technology

1990-05-10

5000 61153N RR04108 441f722 11. TITLE (include Security Classification) (U) The role of neuropeptides in persistent virus infections of the central...identify by block number) FIELD GROUP SUB-GROUP opioids, lymphocytes, infections , nervous system, virus, immunity, neuropeptides 19 ABSTRACT (Continue on...endorphin, 24 h after reconstitution of nude mice with splenocytes and 24 h prior to infection with virus, re- sulted in 74% survival; and 39% of the

Neuropeptide-Y both Improves and Impairs Delayed Matching-to-Sample Performance in Rats

DTIC Science & Technology

1991-01-01

Neuropeptide Y distribution in the 422 THOMAS AND AHLERS rat brain. Science 221:877-879; 1983. of animal learning. In: Roitblat , H. L.; Bever, T. G.; Terrace, H...Sources of proactive interference in memory. Hillsdale, NJ: Erlbaum; 1976. animal memory. J. Exp. Psychol. (Anim. Behav.) 1456-70; 1988. 32. Roitblat , H...memory processing by neuropeptide Y varies with brain 33. Roitblat , H. L., Scopatz, R. A. Sequential effects in pigeons de- injection site. Brain Res

Neuropeptides encoded by the genomes of the Akoya pearl oyster Pinctata fucata and Pacific oyster Crassostrea gigas: a bioinformatic and peptidomic survey.

PubMed

Stewart, Michael J; Favrel, Pascal; Rotgans, Bronwyn A; Wang, Tianfang; Zhao, Min; Sohail, Manzar; O'Connor, Wayne A; Elizur, Abigail; Henry, Joel; Cummins, Scott F

2014-10-02

Oysters impart significant socio-ecological benefits from primary production of food supply, to estuarine ecosystems via reduction of water column nutrients, plankton and seston biomass. Little though is known at the molecular level of what genes are responsible for how oysters reproduce, filter nutrients, survive stressful physiological events and form reef communities. Neuropeptides represent a diverse class of chemical messengers, instrumental in orchestrating these complex physiological events in other species. By a combination of in silico data mining and peptide analysis of ganglia, 74 putative neuropeptide genes were identified from genome and transcriptome databases of the Akoya pearl oyster, Pinctata fucata and the Pacific oyster, Crassostrea gigas, encoding precursors for over 300 predicted bioactive peptide products, including three newly identified neuropeptide precursors PFGx8amide, RxIamide and Wx3Yamide. Our findings also include a gene for the gonadotropin-releasing hormone (GnRH) and two egg-laying hormones (ELH) which were identified from both oysters. Multiple sequence alignments and phylogenetic analysis supports similar global organization of these mature peptides. Computer-based peptide modeling of the molecular tertiary structures of ELH highlights the structural homologies within ELH family, which may facilitate ELH activity leading to the release of gametes. Our analysis demonstrates that oysters possess conserved molluscan neuropeptide domains and overall precursor organization whilst highlighting many previously unrecognized bivalve idiosyncrasies. This genomic analysis provides a solid foundation from which further studies aimed at the functional characterization of these molluscan neuropeptides can be conducted to further stimulate advances in understanding the ecology and cultivation of oysters.

Brain clock driven by neuropeptides and second messengers

NASA Astrophysics Data System (ADS)

Miro-Bueno, Jesus; Sosík, Petr

2014-09-01

The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles.

Brain clock driven by neuropeptides and second messengers.

PubMed

Miro-Bueno, Jesus; Sosík, Petr

2014-09-01

The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles.

Endogenous anti-inflammatory neuropeptides and pro-resolving lipid mediators: a new therapeutic approach for immune disorders

PubMed Central

Anderson, Per; Delgado, Mario

2008-01-01

Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of inflammatory and autoimmune diseases. Although much is known about the molecular basis of initiating signals and pro-inflammatory chemical mediators in inflammation, it has only recently become apparent that endogenous stop signals are critical at early checkpoints within the temporal events of inflammation. Some neuropeptides and lipid mediators that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance and/or inflammation resolution. Here we examine the latest research findings, which indicate that neuropeptides participate in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. On the other hand, we also focus on lipid mediators biosynthesized from ω-3 and ω-6 polyunsaturated fatty-acids in inflammatory exudates that promote the resolution phase of acute inflammation by regulating leucocyte influx to and efflux from local inflamed sites. Both anti-inflammatory neuropeptides and pro-resolving lipid mediators have shown therapeutic potential for a variety of inflammatory and autoimmune disorders and could be used as biotemplates for the development of novel pharmacologic agents. PMID:18554314

Interactions of Circadian Rhythmicity, Stress and Orexigenic Neuropeptide Systems: Implications for Food Intake Control.

PubMed

Blasiak, Anna; Gundlach, Andrew L; Hess, Grzegorz; Lewandowski, Marian H

2017-01-01

Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the "control" of the "master biological clock" reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements.

Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P.

PubMed Central

Jones, D. A.; Cummings, J.; Langdon, S. P.; Maclellan, A. J.; Higgins, T.; Rozengurt, E.; Smyth, J. F.

1996-01-01

Broad-spectrum neuropeptide growth factor antagonists, such as [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised and the structures of two major metabolites have been elucidated by amino acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated]-antagonist D (metabolite 1) and [des-Leu11]-antagonist D (metabolite 2) as the major metabolites. Biological characterisation of the metabolites demonstrated that these relatively minor changes in structure resulted in a loss of antagonist activity. These results provide some of the first structure-activity information on the factors that determine which neuropeptides these compounds inhibit and on the relative potency of that inhibition. PMID:8611370

Relationship between levels of neuropeptide Substance P in periodontal disease and chronic pain: a literature review.

PubMed

de Avila, Erica Dorigatti; de Molon, Rafael Scaf; de Godoi Gonçalves, Daniela Aparecida; Camparis, Cinara Maria

2014-05-01

The aim of the current review was to investigate the relationship between levels of neuropeptide Substance P in periodontal disease and chronic pain. Substance P is a neuropeptide that is directly related with pain. In periodontal disease, it is expressed during the inflammatory process, and is one of the factors responsible for bone resorption. Studies have shown that Substance P levels are highest in the gingival crevicular fluid from sites with active periodontal disease and bone loss. The persistence of these substances could be sufficient to stimulate neurogenic inflammation in susceptible tissues, and cause pain. The scientific literature shows that Substance P expressed during periodontal disease can be a risk factor for patients with systemic inflammatory pathologies, such as chronic arthritis or rheumatoid arthritis. Additional research is needed to confirm the participation of this substance in the origin of some types of chronic pain. © 2014 Wiley Publishing Asia Pty Ltd.

CD and 31P NMR studies of tachykinin and MSH neuropeptides in SDS and DPC micelles

NASA Astrophysics Data System (ADS)

Schneider, Sydney C.; Brown, Taylor C.; Gonzalez, Javier D.; Levonyak, Nicholas S.; Rush, Lydia A.; Cremeens, Matthew E.

2016-02-01

Secondary structural characteristics of substance P (SP), neurokinin A (NKA), neurokinin B (NKB), α-melanocyte stimulating hormone peptide (α-MSH), γ1-MSH, γ2-MSH, and melittin were evaluated with circular dichroism in phosphite buffer, DPC micelles, and SDS micelles. CD spectral properties of γ1-MSH and γ2-MSH as well as 31P NMR of DPC micelles with all the peptides are reported for the first time. Although, a trend in the neuropeptide/micelle CD data appears to show increased α-helix content for the tachykinin peptides (SP, NKA, NKB) and increased β-sheet content for the MSH peptides (α-MSH, γ1-MSH, γ2-MSH) with increasing peptide charge, the lack of perturbed 31P NMR signals for all neuropeptides could suggest that the reported antimicrobial activity of SP and α-MSH might not be related to a membrane disruption mode of action.

Central neuropeptide B administration activates stress hormone secretion and stimulates feeding in male rats.

PubMed

Samson, W K; Baker, J R; Samson, C K; Samson, H W; Taylor, M M

2004-10-01

Neuropeptide B (NPB) was identified to be an endogenous, peptide ligand for the orphan receptors GPR7 and GPR8. Because GPR7 is expressed in rat brain and, in particular, in the hypothalamus, we hypothesized that NPB might interact with neuroendocrine systems that control hormone release from the anterior pituitary gland. No significant effects of NPB were observed on the in vitro releases of prolactin, adrenocorticotropic hormone (ACTH) or growth hormone (GH) when log molar concentrations ranging from 1 pM to 100 nM NPB were incubated with dispersed anterior pituitary cells harvested from male rats. In addition NPB (100 nM) did not alter the concentration response stimulation of prolactin secretion by thyrotropin-releasing hormone, ACTH secretion by corticotropin-releasing factor (CRF) and GH secretion by GH-releasing hormone. However, NPB, when injected into the lateral cerebroventricle (i.c.v.) of conscious, unrestrained male rats, elevated prolactin and corticosterone, and lowered GH levels in circulation. The threshold dose for the effect on corticosterone and prolactin levels was 1.0 nmol, while that for the effect on GH release was 3.0 nmol NPB. Pretreatment with a polyclonal anti-CRF antiserum completely blocked the ability of NPB to stimulate ACTH release and significantly inhibited the effect of NPB on plasma corticosterone levels. NPB administration i.c.v. did not significantly alter plasma vasopressin and oxytocin levels in conscious rats. It did stimulate feeding (minimum effective dose 1.0 nmol) in sated animals in a manner similar to that of the other endogenous ligand for GPR7, neuropeptide W. We conclude that NPB can act in the brain to modulate neuroendocrine signals accessing the anterior pituitary gland, but does not itself act as a releasing or inhibiting factor in the gland, at least with regard to prolactin, ACTH and GH secretion.

Prenatal hypoxia leads to increased muscle sympathetic nerve activity, sympathetic hyperinnervation, premature blunting of neuropeptide Y signaling, and hypertension in adult life.

PubMed

Rook, William; Johnson, Christopher D; Coney, Andrew M; Marshall, Janice M

2014-12-01

Adverse conditions prenatally increase the risk of cardiovascular disease, including hypertension. Chronic hypoxia in utero (CHU) causes endothelial dysfunction, but whether sympathetic vasoconstrictor nerve functioning is altered is unknown. We, therefore, compared in male CHU and control (N) rats muscle sympathetic nerve activity, vascular sympathetic innervation density, and mechanisms of sympathetic vasoconstriction. In young (Y)-CHU and Y-N rats (≈3 months), baseline arterial blood pressure was similar. However, tonic muscle sympathetic nerve activity recorded focally from arterial vessels of spinotrapezius muscle had higher mean frequency in Y-CHU than in Y-N rats (0.56±0.075 versus 0.33±0.036 Hz), and the proportions of single units with high instantaneous frequencies (1-5 and 6-10 Hz) being greater in Y-CHU rats. Sympathetic innervation density of tibial arteries was ≈50% greater in Y-CHU than in Y-N rats. Increases in femoral vascular resistance evoked by sympathetic stimulation at low frequency (2 Hz for 2 minutes) and bursts at 20 Hz were substantially smaller in Y-CHU than in Y-N rats. In Y-N only, the neuropeptide Y Y1-receptor antagonist BIBP3226 attenuated these responses. By contrast, baseline arterial blood pressure was higher in middle-aged (M)-CHU than in M-N rats (≈9 months; 139±3 versus 126±3 mm Hg, respectively). BIBP3226 had no effect on femoral vascular resistance increases evoked by 2 Hz or 20 Hz bursts in M-N or M-CHU rats. These results indicate that fetal programming induced by prenatal hypoxia causes an increase in centrally generated muscle sympathetic nerve activity in youth and hypertension by middle age. This is associated with blunting of sympathetically evoked vasoconstriction and its neuropeptide Y component that may reflect premature vascular aging and contribute to increased risk of cardiovascular disease. © 2014 American Heart Association, Inc.

The Neuropeptides FLP-2 and PDF-1 Act in Concert To Arouse Caenorhabditis elegans Locomotion

PubMed Central

Chen, Didi; Taylor, Kelsey P.; Hall, Qi; Kaplan, Joshua M.

2016-01-01

During larval molts, Caenorhabditis elegans exhibits a sleep-like state (termed lethargus) that is characterized by the absence of feeding and profound locomotion quiescence. The rhythmic pattern of locomotion quiescence and arousal linked to the molting cycle is mediated by reciprocal changes in sensory responsiveness, whereby arousal is associated with increased responsiveness. Sensory neurons arouse locomotion via release of a neuropeptide (PDF-1) and glutamate. Here we identify a second arousing neuropeptide (FLP-2). We show that FLP-2 acts via an orexin-like receptor (FRPR-18), and that FLP-2 and PDF-1 secretion are regulated by reciprocal positive feedback. These results suggest that the aroused behavioral state is stabilized by positive feedback between two neuropeptides. PMID:27585848

All-Electronic Quantification of Neuropeptide-Receptor Interaction Using a Bias-Free Functionalized Graphene Microelectrode.

PubMed

Ping, Jinglei; Vishnubhotla, Ramya; Xi, Jin; Ducos, Pedro; Saven, Jeffery G; Liu, Renyu; Johnson, Alan T Charlie

2018-05-22

Opioid neuropeptides play a significant role in pain perception, appetite regulation, sleep, memory, and learning. Advances in understanding of opioid peptide physiology are held back by the lack of methodologies for real-time quantification of affinities and kinetics of the opioid neuropeptide-receptor interaction at levels typical of endogenous secretion (<50 pM) in biosolutions with physiological ionic strength. To address this challenge, we developed all-electronic opioid-neuropeptide biosensors based on graphene microelectrodes functionalized with a computationally redesigned water-soluble μ-opioid receptor. We used the functionalized microelectrode in a bias-free charge measurement configuration to measure the binding kinetics and equilibrium binding properties of the engineered receptor with [d-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin and β-endorphin at picomolar levels in real time.

Microwave irradiation increases recovery of neuropeptides from brain tissues.

PubMed

Theodorsson, E; Stenfors, C; Mathé, A A

1990-01-01

The effect of focused high energy microwave treatment (MW) on brain concentrations and molecular forms of substance P, neurokinin A, neuropeptide Y, neurotensin, galanin and calcitonin gene-related peptide was investigated. Groups of rats were treated as follows: 1) MW, storage for 60 min at 22 degrees C, 2) Decapitation, storage for 60 min at 22 degrees C. 3) Decapitation, storage for 60 min at 22 degrees C, MW treatment, 4) MW, decapitation, storage for 2 min at 22 degrees C and 5) Decapitation, storage for 2 min at 22 degrees C. Peptide concentrations were in all instances highest in the MW sacrificed groups. MW increased the concentration of intact peptides by rapid inhibition of peptidase activity and increase in peptide solubility/extractability.

Neuropeptide Y in phaeochromocytomas and ganglioneuroblastomas.

PubMed

Adrian, T E; Allen, J M; Terenghi, G; Bacarese-Hamilton, A J; Brown, M J; Polak, J M; Bloom, S R

1983-09-03

Tumour tissue from nineteen patients with phaeochromocytomas and nine with ganglioneuroblastomas contained large numbers of neuropeptide Y (NPY) producing cells and extracts of these tumours had very high concentrations of immunoreactive NPY. Plasma NPY concentrations were also raised, averaging 460 pmol/l in patients with tumours of the sympathetic chain and 55 pmol/l in healthy controls. Since plasma NPY is straightforward to measure and relatively stable, its estimation may prove helpful as a screening tests for phaeochromocytoma.

Neuropeptide F neurons modulate sugar reward during associative olfactory learning of Drosophila larvae.

PubMed

Rohwedder, Astrid; Selcho, Mareike; Chassot, Bérénice; Thum, Andreas S

2015-12-15

All organisms continuously have to adapt their behavior according to changes in the environment in order to survive. Experience-driven changes in behavior are usually mediated and maintained by modifications in signaling within defined brain circuits. Given the simplicity of the larval brain of Drosophila and its experimental accessibility on the genetic and behavioral level, we analyzed if Drosophila neuropeptide F (dNPF) neurons are involved in classical olfactory conditioning. dNPF is an ortholog of the mammalian neuropeptide Y, a highly conserved neuromodulator that stimulates food-seeking behavior. We provide a comprehensive anatomical analysis of the dNPF neurons on the single-cell level. We demonstrate that artificial activation of dNPF neurons inhibits appetitive olfactory learning by modulating the sugar reward signal during acquisition. No effect is detectable for the retrieval of an established appetitive olfactory memory. The modulatory effect is based on the joint action of three distinct cell types that, if tested on the single-cell level, inhibit and invert the conditioned behavior. Taken together, our work describes anatomically and functionally a new part of the sugar reinforcement signaling pathway for classical olfactory conditioning in Drosophila larvae. © 2015 Wiley Periodicals, Inc.

Transcriptome and Peptidome Characterisation of the Main Neuropeptides and Peptidic Hormones of a Euphausiid: The Ice Krill, Euphausia crystallorophias

PubMed Central

Toullec, Jean-Yves; Corre, Erwan; Bernay, Benoît; Thorne, Michael A. S.; Cascella, Kévin; Ollivaux, Céline; Henry, Joël; Clark, Melody S.

2013-01-01

Background The Ice krill, Euphausia crystallorophias is one of the species at the base of the Southern Ocean food chain. Given their significant contribution to the biomass of the Southern Ocean, it is vitally important to gain a better understanding of their physiology and, in particular, anticipate their responses to climate change effects in the warming seas around Antarctica. Methodology/Principal Findings Illumina sequencing was used to produce a transcriptome of the ice krill. Analysis of the assembled contigs via two different methods, produced 36 new pre-pro-peptides, coding for 61 neuropeptides or peptide hormones belonging to the following families: Allatostatins (A, B et C), Bursicon (α and β), Crustacean Hyperglycemic Hormones (CHH and MIH/VIHs), Crustacean Cardioactive Peptide (CCAP), Corazonin, Diuretic Hormones (DH), the Eclosion Hormone (EH), Neuroparsin, Neuropeptide F (NPF), small Neuropeptide F (sNPF), Pigment Dispersing Hormone (PDH), Red Pigment Concentrating Hormone (RPCH) and finally Tachykinin. LC/MS/MS proteomics was also carried out on eyestalk extracts, which are the major site of neuropeptide synthesis in decapod crustaceans. Results confirmed the presence of six neuropeptides and six precursor-related peptides previously identified in the transcriptome analyses. Conclusions This study represents the first comprehensive analysis of neuropeptide hormones in a Eucarida non-decapod Malacostraca, several of which are described for the first time in a non-decapod crustacean. Additionally, there is a potential expansion of PDH and Neuropeptide F family members, which may reflect certain life history traits such as circadian rhythms associated with diurnal migrations and also the confirmation via mass spectrometry of several novel pre-pro-peptides, of unknown function. Knowledge of these essential hormones provides a vital framework for understanding the physiological response of this key Southern Ocean species to climate change and provides

The Neuropeptides FLP-2 and PDF-1 Act in Concert To Arouse Caenorhabditis elegans Locomotion.

PubMed

Chen, Didi; Taylor, Kelsey P; Hall, Qi; Kaplan, Joshua M

2016-11-01

During larval molts, Caenorhabditis elegans exhibits a sleep-like state (termed lethargus) that is characterized by the absence of feeding and profound locomotion quiescence. The rhythmic pattern of locomotion quiescence and arousal linked to the molting cycle is mediated by reciprocal changes in sensory responsiveness, whereby arousal is associated with increased responsiveness. Sensory neurons arouse locomotion via release of a neuropeptide (PDF-1) and glutamate. Here we identify a second arousing neuropeptide (FLP-2). We show that FLP-2 acts via an orexin-like receptor (FRPR-18), and that FLP-2 and PDF-1 secretion are regulated by reciprocal positive feedback. These results suggest that the aroused behavioral state is stabilized by positive feedback between two neuropeptides. Copyright © 2016 by the Genetics Society of America.

Allatotropin: A pleiotropic neuropeptide that elicits mosquito immune responses

PubMed Central

Sánchez-Zavaleta, Minerva; Brito, Kevin; Herrera-Ortiz, Antonia; Ons, Sheila; Noriega, Fernando G.

2017-01-01

Allatotropins (AT) are neuropeptides with pleotropic functions on a variety of insect tissues. They affect processes such as juvenile hormone biosynthesis, cardiac rhythm, oviduct and hindgut contractions, nutrient absorption and circadian cycle. The present work provides experimental evidence that AT elicits immune responses in two important mosquito disease vectors, Anopheles albimanus and Aedes aegypti. Hemocytes and an immune-competent mosquito cell line responded to AT by showing strong morphological changes and increasing bacterial phagocytic activity. Phenoloxidase activity in hemolymph was also increased in Ae. aegypti mosquitoes treated with AT but not in An. albimanus, suggesting differences in the AT-dependent immune activation in the two species. In addition, two important insect immune markers, nitric oxide levels and expression of antimicrobial peptide genes, were increased in An. albimanus guts after AT treatment. AT conjugated to quantum dot nanocrystals (QDots) specifically labeled hemocytes in vivo in both mosquito species, implying molecular interactions between AT and hemocytes. The results of our studies suggest a new role for AT in the modulation of the immune response in mosquitoes. PMID:28426765

Allatotropin: A pleiotropic neuropeptide that elicits mosquito immune responses.

PubMed

Hernández-Martínez, Salvador; Sánchez-Zavaleta, Minerva; Brito, Kevin; Herrera-Ortiz, Antonia; Ons, Sheila; Noriega, Fernando G

2017-01-01

Allatotropins (AT) are neuropeptides with pleotropic functions on a variety of insect tissues. They affect processes such as juvenile hormone biosynthesis, cardiac rhythm, oviduct and hindgut contractions, nutrient absorption and circadian cycle. The present work provides experimental evidence that AT elicits immune responses in two important mosquito disease vectors, Anopheles albimanus and Aedes aegypti. Hemocytes and an immune-competent mosquito cell line responded to AT by showing strong morphological changes and increasing bacterial phagocytic activity. Phenoloxidase activity in hemolymph was also increased in Ae. aegypti mosquitoes treated with AT but not in An. albimanus, suggesting differences in the AT-dependent immune activation in the two species. In addition, two important insect immune markers, nitric oxide levels and expression of antimicrobial peptide genes, were increased in An. albimanus guts after AT treatment. AT conjugated to quantum dot nanocrystals (QDots) specifically labeled hemocytes in vivo in both mosquito species, implying molecular interactions between AT and hemocytes. The results of our studies suggest a new role for AT in the modulation of the immune response in mosquitoes.

Profound loss of neprilysin accompanied by decreased levels of neuropeptides and increased CRP in ulcerative colitis.

PubMed

Sargın, Zeynep Gök; Erin, Nuray; Tazegul, Gokhan; Elpek, Gülsüm Özlem; Yıldırım, Bülent

2017-01-01

Neprilysin (NEP, CD10) acts to limit excessive inflammation partly by hydrolyzing neuropeptides. Although deletion of NEP exacerbates intestinal inflammation in animal models, its role in ulcerative colitis (UC) is not well explored. Herein, we aimed to demonstrate changes in NEP and associated neuropeptides at the same time in colonic tissue. 72 patients with UC and 27 control patients were included. Patients' demographic data and laboratory findings, five biopsy samples from active colitis sites and five samples from uninvolved mucosa were collected. Substance P (SP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) were extracted from freshly frozen tissues and measured using ELISA. Levels of NEP expression were determined using immunohistochemistry and immunoreactivity scores were calculated. GEBOES grading system was also used. We demonstrated a profound loss (69.4%) of NEP expression in UC, whereas all healthy controls had NEP expression. Patients with UC had lower neuronal SP; however non-neuronal SP remained similar. UC patients had also lower neuronal and non-neuronal VIP levels. CGRP were low in general and no significant changes were observed. Additionally, CRP positive patients with UC had higher rates of NEP loss (80% vs 51.9%) and lower SP levels when compared with CRP negative patients with UC. Concurrent decreases in SP and VIP with profound loss of NEP expression observed in UC is likely to be one of the factors in pathogenesis. Further studies are required to define the role of neuropeptides and NEP in UC.

Profound loss of neprilysin accompanied by decreased levels of neuropeptides and increased CRP in ulcerative colitis

PubMed Central

Sargın, Zeynep Gök; Tazegul, Gokhan; Elpek, Gülsüm Özlem; Yıldırım, Bülent

2017-01-01

Neprilysin (NEP, CD10) acts to limit excessive inflammation partly by hydrolyzing neuropeptides. Although deletion of NEP exacerbates intestinal inflammation in animal models, its role in ulcerative colitis (UC) is not well explored. Herein, we aimed to demonstrate changes in NEP and associated neuropeptides at the same time in colonic tissue. 72 patients with UC and 27 control patients were included. Patients’ demographic data and laboratory findings, five biopsy samples from active colitis sites and five samples from uninvolved mucosa were collected. Substance P (SP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) were extracted from freshly frozen tissues and measured using ELISA. Levels of NEP expression were determined using immunohistochemistry and immunoreactivity scores were calculated. GEBOES grading system was also used. We demonstrated a profound loss (69.4%) of NEP expression in UC, whereas all healthy controls had NEP expression. Patients with UC had lower neuronal SP; however non-neuronal SP remained similar. UC patients had also lower neuronal and non-neuronal VIP levels. CGRP were low in general and no significant changes were observed. Additionally, CRP positive patients with UC had higher rates of NEP loss (80% vs 51.9%) and lower SP levels when compared with CRP negative patients with UC. Concurrent decreases in SP and VIP with profound loss of NEP expression observed in UC is likely to be one of the factors in pathogenesis. Further studies are required to define the role of neuropeptides and NEP in UC. PMID:29232715

Enduring Effects Of Traumatic Stress On Brain Neuropeptide Y (NPY) and Corticotropin-Releasing Factor (CRF) Systems: Molecular and Neuropharmacologic Studies

DTIC Science & Technology

2009-12-01

neuropeptide, corticotropin-releasing factor, neuropeptide Y, anxiety, depression, behavior, treatment , gene expression. 16. SECURITY CLASSIFICATION OF...preclinical evidence that neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) systems acutely modulate stress and dysphoria responses and 2...2.5 weeks after the final defeat (data not shown). Treatment with twice daily imipramine (i.p., 2.5 mg/kg) for 2.5 weeks, eliminated the effects of

Adeno-Associated Viral Vector-Induced Overexpression of Neuropeptide Y Y2 Receptors in the Hippocampus Suppresses Seizures

ERIC Educational Resources Information Center

Woldbye, David P. D.; Angehagen, Mikael; Gotzsche, Casper R.; Elbrond-Bek, Heidi; Sorensen, Andreas T.; Christiansen, Soren H.; Olesen, Mikkel V.; Nikitidou, Litsa; Hansen, Thomas v. O.; Kanter-Schlifke, Irene; Kokaia, Merab

2010-01-01

Gene therapy using recombinant adeno-associated viral vectors overexpressing neuropeptide Y in the hippocampus exerts seizure-suppressant effects in rodent epilepsy models and is currently considered for clinical application in patients with intractable mesial temporal lobe epilepsy. Seizure suppression by neuropeptide Y in the hippocampus is…

Neuropeptide Trefoil factor 3 improves learning and retention of novel object recognition memory in mice.

PubMed

Shi, Hai-Shui; Yin, Xi; Song, Li; Guo, Qing-Jun; Luo, Xiang-Heng

2012-02-01

Accumulating evidence has implicated neuropeptides in modulating recognition, learning and memory. However, to date, no study has investigated the effects of neuropeptide Trefoil factor 3 (TFF3) on the process of learning and memory. In the present study, we evaluated the acute effects of TFF3 administration (0.1 and 0.5mg/kg, i.p.) on the acquisition and retention of object recognition memory in mice. We found that TFF3 administration significantly enhanced both short-term and long-term memory during the retention test, conducted 90 min and 24h after training respectively. Remarkably, acute TFF3 administration transformed a learning event that would not normally result in long-term memory into an event retained for a long-term period and produced no effect on locomotor activity in mice. In conclusion, the present results provide an important role of TFF3 in improving object recognition memory and reserving it for a longer time, which suggests a potential therapeutic application for diseases with recognition and memory impairment. Copyright © 2011 Elsevier B.V. All rights reserved.

Glucokinase inhibitor glucosamine stimulates feeding and activates hypothalamic neuropeptide Y and orexin neurons.

PubMed

Zhou, Ligang; Yueh, Chen-Yu; Lam, Daniel D; Shaw, Jill; Osundiji, Mayowa; Garfield, Alastair S; Evans, Mark; Heisler, Lora K

2011-09-12

Maintaining glucose levels within the appropriate physiological range is necessary for survival. The identification of specific neuronal populations, within discreet brain regions, sensitive to changes in glucose concentration has led to the hypothesis of a central glucose-sensing system capable of directly modulating feeding behaviour. Glucokinase (GK) has been identified as a glucose-sensor responsible for detecting such changes both within the brain and the periphery. We previously reported that antagonism of centrally expressed GK by administration of glucosamine (GSN) was sufficient to induce protective glucoprivic feeding in rats. Here we examine a neurochemical mechanism underlying this effect and report that GSN stimulated food intake is highly correlated with the induction of the neuronal activation marker cFOS within two nuclei with a demonstrated role in central glucose sensing and appetite, the arcuate nucleus of the hypothalamus (ARC) and lateral hypothalamic area (LHA). Furthermore, GSN stimulated cFOS within the ARC was observed in orexigenic neurons expressing the endogenous melanocortin receptor antagonist agouti-related peptide (AgRP) and neuropeptide Y (NPY), but not those expressing the anorectic endogenous melanocortin receptor agonist alpha-melanocyte stimulating hormone (α-MSH). In the LHA, GSN stimulated cFOS was found within arousal and feeding associated orexin/hypocretin (ORX), but not orexigenic melanin-concentrating hormone (MCH) expressing neurons. Our data suggest that GK within these specific feeding and arousal related populations of AgRP/NPY and ORX neurons may play a modulatory role in the sensing of and appetitive response to hypoglycaemia. Copyright © 2011 Elsevier B.V. All rights reserved.

Targeting NPY, CRF/UCNs and NPS Neuropeptide Systems to Treat Alcohol Use Disorder (AUD).

PubMed

Rodriguez, Francisco D; Coveñas, Rafael

2017-01-01

The term Alcohol Use Disorder (AUD) incorporates different states of disease related to the recurrent use of alcohol and linked to the relevant impairment, disability and failure to perform major responsibilities in different realms. Many neurotransmitter systems are involved in the phases or states of alcoholism from reward mechanisms, associated to binge intoxication, to stress and anxiety linked to relapse and withdrawal. Some neuropeptides play a key function in the control of anxiety and stress, and establish a close relationship with the pathological mechanisms underlying alcohol addiction. Among them, Neuropeptide Y (NPY), Corticotropin-releasing factor (CRF)/Urocortins and Neuropeptide S (NPS) cross-talk, and are responsible for some of the maladaptation processes that the brain exhibits during the progression of the disease. In this study, we review the literature mainly focused on the participation of these neuropeptides in the pathophysiology of AUD, as well as on the use of antagonists designed to investigate signaling mechanisms initiated after ligand binding and their connection to biochemical adaptation events coupled to alcohol addiction. The possibility that these systems may serve as therapeutic objectives to mitigate or eliminate the harm that drinking ethanol generates, is also discussed. The peptide systems reviewed here, together with other neurotransmitter systems and their mutual relationships, are firm candidates to be targeted to treat AUD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Long-term treatment with haloperidol affects neuropeptide S and NPSR mRNA levels in the rat brain.

PubMed

Palasz, Artur; Rojczyk, Ewa; Golyszny, Milosz; Filipczyk, Lukasz; Worthington, John J; Wiaderkiewicz, Ryszard

2016-04-01

The brainstem-derived neuropeptide S (NPS) has a multidirectional regulatory activity, especially as a potent anxiolytic factor. Accumulating data suggests that neuroleptics affect peptidergic signalling in various brain structures. However, there is no information regarding the influence of haloperidol on NPS and NPS receptor (NPSR) expression. We assessed NPS and NPSR mRNA levels in brains of rats treated with haloperidol using quantitative real-time polymerase chain reaction. Chronic haloperidol treatment (4 weeks) led to a striking upregulation of NPS and NPSR expression in the rat brainstem. Conversely, the NPSR mRNA expression was decreased in the hippocampus and striatum. This stark increase of NPS in response to haloperidol treatment supports the hypothesis that this neuropeptide is involved in the dopamine-dependent anxiolytic actions of neuroleptics and possibly also in the pathophysiology of mental disorders. Furthermore, our findings underline the complex nature of potential interactions between dopamine receptors and brain peptidergic pathways, which has potential clinical applications.

The effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women

PubMed Central

Khoshdel, Abolfazl; Kheiri, Soleiman; Nasiri, Jafar; Tehran, Hoda Ahmari; Heidarian, Esfandiar

2014-01-01

Background: Many pregnant Muslim women choose to fast during Ramadan every year worldwide. This study aimed to examine the effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women and find whether fasting during pregnancy could have a negative effect on the health of mothers and fetuses. Methods: This cross-sectional study was conducted on 39 healthy volunteer fasting pregnant women. Serum leptin, neuropeptide Y, insulin levels, body mass index and weight were measured five times on 0, 7th, 14th and 28th days of Ramadan and on the 14th day post-Ramadan. The data were analyzed by SPSS software (version 11.5) using repeated measures ANOVA to find whether any changes occurred in the variables of interest during the study, and Pearson correlation coefficient was used to examine the relations among the variables. Results: A significant change in fasting blood sugar, neuropeptide Y and leptin was observed during the study (p< 0.05). Fasting blood sugar decreased significantly during Ramadan and increased after Ramadan, with the lowest value at the end of Ramadan. Neuropeptide Y increased both during Ramadan and two weeks after Ramadan. Also, leptin decreased significantly two weeks after Ramadan compared to the end of Ramadan. No significant change was observed in insulin level during the study (p>0.05). Conclusion: The result of this study revealed the important role of leptin and neuropeptide Y in the long term regulation of energy balance in pregnant women with chronic diurnal fasting, and it further revealed that Ramadan fasting did not significantly change the serum insulin level. PMID:25664293

Cerebrospinal fluid prohormone processing and neuropeptides stimulating feed intake of dairy cows during early lactation.

PubMed

Kuhla, Björn; Laeger, Thomas; Husi, Holger; Mullen, William

2015-02-06

After parturition, feed intake of dairy cows increases within the first weeks of lactation, but the molecular mechanisms stimulating or delaying the slope of increase are poorly understood. Some of the molecules controlling feed intake are neuropeptides that are synthesized as propeptides and subsequently processed before they bind to specific receptors in feeding centers of the brain. Cerebrospinal fluid surrounds most of the feed intake regulatory centers and contains numerous neuropeptides. In the present study, we used a proteomic approach to analyze the neuropeptide concentrations in cerebrospinal fluid taken from dairy cows between day -18 and -10, and between day +10 and +20 relative to parturition. We found 13 proteins which were only present in samples taken before parturition, 13 proteins which were only present in samples taken after parturition, and 25 proteins which were commonly present, before and after parturition. Among them, differences in pro-neuropeptide Y, proenkephalin-A, neuroendocrine convertase-2, neurosecretory protein VGF, chromogranin-A, and secretogranin-1 and -3 concentrations relative to parturition highlight propeptides and prohormone processings involved in the control of feed intake and energy homeostasis. Scaffold analysis further emphasized an increased tone of endogenous opioids associated with the postparturient increase of feed intake.

Differential insulin receptor substrate-1 (IRS1)-related modulation of neuropeptide Y and proopiomelanocortin expression in nondiabetic and diabetic IRS2-/- mice.

PubMed

Burgos-Ramos, Emma; González-Rodríguez, Agueda; Canelles, Sandra; Baquedano, Eva; Frago, Laura M; Revuelta-Cervantes, Jesús; Gómez-Ambrosi, Javier; Frühbeck, Gema; Chowen, Julie A; Argente, Jesús; Valverde, Angela M; Barrios, Vicente

2012-03-01

Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2(-/-)) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2(-/-) mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2(-/-) mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2(-/-). Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2(-/-) mice, with FOXO1 showing mainly nuclear localization in D IRS2(-/-) and cytoplasmic in ND IRS2(-/-) mice. D IRS2(-/-) mice exhibited higher hypothalamic inflammation markers than ND IRS2(-/-) mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes.

Involvement of neuropeptide Y Y1 receptors in the regulation of neuroendocrine corticotropin-releasing hormone neuronal activity.

PubMed

Dimitrov, Eugene L; DeJoseph, M Regina; Brownfield, Mark S; Urban, Janice H

2007-08-01

The neuroendocrine parvocellular CRH neurons in the paraventricular nucleus (PVN) of the hypothalamus are the main integrators of neural inputs that initiate hypothalamic-pituitary-adrenal (HPA) axis activation. Neuropeptide Y (NPY) expression is prominent within the PVN, and previous reports indicated that NPY stimulates CRH mRNA levels. The purpose of these studies was to examine the participation of NPY receptors in HPA axis activation and determine whether neuroendocrine CRH neurons express NPY receptor immunoreactivity. Infusion of 0.5 nmol NPY into the third ventricle increased plasma corticosterone levels in conscious rats, with the peak of hormone levels occurring 30 min after injection. This increase was prevented by pretreatment with the Y1 receptor antagonist BIBP3226. Immunohistochemistry showed that CRH-immunoreactive neurons coexpressed Y1 receptor immunoreactivity (Y1r-ir) in the PVN, and a majority of these neurons (88.8%) were neuroendocrine as determined by ip injections of FluoroGold. Bilateral infusion of the Y1/Y5 agonist, [leu(31)pro(34)]NPY (110 pmol), into the PVN increased c-Fos and phosphorylated cAMP response element-binding protein expression and elevated plasma corticosterone levels. Increased expression of c-Fos and phosphorylated cAMP response element-binding protein was observed in populations of CRH/Y1r-ir cells. The current findings present a comprehensive study of NPY Y1 receptor distribution and activation with respect to CRH neurons in the PVN. The expression of NPY Y1r-ir by neuroendocrine CRH cells suggests that alterations in NPY release and subsequent activation of NPY Y1 receptors plays an important role in the regulation of the HPA.

Gustatory stimuli representing different perceptual qualities elicit distinct patterns of neuropeptide secretion from taste buds.

PubMed

Geraedts, Maartje C P; Munger, Steven D

2013-04-24

Taste stimuli that evoke different perceptual qualities (e.g., sweet, umami, bitter, sour, salty) are detected by dedicated subpopulations of taste bud cells that use distinct combinations of sensory receptors and transduction molecules. Here, we report that taste stimuli also elicit unique patterns of neuropeptide secretion from taste buds that are correlated with those perceptual qualities. We measured tastant-dependent secretion of glucagon-like peptide-1 (GLP-1), glucagon, and neuropeptide Y (NPY) from circumvallate papillae of Tas1r3(+/+), Tas1r3(+/-) and Tas1r3 (-/-) mice. Isolated tongue epithelia were mounted in modified Ussing chambers, permitting apical stimulation of taste buds; secreted peptides were collected from the basal side and measured by specific ELISAs. Appetitive stimuli (sweet: glucose, sucralose; umami: monosodium glutamate; polysaccharide: Polycose) elicited GLP-1 and NPY secretion and inhibited basal glucagon secretion. Sweet and umami stimuli were ineffective in Tas1r3(-/-) mice, indicating an obligatory role for the T1R3 subunit common to the sweet and umami taste receptors. Polycose responses were unaffected by T1R3 deletion, consistent with the presence of a distinct polysaccharide taste receptor. The effects of sweet stimuli on peptide secretion also required the closing of ATP-sensitive K(+) (KATP) channels, as the KATP channel activator diazoxide inhibited the effects of glucose and sucralose on both GLP-1 and glucagon release. Both sour citric acid and salty NaCl increased NPY secretion but had no effects on GLP-1 or glucagon. Bitter denatonium showed no effects on these peptides. Together, these results suggest that taste stimuli of different perceptual qualities elicit unique patterns of neuropeptide secretion from taste buds.

Adolescent Alcohol Exposure-Induced Changes in Alpha-Melanocyte Stimulating Hormone and Neuropeptide Y Pathways via Histone Acetylation in the Brain During Adulthood.

PubMed

Kokare, Dadasaheb M; Kyzar, Evan J; Zhang, Huaibo; Sakharkar, Amul J; Pandey, Subhash C

2017-09-01

hypothalamus of adolescent intermittent ethanol-exposed adult rats compared with controls. Increased melanocortin and decreased neuropeptide Y activity due to changes in histone acetylation in emotional brain circuitry may play a role in adolescent intermittent ethanol-induced anxiety phenotypes in adulthood. Published by Oxford University Press on behalf of CINP 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Neuropeptide S receptor ligands: a patent review (2005-2016).

PubMed

Ruzza, Chiara; Calò, Girolamo; Di Maro, Salvatore; Pacifico, Salvatore; Trapella, Claudio; Salvadori, Severo; Preti, Delia; Guerrini, Remo

2017-03-01

Neuropeptide S (NPS) is a 20-residue peptide and endogenous ligand of the NPS receptor (NPSR). This receptor was a formerly orphan GPCR whose activation increases calcium and cyclic adenosine monophosphate levels. The NPS/NPSR system is expressed in several brain regions where it controls important biological functions including locomotor activity, arousal and sleep, anxiety, food intake, memory, pain, and drug addiction. Areas covered: This review furnishes an updated overview of the patent literature covering NPSR ligands since 2005, when the first example of an NPSR antagonist was disclosed. Expert opinion: Several potent NPSR antagonists are available as valuable pharmacological tools despite showing suboptimal pharmacokinetic properties in vivo. The optimization of these ligands is needed to speed up their potential clinical advancement as pharmaceuticals to treat drug addiction. In order to support the design of novel NPSR antagonists, we performed a ligand-based conformational analysis recognizing some structural requirements for NPSR antagonism. The identification of small-molecule NPSR agonists now represents an unmet challenge to be addressed. These molecules will allow investigation of the beneficial effects of selective NPSR activation in a large panel of psychiatric disorders and to foresee their therapeutic potential as anxiolytics, nootropics, and analgesics.

Brain-midgut short neuropeptide F mechanism that inhibits digestive activity of the American cockroach, Periplaneta americana upon starvation.

PubMed

Mikani, Azam; Wang, Qiu-Shi; Takeda, Makio

2012-03-01

Immunohistochemical reactivity against short neuropeptide F (sNPF) was observed in the brain-corpus cardiacum and midgut paraneurons of the American cockroach, Periplaneta americana. Four weeks of starvation increased the number of sNPF-ir cells in the midgut epithelium but the refeeding decreased the number in 3h. Dramatic rises in sNPF contents in the midgut epithelium and hemolymph of roaches starved for 4 weeks were confirmed by ELISA. Starvation for 4 weeks reduced α-amylase, protease and lipase activities in the midgut of P. americana but refeeding restored these to high levels. Co-incubation of dissected midgut with sNPF at physiological concentrations inhibited α-amylase, protease and lipase activities. sNPF injection into the hemocoel led to a decrease in α-amylase, protease and lipase activities, whereas PBS injection had no effects. The injection of d-(+)-trehalose and l-proline into the hemocoel of decapitated adult male cockroaches that had been starved for 4 weeks had no effect on these digestive enzymes. However, injection into the hemocoel of head-intact starved cockroaches stimulated digestive activity. Injection of d-(+)-trehalose and l-proline into the lumen of decapitated cockroaches that had been starved for 4 weeks increased enzymes activities and suppressed sNPF in the midgut. Our data indicate that sNPF from the midgut paraneurons suppresses α-amylase, protease and lipase activities during starvation. Injection of d-(+)-trehalose/l-proline into the hemocoel of head-intact starved cockroach decreased the hemolymph sNPF content, which suggests that sNPF could be one of the brain factors, demonstrating brain-midgut interplay in the regulation of digestive activities and possibly nutrition-associated behavioral modifications. Copyright © 2011 Elsevier Inc. All rights reserved.

The insect capa neuropeptides impact desiccation and cold stress responses

USDA-ARS?s Scientific Manuscript database

Background: Insects are so successful because of great resistance to environmental stress, yet little is known about how such responses may be mediated by the neuroendocrine system. Results: We provide evidence that the capability (capa) neuropeptide gene and peptide are critical mediators of desic...

The effects of myomodulin and structurally related neuropeptides on skeletal neuromuscular transmission in the locust.

PubMed

Evans, P D

1994-05-01

1. The modulatory actions of myomodulin A on tension generated in the extensortibiae muscle of the locust hindleg by stimulation of the slow excitatory motoneurone (SETi) depend upon the frequency of stimulation. Myomodulin A has no consistent effect on the tension induced by the fast extensor motoneurone (FETi) or upon the myogenic rhythm present in the extensor. The effects of a range of structurally related neuropeptides have also been assessed. 2. At low frequencies of SETi stimulation (1 Hz and below), the predominant modulatory effects are increases in the amplitude, contraction rate and relaxation rate of twitch tension. At higher frequencies, where twitches summate but tetanus is incomplete (up to 20 Hz), these effects are superimposed upon an increase of maintained tension. 3. The modulatory actions of myomodulin-like peptides show some similarities to and some differences from the modulatory actions of octopamine, proctolin and FMRFamide-like neuropeptides in this preparation, but are likely to be mediated via a distinct set of receptors. 4. The results of the present study, taken together with the localization of myomodulin-like immunoreactivity in specific sets of neurones in the locust nervous system, suggest the presence of a novel modulatory system in insects that uses myomodulin-like neuropeptides. It also indicates that myomodulins, which were first identified in molluscs, may represent another interphyletic family of neuropeptides.

Loss of Female Sex Hormones Exacerbates Cerebrovascular and Cognitive Dysfunction in Aortic Banded Miniswine Through a Neuropeptide Y-Ca2+-Activated Potassium Channel-Nitric Oxide Mediated Mechanism.

PubMed

Olver, T Dylan; Hiemstra, Jessica A; Edwards, Jenna C; Schachtman, Todd R; Heesch, Cheryl M; Fadel, Paul J; Laughlin, M Harold; Emter, Craig A

2017-10-31

Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [AB]) and the loss of female sex hormones (ovariectomy [OVX]) impairs cerebrovascular control and spatial memory. Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB, (3) OVX, and (4) AB-OVX. Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole-board task) were lower in the OVX groups ( P <0.05), with significant impairments in the AB-OVX group ( P <0.05). Resting carotid artery β stiffness and vascular resistance during central hypovolemia were increased in the AB-OVX group ( P <0.05), and blood flow recovery after central hypovolemia was reduced in both OVX groups ( P <0.05). Isolated pial artery (pressure myography) vasoconstriction to neuropeptide Y was greatest in the AB-OVX group ( P <0.05), and vasodilation to the Ca 2+ -activated potassium channel α-subunit agonist NS-1619 was impaired in both AB groups ( P <0.05). The ratio of phosphorylated endothelial nitric oxide synthase:total endothelial nitric oxide synthase was depressed and Ca 2+ -activated potassium channel α-subunit protein was increased in AB groups ( P <0.05). Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y-induced vasoconstriction along with reduced vasodilation associated with decreased Ca 2+ -activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated beta-tubulin isotype.

PubMed Central

Caccamo, D. V.; Herman, M. M.; Frankfurter, A.; Katsetos, C. D.; Collins, V. P.; Rubinstein, L. J.

1989-01-01

Approximately one third of the female mice of the LTXBO strain develop spontaneous ovarian teratomas. These tumors contain a large neuroepithelial component, which includes primitive neural structures resembling embryonic neural tubes (medulloepithelial rosettes), ependymoblastic and ependymal rosettes, neuroblasts, mature ganglionic neurons, myelinated neurites, and astrocytes. The purpose of this study was to characterize these tumors according to the immunohistochemical location of some well-characterized trophic and regulatory neuropeptides and neurotransmitters, several neuronal-associated cytoskeletal proteins, and other proteins indicative of neuronal and glial differentiation. Medulloepithelial rosettes showed focal serotonin-like, opioid peptide-like and gamma-amino butyric acid-like immunoreactivity, and displayed immunostaining for the neuron-associated class III beta-tubulin isotype. The mature ganglion cells were also immunoreactive for these markers, and, in addition, for somatostatin, cholecystokinin, bombesin, glucagon, vasoactive intestinal peptide, and neuropeptide Y. Mature ganglion cells were also immunoreactive for proteins associated with the neuronal cytoskeleton (including microtubule-associated proteins, MAP2 and tau, and higher molecular weight phosphorylated and non-phosphorylated neurofilament subunits), neuron-specific enolase, and synaptophysin. Undifferentiated stem cells, ependymoblastic and ependymal rosettes, and astroglia all stained with a monoclonal antibody that recognizes all mammalian beta-tubulin isotypes, but did not react with antibodies to neuronal-associated cytoskeletal proteins or neuropeptides. Neuropeptide-like immunoreactivity and demonstration of the class III beta-tubulin isotype indicate early neuronal commitment in neoplastic primitive neuroepithelium. These patterns of immunoreactivity closely follow those encountered in the normal neurocytogenesis of the mammalian and avian forebrain, and increase the

Neuropeptide Y in human spinal cord.

PubMed

Allen, J M; Gibson, S J; Adrian, T E; Polak, J M; Bloom, S R

1984-08-06

The distribution of a newly described peptide, neuropeptide Y (NPY) within the human spinal cord has been determined using radioimmunoassay and immunocytochemistry. Higher concentrations were found in the lumbar (49.9 +/- 6.8 pmol/g) and sacral (47.0 +/- 10.6 pmol/g) regions than in the cervical (27.6 +/- 2.7 pmol/g) and thoracic spinal cord (33.8 +/- 5.3 pmol/g). Immunocytochemistry revealed numerous nerve fibers containing NPY in the spinal cord; these were particularly concentrated in the substantia gelatinosa of the dorsal horn. In the ventral spinal cord NPY-containing nerves were sparse becoming more abundant in lumbosacral segments.

Inhibition of hypothalamic MCT1 expression increases food intake and alters orexigenic and anorexigenic neuropeptide expression

PubMed Central

Elizondo-Vega, Roberto; Cortés-Campos, Christian; Barahona, María José; Carril, Claudio; Ordenes, Patricio; Salgado, Magdiel; Oyarce, Karina; García-Robles, María de los Angeles

2016-01-01

Hypothalamic glucosensing, which involves the detection of glucose concentration changes by brain cells and subsequent release of orexigenic or anorexigenic neuropeptides, is a crucial process that regulates feeding behavior. Arcuate nucleus (AN) neurons are classically thought to be responsible for hypothalamic glucosensing through a direct sensing mechanism; however, recent data has shown a metabolic interaction between tanycytes and AN neurons through lactate that may also be contributing to this process. Monocarboxylate transporter 1 (MCT1) is the main isoform expressed by tanycytes, which could facilitate lactate release to hypothalamic AN neurons. We hypothesize that MCT1 inhibition could alter the metabolic coupling between tanycytes and AN neurons, altering feeding behavior. To test this, we inhibited MCT1 expression using adenovirus-mediated transfection of a shRNA into the third ventricle, transducing ependymal wall cells and tanycytes. Neuropeptide expression and feeding behavior were measured in MCT1-inhibited animals after intracerebroventricular glucose administration following a fasting period. Results showed a loss in glucose regulation of orexigenic neuropeptides and an abnormal expression of anorexigenic neuropeptides in response to fasting. This was accompanied by an increase in food intake and in body weight gain. Taken together, these results indicate that MCT1 expression in tanycytes plays a role in feeding behavior regulation. PMID:27677351

Inhibition of hypothalamic MCT1 expression increases food intake and alters orexigenic and anorexigenic neuropeptide expression.

PubMed

Elizondo-Vega, Roberto; Cortés-Campos, Christian; Barahona, María José; Carril, Claudio; Ordenes, Patricio; Salgado, Magdiel; Oyarce, Karina; García-Robles, María de Los Angeles

2016-09-28

Hypothalamic glucosensing, which involves the detection of glucose concentration changes by brain cells and subsequent release of orexigenic or anorexigenic neuropeptides, is a crucial process that regulates feeding behavior. Arcuate nucleus (AN) neurons are classically thought to be responsible for hypothalamic glucosensing through a direct sensing mechanism; however, recent data has shown a metabolic interaction between tanycytes and AN neurons through lactate that may also be contributing to this process. Monocarboxylate transporter 1 (MCT1) is the main isoform expressed by tanycytes, which could facilitate lactate release to hypothalamic AN neurons. We hypothesize that MCT1 inhibition could alter the metabolic coupling between tanycytes and AN neurons, altering feeding behavior. To test this, we inhibited MCT1 expression using adenovirus-mediated transfection of a shRNA into the third ventricle, transducing ependymal wall cells and tanycytes. Neuropeptide expression and feeding behavior were measured in MCT1-inhibited animals after intracerebroventricular glucose administration following a fasting period. Results showed a loss in glucose regulation of orexigenic neuropeptides and an abnormal expression of anorexigenic neuropeptides in response to fasting. This was accompanied by an increase in food intake and in body weight gain. Taken together, these results indicate that MCT1 expression in tanycytes plays a role in feeding behavior regulation.

Central Nervous System Neuropeptide Y Signaling Modulates VLDL Triglyceride Secretion

PubMed Central

Stafford, John M.; Yu, Fang; Printz, Richard; Hasty, Alyssa H.; Swift, Larry L.; Niswender, Kevin D.

2014-01-01

OBJECTIVE Elevated triglyceride (TG) is the major plasma lipid abnormality in obese and diabetic patients and contributes to cardiovascular morbidity in these disorders. We sought to identify novel mechanisms leading to hypertriglyceridemia. Resistance to negative feedback signals from adipose tissue in key central nervous system (CNS) energy homeostatic circuits contributes to the development of obesity. Because triglycerides both represent the largest energy depot in the body and are elevated in both the plasma and adipose in obesity and diabetes, we hypothesized that the same neural circuits that regulate energy balance also regulate the secretion of TGs into plasma. RESEARCH DESIGN AND METHODS In normal fasting rats, the TG secretion rate was estimated by serial blood sampling after intravascular tyloxapol pretreatment. Neuropeptide Y (NPY) signaling in the CNS was modulated by intracerebroventricular injection of NPY, receptor antagonist, and receptor agonist. RESULTS A single intracerebroventricular injection of NPY increased TG secretion by 2.5-fold in the absence of food intake, and this was determined to be VLDL by fast performance liquid chromatography (FPLC). This effect was recapitulated by activating NPY signaling in downstream neurons with an NPY-Y5 receptor agonist. An NPY-Y1 receptor antagonist decreased the elevated TGs in the form of VLDL secretion rate by 50% compared with vehicle. Increased TG secretion was due to increased secretion of VLDL particles, rather than secretion of larger particles, because apolipoprotein B100 was elevated in FPLC fractions corresponding to VLDL. CONCLUSIONS We find that a key neuropeptide system involved in energy homeostasis in the CNS exerts control over VLDL-TG secretion into the bloodstream. PMID:18332095

Neuropeptide Y in the guinea-pig biliary tract.

PubMed

Allen, J M; Gu, J; Adrian, T E; Polak, J M; Bloom, S R

1984-07-15

High concentrations of neuropeptide Y (NPY) have been demonstrated in the gall bladder (16.7 +/- 5.4 pmol/g), cystic duct (25.4 +/- 9.2 pmol/g) and common bile duct (54.7 +/- 11.5 pmol/g) of the guinea-pig using a recently developed radioimmunoassay. Immunoreactive NPY containing nerves were demonstrated in all layers of the biliary tree using immunocytochemistry, being particularly dense in the myenteric and mucosal plexuses.

Neuropeptide Y as an indicator of successful alterations in sympathetic nervous activity after renal sympathetic denervation.

PubMed

Dörr, Oliver; Ewen, Sebastian; Liebetrau, Christoph; Möllmann, Helge; Gaede, Luise; Linz, Dominik; Hohl, Mathias; Troidl, Christian; Bauer, Timm; Böhm, Michael; Hamm, Christian; Mahfoud, Felix; Nef, Holger

2015-12-01

Renal sympathetic denervation (RSD) represents a safe and effective treatment option for certain patients with resistant hypertension and has been shown to decrease sympathetic activity. Neuropeptide Y (NPY) is a neurotransmitter that is co-released with norepinephrine and is up-regulated during increased sympathetic activity. The aim of the present study was to examine the effect of RSD on NPY and to analyze the association between changes in NPY levels and blood pressure reduction after RSD. A total of 150 consecutive patients (age 64.9 ± 10.2 years) from three clinical centers undergoing RSD were included in this study. Response to RSD was defined as an office systolic blood pressure (SBP) reduction of >10 mmHg 6 months after RSD. Venous blood samples for measurement of NPY were collected prior to and 6 months after RSD. BP and NPY levels were significantly reduced by 23/9 mmHg (p = 0.001/0.001) and 0.24 mg/dL (p < 0.01) 6 months after RSD. There was a significant correlation between baseline SBP- and RSD-related systolic BP reduction (r = -0.43; p < 0.001) and between serum NPY baseline values and NPY level changes (r = -0.52; p < 0.001) at the 6-month follow-up. The BP response to RSD (>10 mmHg) was associated with a significantly greater reduction in NPY level when compared with BP non-responders (p = 0.001). This study demonstrates an effect of RSD on serum NPY levels, a specific marker for sympathetic activity. The association between RSD-related changes in SBP and NPY levels provides further evidence of the effect of RSD on the sympathetic nervous system.

Separation of Bombyxin from a neuropeptide of Bombyx mori showing Summer-morph-producing Hormone (SMPH) activity in the Asian Comma Butterfly, Polygonia c-aureum L.

PubMed

Endo, K; Yamanaka, A; Mitsumasu, K; Sakurama, T; Tanaka, D

1997-02-21

A neuropeptide from brain-suboesophageal ganglion (Br-SG) complexes of the silkmoth, Bombyx mori, shows summer-morph-producing hormone (SMPH) activity in the Asian comma butterfly, P. c-aureum. The SMPH-active peptide was extracted and demonstrated to be almost the same molecular size as bombyxin (4-5kD), a nueropeptide which shows prothoracicotropic hormone (PTTH) activity when assayed in vitro with prothoracic glands (PGs) of 4th-instar B. mori larvae in vitro. A Sephadex G-50 fraction of 3-8kD molecules prepared from Br-SG complexes of B. mori adults was applied to CM-, SP-, DEAE- or QAE- Toyoperal columns at pH 5.6 (or pH 6.9). The SMPH-activity could be separated from the PTTH-activity (or bombyxin) by subjecting a SMPH- and PTTH-active preparation of B. mori to anion-exchange chromatography at pH 6.9. By reversed-phase HPLC following an anion-exchange chromatography, SMPH-activity was recovered in two fractions of 40-45% acetonitril. Results demonstrate that the B. mori peptide showing the SMPH-activity in P. c-aureum is a different molecule than bombyxin.

Nociceptive Neuropeptide Increases and Periorbital Allodynia in a Model of Traumatic Brain Injury

PubMed Central

Elliott, Melanie B.; Oshinsky, Michael L.; Amenta, Peter S.; Awe, Olatilewa O.; Jallo, Jack I.

2014-01-01

Objective This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury. Methods Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1–labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization. Results Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P < .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P < .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P < .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P < .0001. There was a significant correlation between CGRP and periorbital allodynia (P < .0001, r = −0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks

Estrogen Maintains Skeletal Muscle in Septic Rats Associated with Altering Hypothalamic Inflammation and Neuropeptides.

PubMed

Zhao, Chenyan; Li, Jun; Cheng, Minhua; Shi, Jialing; Shen, Juanhong; Gao, Tao; Xi, Fengchan; Yu, Wenkui

2017-03-01

Muscle wasting is one of the main contributors to the worse outcomes in sepsis. Whether estrogen could alleviate muscle wasting induced by sepsis remains unclear. This study was designed to test the effect of estrogen on muscle wasting and its relationship with central alteration in sepsis. Thirty Sprague-Dawley rats were divided into 3 groups: control group, sepsis group, and estrogen treated sepsis group. Animals were intraperitoneally injected with lipopolysaccharide (10 mg/kg) or saline, followed by subcutaneous injection of 17β-estradiol (1 mg/kg) or saline. Twenty-four hours later, all animals were killed and their hypothalamus and skeletal muscles were harvested for analysis. Muscle wasting markers, hypothalamic neuropeptides, and hypothalamic inflammatory markers were measured. As a result, lipopolysaccharide administration caused a significant increase in muscle wasting, hypothalamic inflammation, and anorexigenic neuropeptides (POMC and CART) gene expression, and a significant decrease in orexigenic neuropeptides (AgRP and NPY) gene expression. Administration of estrogen signifcantl attenuated lipopolysaccharide-induced muscle wasting (body weight and extensor digitorum longus loss [52 and 62 %], tyrosine and 3-methylhistidine release [17 and 22 %], muscle ring fnger 1 [MuRF-1; 65 %], and muscle atrophy F-box [MAFbx] gene expression), hypothalamic inflammation (Tumor necrosis factor-α and interlukin-1β [69 and 70%]) as well as alteration of POMC, CART and AgRP (61, 37, and 1008 %) expression.In conclusion, estrogen could alleviate sepsis-induced muscle wasting and it was associated with reducing hypothalamic inflammation and alteration of hypothalamic neuropeptides. © Georg Thieme Verlag KG Stuttgart · New York.

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans.

PubMed

Yi, Min; Li, Hekai; Wu, Zhiye; Yan, Jianyun; Liu, Qicai; Ou, Caiwen; Chen, Minsheng

2018-01-01

Human neuropeptide Y (hNPY) is one of the most widely expressed neurotransmitters in the human central and peripheral nervous systems. It consists of 36 highly conserved amino acid residues, and was first isolated from the porcine hypothalamus in 1982. While it is the most recently discovered member of the pancreatic polypeptide family (which includes neuropeptide Y, gut-derived hormone peptide YY, and pancreatic polypeptide), NPY is the most abundant peptide found in the mammalian brain. In order to exert particular functions, NPY needs to bind to the NPY receptor to activate specific signaling pathways. NPY receptors belong to the class A or rhodopsin-like G-protein coupled receptor (GPCR) family and signal via cell-surface receptors. By binding to GPCRs, NPY plays a crucial role in various biological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function. Abnormal regulation of NPY is involved in the development of a wide range of diseases, including obesity, hypertension, atherosclerosis, epilepsy, metabolic disorders, and many cancers. Thus far, five receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6), but only four of these (hY1, hY2, hY4, and hY5) are functional in humans. In this review, we summarize the structural characteristics of human NPY receptors and their role in metabolic diseases. © 2018 The Author(s). Published by S. Karger AG, Basel.

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis.

PubMed

Prévost, Gaëtan; Jeandel, Lydie; Arabo, Arnaud; Coëffier, Moïse; El Ouahli, Mariama; Picot, Marie; Alexandre, David; Gobet, Françoise; Leprince, Jérôme; Berrahmoune, Hind; Déchelotte, Pierre; Malagon, Maria; Bonner, Caroline; Kerr-Conte, Julie; Chigr, Fatiha; Lefebvre, Hervé; Anouar, Youssef; Chartrel, Nicolas

2015-08-01

26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a high-fat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic β-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

The α-helical structure of prodomains promotes translocation of intrinsically disordered neuropeptide hormones into the endoplasmic reticulum.

PubMed

Dirndorfer, Daniela; Seidel, Ralf P; Nimrod, Guy; Miesbauer, Margit; Ben-Tal, Nir; Engelhard, Martin; Zimmermann, Richard; Winklhofer, Konstanze F; Tatzelt, Jörg

2013-05-17

Different neuropeptide hormones, which are either too small to adopt a stable conformation or are predicted to be intrinsically disordered, are synthesized as larger precursors containing a prodomain in addition to an N-terminal signal peptide. We analyzed the biogenesis of three unstructured neuropeptide hormones and observed that translocation of these precursors into the lumen of the endoplasmic reticulum (ER) is critically dependent on the presence of the prodomain. The hormone domains could be deleted from the precursors without interfering with ER import and secretion, whereas constructs lacking the prodomain remained in the cytosol. Domain-swapping experiments revealed that the activity of the prodomains to promote productive ER import resides in their ability to adopt an α-helical structure. Removal of the prodomain from the precursor did not interfere with co-translational targeting of the nascent chain to the Sec61 translocon but with its subsequent productive translocation into the ER lumen. Our study reveals a novel function of prodomains to enable import of small or intrinsically disordered secretory proteins into the ER based on their ability to adopt an α-helical conformation.

Differential Regulation of Neuropeptide Y In the Amygdala and Prefrontal Cortex During Recovery from Chronic Variable Stress

DTIC Science & Technology

2011-09-01

T., Pabst, R., and Von Horsten, S. (2003). Behav- ioral effects of neuropeptide Y in F344 rat substrains with a reduced dipeptidyl- peptidase IV...studies and pre-clinical animal models supports a role for neuropeptide Y (NPY) in adaptive emotional response following stress. The long-term impact of...stress-related psychopathol- ogy. In these studies, we examined expression of NPY during recovery from a chronic variable stress (CVS) model of

Neutral endopeptidase promotes phorbol ester-induced apoptosis in prostate cancer cells by inhibiting neuropeptide-induced protein kinase C delta degradation.

PubMed

Sumitomo, M; Shen, R; Goldberg, J S; Dai, J; Navarro, D; Nanus, D M

2000-12-01

Phorbol esters induce apoptosis in androgen-sensitive LNCaP cells, which express neutral endopeptidase (NEP), but not in androgen-independent prostate cancer (PC) cells, which lack NEP expression. We investigated the role of NEP in PC cell susceptibility to 12-O-tetradecanoylphorbol-13-acetate (TPA). Western analysis showed that expression of NEP and protein kinase Cdelta (PKCdelta) correlated with PC cell sensitivity to TPA-induced growth arrest and apoptosis in LNCaP cells and in TSU-Prl cells expressing an inducible wild-type NEP protein. Inhibition of NEP enzyme activity using the specific NEP inhibitor CGS24592, or inhibition of PKCdelta using Rottlerin at concentrations that inhibit PKCdelta but not PKCalpha, significantly inhibited TPA-induced growth inhibition and cell death. Furthermore, pulse-chase experiments showed PKCdelta is stabilized in LNCaP cells and in TSU-Pr1 cells overexpressing wild-type NEP compared with PC cells lacking NEP expression. This results from NEP inactivation of its neuropeptide substrates (bombesin and endothelin-1), which in the absence of NEP stimulate cSrc kinase activity and induce rapid degradation of PKCdelta protein. These results indicate that expression of enzymatically active NEP by PC cells is necessary for TPA-induced apoptosis, and that NEP inhibits neuropeptide-induced, cSrc-mediated PKCdelta degradation.

Inflammation and Neuropeptides: The Connection in Diabetic Wound Healing

PubMed Central

Pradhan, Leena; Nabzdyk, Christoph; Andersen, Nicholas D; LoGerfo, Frank W; Veves, Aristidis

2013-01-01

This article provides a broad overview of the interaction between neuropeptides and inflammatory mediators as it pertains to diabetic wound healing. Abnormal wound healing is a major complication of both type I and type II diabetes and is the most frequent cause of non-traumatic lower limb amputation. Wound healing requires the orchestrated integration of complex biological and molecular events. Inflammation, proliferation and migration of cells followed by angiogenesis and re-epithelization are essential phases of wound healing. The link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30–50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. The bidirectional connection between the nervous and the immune systems and the role it plays in wound healing has emerged as one of the focal features of the wound healing dogma. The mediators of this connection include neuropeptides and the cytokines released from different cells including immune and cutaneous cells. Therefore, to develop successful wound healing therapies, it is vital to understand in depth the signaling pathways in the neuro-immune axis and their implication in diabetic wound healing. PMID:19138453

Drosophila Neuropeptide F Signaling Independently Regulates Feeding and Sleep-Wake Behavior.

PubMed

Chung, Brian Y; Ro, Jennifer; Hutter, Sabine A; Miller, Kylie M; Guduguntla, Lakshmi S; Kondo, Shu; Pletcher, Scott D

2017-06-20

Proper regulation of sleep-wake behavior and feeding is essential for organismal health and survival. While previous studies have isolated discrete neural loci and substrates important for either sleep or feeding, how the brain is organized to coordinate both processes with respect to one another remains poorly understood. Here, we provide evidence that the Drosophila Neuropeptide F (NPF) network forms a critical component of both adult sleep and feeding regulation. Activation of NPF signaling in the brain promotes wakefulness and adult feeding, likely through its cognate receptor NPFR. Flies carrying a loss-of-function NPF allele do not suppress sleep following prolonged starvation conditions, suggesting that NPF acts as a hunger signal to keep the animal awake. NPF-expressing cells, specifically those expressing the circadian photoreceptor cryptochrome, are largely responsible for changes to sleep behavior caused by NPF neuron activation, but not feeding, demonstrating that different NPF neurons separately drive wakefulness and hunger. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

MALDI Imaging Analysis of Neuropeptides in Africanized Honeybee (Apis mellifera) Brain: Effect of Aggressiveness.

PubMed

Pratavieira, Marcel; Menegasso, Anally Ribeiro da Silva; Esteves, Franciele Grego; Sato, Kenny Umino; Malaspina, Osmar; Palma, Mario Sérgio

2018-05-18

The aggressiveness in honeybees seems to be regulated by multiple genes, under the influence of different factors, such as polyethism of workers, environmental factors, and response to alarm pheromones, creating a series of behavioral responses. It is suspected that neuropeptides seem to be involved with the regulation of the aggressive behavior. The role of allatostatin and tachykinin-related neuropeptides in honeybee brain during the aggressive behavior is unknown; thus, worker honeybees were stimulated to attack and to sting leather targets hanged in front of the colonies. The aggressive individuals were collected and immediately frozen in liquid nitrogen; the heads were removed, and sliced at sagittal plan. The brain slices were submitted to MALDI-Spectral-Imaging analysis, and the results of the present study reported the processing of the precursors proteins into mature forms of the neuropeptides AmAST A (59-76) (AYTYVSEYKRLPVYNFGL-NH2), AmAST A (69-76) (LPVYNFGL-NH2), AmTRP (88 - 96) (APMGFQGMR-NH2), and AmTRP (254 - 262) (ARMGFHGMR-NH2), which apparently acted in different neuropils of honeybee brain, during the aggressive behavior, possibly playing the neuromodulation of different aspects of this complex behavior. These results were biologically validated performing aggressiveness-related behavioral assays, using young honeybee workers that received 1 ng of AmAST A (69-76) or AmTRP (88 - 96) via hemocele. The young workers that were not expected to be aggressive individuals, presented a complete series of the aggressive behaviors, in presence of the neuropeptides, corroborating the hypothesis that correlates the presence of mature AmASTs A and AmTRPs in honeybee brain with the aggressiveness of this insect.

Energy Balance Regulating Neuropeptides Are Expressed through Pregnancy and Regulated by Interleukin-6 Deficiency in Mouse Placenta.

PubMed

Pazos, Patricia; Lima, Luis; Diéguez, Carlos; García, María C

2014-01-01

The placenta produces a number of signaling molecules including metabolic and reproductive hormones as well as several inflammatory mediators. Among them, Interleukin-6 (IL-6), a well-known immune and metabolic regulator, acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. IL-6 interacts with key hypothalamic neuropeptidergic systems controlling energy homeostasis such as those producing the orexigenic/anabolic: neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorectic/catabolic neuropeptides: proopiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART). Human and rat placenta have been identified as source of these neuropeptides, but their expression and regulation in murine placental tissues remain unknown. Therefore, placental mRNA levels of IL-6, NPY, AgRP, POMC, and CART at different pregnancy stages (gestational days 13, 15, and 18) were analyzed by real time PCR, as were the effect of IL-6 deficiency (IL-6 knockout mice) on their placental expression. Our results showed that placenta-derived neuropeptides were regulated by gestational age and IL-6 throughout the second half of mouse pregnancy. These data suggest that IL-6 may participate in the fine tune control of energy balance during pregnancy by extending its action as a metabolic signal to the main organ at the fetomaternal interface: the placenta.

A Multifaceted Mass Spectrometric Method to Probe Feeding Related Neuropeptide Changes in Callinectes sapidus and Carcinus maenas

NASA Astrophysics Data System (ADS)

Zhang, Yuzhuo; DeLaney, Kellen; Hui, Limei; Wang, Junhua; Sturm, Robert M.; Li, Lingjun

2018-02-01

Food intake is regulated by various neuromodulators, including numerous neuropeptides. However, it remains elusive at the molecular and cellular level as to how these important chemicals regulate internal processes and which regions of the neuronal organs are responsible for regulating the behavior. Here we report a comparative neuropeptidomic analysis of the brain and pericardial organ (PO) in response to feeding in two well-studied crustacean physiology model organisms, Callinectes sapidus and Carcinus maenas, using mass spectrometry (MS) techniques. A multifaceted MS-based approach has been developed to obtain complementary information on the expression changes of a large array of neuropeptides in the brain and PO. The method employs stable isotope labeling of brain and PO extracts for relative MS quantitation, capillary electrophoresis (CE)-MS for fractionation and high-specificity analysis, and mass spectrometric imaging (MSI) for in-situ molecular mapping of peptides. A number of neuropeptides, including RFamides, B-type allatostatins (AST-B), RYamides, and orcokinins exhibit significant changes in abundance after feeding in this investigation. Peptides from the AST-B family found in PO tissue were shown to have both altered expression and localization changes after feeding, indicating that they may be a class of vital neuropeptide regulators involved in feeding behavior. [Figure not available: see fulltext.

A Multifaceted Mass Spectrometric Method to Probe Feeding Related Neuropeptide Changes in Callinectes sapidus and Carcinus maenas

NASA Astrophysics Data System (ADS)

Zhang, Yuzhuo; DeLaney, Kellen; Hui, Limei; Wang, Junhua; Sturm, Robert M.; Li, Lingjun

2018-05-01

Food intake is regulated by various neuromodulators, including numerous neuropeptides. However, it remains elusive at the molecular and cellular level as to how these important chemicals regulate internal processes and which regions of the neuronal organs are responsible for regulating the behavior. Here we report a comparative neuropeptidomic analysis of the brain and pericardial organ (PO) in response to feeding in two well-studied crustacean physiology model organisms, Callinectes sapidus and Carcinus maenas, using mass spectrometry (MS) techniques. A multifaceted MS-based approach has been developed to obtain complementary information on the expression changes of a large array of neuropeptides in the brain and PO. The method employs stable isotope labeling of brain and PO extracts for relative MS quantitation, capillary electrophoresis (CE)-MS for fractionation and high-specificity analysis, and mass spectrometric imaging (MSI) for in-situ molecular mapping of peptides. A number of neuropeptides, including RFamides, B-type allatostatins (AST-B), RYamides, and orcokinins exhibit significant changes in abundance after feeding in this investigation. Peptides from the AST-B family found in PO tissue were shown to have both altered expression and localization changes after feeding, indicating that they may be a class of vital neuropeptide regulators involved in feeding behavior. [Figure not available: see fulltext.

A Multifaceted Mass Spectrometric Method to Probe Feeding Related Neuropeptide Changes in Callinectes sapidus and Carcinus maenas.

PubMed

Zhang, Yuzhuo; DeLaney, Kellen; Hui, Limei; Wang, Junhua; Sturm, Robert M; Li, Lingjun

2018-05-01

Food intake is regulated by various neuromodulators, including numerous neuropeptides. However, it remains elusive at the molecular and cellular level as to how these important chemicals regulate internal processes and which regions of the neuronal organs are responsible for regulating the behavior. Here we report a comparative neuropeptidomic analysis of the brain and pericardial organ (PO) in response to feeding in two well-studied crustacean physiology model organisms, Callinectes sapidus and Carcinus maenas, using mass spectrometry (MS) techniques. A multifaceted MS-based approach has been developed to obtain complementary information on the expression changes of a large array of neuropeptides in the brain and PO. The method employs stable isotope labeling of brain and PO extracts for relative MS quantitation, capillary electrophoresis (CE)-MS for fractionation and high-specificity analysis, and mass spectrometric imaging (MSI) for in-situ molecular mapping of peptides. A number of neuropeptides, including RFamides, B-type allatostatins (AST-B), RYamides, and orcokinins exhibit significant changes in abundance after feeding in this investigation. Peptides from the AST-B family found in PO tissue were shown to have both altered expression and localization changes after feeding, indicating that they may be a class of vital neuropeptide regulators involved in feeding behavior. Graphical Abstract ᅟ.

Energy Balance Regulating Neuropeptides Are Expressed through Pregnancy and Regulated by Interleukin-6 Deficiency in Mouse Placenta

PubMed Central

Pazos, Patricia; Lima, Luis; Diéguez, Carlos; García, María C.

2014-01-01

The placenta produces a number of signaling molecules including metabolic and reproductive hormones as well as several inflammatory mediators. Among them, Interleukin-6 (IL-6), a well-known immune and metabolic regulator, acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. IL-6 interacts with key hypothalamic neuropeptidergic systems controlling energy homeostasis such as those producing the orexigenic/anabolic: neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorectic/catabolic neuropeptides: proopiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART). Human and rat placenta have been identified as source of these neuropeptides, but their expression and regulation in murine placental tissues remain unknown. Therefore, placental mRNA levels of IL-6, NPY, AgRP, POMC, and CART at different pregnancy stages (gestational days 13, 15, and 18) were analyzed by real time PCR, as were the effect of IL-6 deficiency (IL-6 knockout mice) on their placental expression. Our results showed that placenta-derived neuropeptides were regulated by gestational age and IL-6 throughout the second half of mouse pregnancy. These data suggest that IL-6 may participate in the fine tune control of energy balance during pregnancy by extending its action as a metabolic signal to the main organ at the fetomaternal interface: the placenta. PMID:24744782

A small group of neurosecretory cells expressing the transcriptional regulator apontic and the neuropeptide corazonin mediate ethanol sedation in Drosophila.

PubMed

McClure, Kimberly D; Heberlein, Ulrike

2013-02-27

In the fruit fly Drosophila melanogaster, as in mammals, acute exposure to a high dose of ethanol leads to stereotypical behavioral changes beginning with increased activity, followed by incoordination, loss of postural control, and eventually, sedation. The mechanism(s) by which ethanol impacts the CNS leading to ethanol-induced sedation and the genes required for normal sedation sensitivity remain largely unknown. Here we identify the gene apontic (apt), an Myb/SANT-containing transcription factor that is required in the nervous system for normal sensitivity to ethanol sedation. Using genetic and behavioral analyses, we show that apt mediates sensitivity to ethanol sedation by acting in a small set of neurons that express Corazonin (Crz), a neuropeptide likely involved in the physiological response to stress. The activity of Crz neurons regulates the behavioral response to ethanol, as silencing and activating these neurons affects sedation sensitivity in opposite ways. Furthermore, this effect is mediated by Crz, as flies with reduced crz expression show reduced sensitivity to ethanol sedation. Finally, we find that both apt and crz are rapidly upregulated by acute ethanol exposure. Thus, we have identified two genes and a small set of peptidergic neurons that regulate sensitivity to ethanol-induced sedation. We propose that Apt regulates the activity of Crz neurons and/or release of the neuropeptide during ethanol exposure.

A Small Group of Neurosecretory Cells Expressing the Transcriptional Regulator apontic and the Neuropeptide corazonin Mediate Ethanol Sedation in Drosophila

PubMed Central

2013-01-01

In the fruit fly Drosophila melanogaster, as in mammals, acute exposure to a high dose of ethanol leads to stereotypical behavioral changes beginning with increased activity, followed by incoordination, loss of postural control, and eventually, sedation. The mechanism(s) by which ethanol impacts the CNS leading to ethanol-induced sedation and the genes required for normal sedation sensitivity remain largely unknown. Here we identify the gene apontic (apt), an Myb/SANT-containing transcription factor that is required in the nervous system for normal sensitivity to ethanol sedation. Using genetic and behavioral analyses, we show that apt mediates sensitivity to ethanol sedation by acting in a small set of neurons that express Corazonin (Crz), a neuropeptide likely involved in the physiological response to stress. The activity of Crz neurons regulates the behavioral response to ethanol, as silencing and activating these neurons affects sedation sensitivity in opposite ways. Furthermore, this effect is mediated by Crz, as flies with reduced crz expression show reduced sensitivity to ethanol sedation. Finally, we find that both apt and crz are rapidly upregulated by acute ethanol exposure. Thus, we have identified two genes and a small set of peptidergic neurons that regulate sensitivity to ethanol-induced sedation. We propose that Apt regulates the activity of Crz neurons and/or release of the neuropeptide during ethanol exposure. PMID:23447613

Neuropeptide Y-mediated sex- and afferent-specific neurotransmissions contribute to sexual dimorphism of baroreflex afferent function.

PubMed

Liu, Yang; Wu, Di; Qu, Mei-Yu; He, Jian-Li; Yuan, Mei; Zhao, Miao; Wang, Jian-Xin; He, Jian; Wang, Lu-Qi; Guo, Xin-Jing; Zuo, Meng; Zhao, Shu-Yang; Ma, Mei-Na; Li, Jun-Nan; Shou, Weinian; Qiao, Guo-Fen; Li, Bai-Yan

2016-10-04

Molecular and cellular mechanisms of neuropeptide-Y (NPY)-mediated gender-difference in blood pressure (BP) regulation are largely unknown. Baroreceptor sensitivity (BRS) was evaluated by measuring the response of BP to phenylephrine/nitroprusside. Serum NPY concentration was determined using ELISA. The mRNA and protein expression of NPY receptors were assessed in tissue and single-cell by RT-PCR, immunoblot, and immunohistochemistry. NPY was injected into the nodose while arterial pressure was monitored. Electrophysiological recordings were performed on nodose neurons from rats by patch-clamp technique. The BRS was higher in female than male and ovariectomized rats, while serum NPY concentration was similar among groups. The sex-difference was detected in Y1R, not Y2R protein expression, however, both were upregulated upon ovariectomy and canceled by estrogen replacement. Immunostaining confirmed Y1R and Y2R expression in myelinated and unmyelinated afferents. Single-cell PCR demonstrated that Y1R expression/distribution was identical between A- and C-types, whereas, expressed level of Y2R was ~15 and ~7 folds higher in Ah- and C-types than A-types despite similar distribution. Activation of Y1R in nodose elevated BP, while activation of Y2R did the opposite. Activation of Y1R did not alter action potential duration (APD) of A-types, but activation of Y2R- and Y1R/Y2R in Ah- and C-types frequency-dependently prolonged APD. N-type ICa was reduced in A-, Ah- and C-types when either Y1R, Y2R, or both were activated. The sex-difference in Y1R expression was also observed in NTS. Sex- and afferent-specific expression of Neuropeptide-Y receptors in baroreflex afferent pathway may contribute to sexual-dimorphic neurocontrol of BP regulation.

Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency.

PubMed

Luo, Na; Marcelin, Genevieve; Liu, Shun Mei; Schwartz, Gary; Chua, Streamson

2011-03-01

Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency.

Neuropeptide Y and Agouti-Related Peptide Mediate Complementary Functions of Hyperphagia and Reduced Energy Expenditure in Leptin Receptor Deficiency

PubMed Central

Luo, Na; Marcelin, Genevieve; Liu, Shun Mei; Schwartz, Gary

2011-01-01

Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency. PMID:21285324

Systemic levels of neuropeptide Y and dipeptidyl peptidase activity in Ewing sarcoma patients – associations with tumor phenotype and survival

PubMed Central

Tilan, Jason U.; Krailo, Mark; Barkauskas, Donald A.; Galli, Susana; Mtaweh, Haifa; Long, Jessica; Wang, Hongkun; Hawkins, Kirsten; Lu, Congyi; Jeha, Dima; Izycka-Swieszewska, Ewa; Lawlor, Elizabeth R.; Toretsky, Jeffrey A.; Kitlinska, Joanna

2014-01-01

Background Ewing sarcoma (ES) is driven by fusion of the EWS gene with an ETS transcription factor, most often FLI1. Neuropeptide Y (NPY) is an EWS-FLI1 transcriptional target. NPY is highly expressed in ES and exerts opposing effects, ranging from ES cell death to angiogenesis and cancer stem cell propagation. The functions of NPY are regulated by dipeptidyl peptidase IV (DPPIV), a hypoxia-inducible enzyme that cleaves the peptide and activates its growth-promoting actions. The goal of this study was to determine clinically relevant functions of NPY by identifying the associations between its concentrations and DPP activity in patients and ES phenotype. Methods NPY concentrations and DPP activity were measured in serum samples from 223 patients with localized and 9 patients with metastatic ES provided by Children’s Oncology Group. Results Serum NPY levels were elevated in ES patients, as compared to healthy control and osteosarcoma populations, independently of the EWS-ETS translocation type. Significantly higher NPY concentrations were detected in ES patients with tumors of pelvic and bone origin. A similar trend was observed in patients with metastatic ES. There was no effect of NPY on survival in patients with localized ES. DPP activity in sera of ES patients was not significantly different from healthy control and osteosarcoma patients. However, high DPP levels were associated with improved survival. Conclusion Systemic NPY is elevated in ES patients and its high levels associate with unfavorable disease features. DPPIV in patients’ sera is derived from non-tumoral sources and its high activity correlates with improved survival. PMID:25387699

Heat Avoidance Is Regulated by Transient Receptor Potential (TRP) Channels and a Neuropeptide Signaling Pathway in Caenorhabditis elegans

PubMed Central

Glauser, Dominique A.; Chen, Will C.; Agin, Rebecca; MacInnis, Bronwyn L.; Hellman, Andrew B.; Garrity, Paul A.; Tan, Man-Wah; Goodman, Miriam B.

2011-01-01

The ability to avoid noxious extremes of hot and cold is critical for survival and depends on thermal nociception. The TRPV subset of transient receptor potential (TRP) channels is heat activated and proposed to be responsible for heat detection in vertebrates and fruit flies. To gain insight into the genetic and neural basis of thermal nociception, we developed assays that quantify noxious heat avoidance in the nematode Caenorhabditis elegans and used them to investigate the genetic basis of this behavior. First, we screened mutants for 18 TRP channel genes (including all TRPV orthologs) and found only minor defects in heat avoidance in single and selected double and triple mutants, indicating that other genes are involved. Next, we compared two wild isolates of C. elegans that diverge in their threshold for heat avoidance and linked this phenotypic variation to a polymorphism in the neuropeptide receptor gene npr-1. Further analysis revealed that loss of either the NPR-1 receptor or its ligand, FLP-21, increases the threshold for heat avoidance. Cell-specific rescue of npr-1 implicates the interneuron RMG in the circuit regulating heat avoidance. This neuropeptide signaling pathway operates independently of the TRPV genes, osm-9 and ocr-2, since mutants lacking npr-1 and both TRPV channels had more severe defects in heat avoidance than mutants lacking only npr-1 or both osm-9 and ocr-2. Our results show that TRPV channels and the FLP-21/NPR-1 neuropeptide signaling pathway determine the threshold for heat avoidance in C. elegans. PMID:21368276

NGFFFamide and echinotocin: structurally unrelated myoactive neuropeptides derived from neurophysin-containing precursors in sea urchins.

PubMed

Elphick, Maurice R; Rowe, Matthew L

2009-04-01

The myoactive neuropeptide NGIWYamide was originally isolated from the holothurian (sea cucumber) Apostichopus japonicus but there is evidence that NGIWYamide-like peptides also occur in other echinoderms. Here we report the discovery of a gene in the sea urchin Strongylocentrotus purpuratus that encodes two copies of an NGIWYamide-like peptide: Asn-Gly-Phe-Phe-Phe-(NH(2)) or NGFFFamide. Interestingly, the C-terminal region of the NGFFFamide precursor shares sequence similarity with neurophysins, carrier proteins hitherto uniquely associated with precursors of vasopressin/oxytocin-like neuropeptides. Thus, the NGFFFamide precursor is the first neurophysin-containing neuropeptide precursor to be discovered that does not contain a vasopressin/oxytocin-like peptide. However, it remains to be determined whether neurophysin acts as a carrier protein for NGFFFamide. The S. purpuratus genome also contains a gene encoding a precursor comprising a neurophysin polypeptide and 'echinotocin' (CFISNCPKGamide) - the first vasopressin/oxytocin-like peptide to be identified in an echinoderm. Therefore, in S. purpuratus there are two genes encoding precursors that have a neurophysin domain but which encode neuropeptides that are structurally unrelated. Furthermore, both NGFFFamide and echinotocin cause contraction of tube foot and oesophagus preparations from the sea urchin Echinus esculentus, consistent with the myoactivity of NGIWYamide in sea cucumbers and the myoactivity of vasopressin/oxytocin-like peptides in other animal phyla. Presumably the NGFFFamide precursor acquired its neurophysin domain following partial or complete duplication of a gene encoding a vasopressin/oxytocin-like peptide, but it remains to be determined when in evolutionary history this occurred.

Radioimmunoassay of neuropeptide Y.

PubMed

Allen, J M; Yeats, J C; Adrian, T E; Bloom, S R

1984-01-01

The development of a radioimmunoassay to the newly isolated peptide, neuropeptide Y is described. Four separate antisera have been developed using different immunisation schedules. Two of these antisera (YNI and YNIO) are directed to the C-terminal region of the peptide and cross-react with the related peptide PYY, whereas YN7 is specific being directed to the N-terminal region of NPY, YN6 is similarly specific for NPY, but is unable to bind the available fragments. These four antisera provide similar results for determination of NPY immunoreactivity within porcine brain extracts, however YN6 consistently undervalues all extracts from the other species examined (human, rat, guinea pig, cat and mouse). Chromatographic analysis by means of reverse phase high pressure liquid chromatography (HPLC) shows that NPY immunoreactivity of human extracts elutes in an earlier position than the porcine standard. It seems likely therefore that human and porcine NPY differ in their amino acid sequences.

Release of neuropeptide FF (FLFQPQRF-NH2) from rat spinal cord.

PubMed

Zhu, J; Jhamandas, K; Yang, H Y

1992-10-02

Neuropeptide FF (FLFQPQRF-NH2), originally isolated from bovine brain, is an FMRF-NH2-like peptide with morphine-modulating activity. Neuropeptide FF (NPFF) is highly localized in the dorsal spinal cords where there are also specific NPFF binding sites. Furthermore, there have been studies indicating that NPFF may participate in the regulation of pain threshold in the spinal cord. However, whether NPFF can be released from the spinal cord is not known. The present experiments, using an in vitro superfusion of an isolated whole rat spinal cord, demonstrated that high concentrations of KCl or substance P caused a release of NPFF immunoreactive material (IR) from the spinal cord into the perfusion medium in a calcium-dependent manner. Substance P (1-11) also produced a detectable release of NPFF-IR in vivo although the response was quite variable. The released NPFF-IR was analyzed by an HPLC study and found to consist of NPFF and other minor immunoreactive peptides. Further studies with substance P-related peptides showed that the in vitro release of NPFF-IR could also be induced by substance P (1-7) but not by [pGlu5,Me-Phe8,Sar9]-substance P (5-11) or substance K. These results suggest that the specific substance P receptor (SP-N), which is recognized by both substance P (1-11) and substance P (1-7) rather than the tachykinin receptor, is involved in NPFF secretion from the spinal cord. In view of the role of substance P (1-11) and substance P (1-7) in sensory transmission, the results of this study further support the role of NPFF in the modulation of antinociception in the spinal cord.

Direct and Indirect Antimicrobial Activities of Neuropeptides and their Therapeutic Potential

PubMed Central

Augustyniak, Daria; Nowak, Judyta; Lundy, Fionnuala T

2012-01-01

As global resistance to conventional antibiotics rises we need to develop new strategies to develop future novel therapeutics. In our quest to design novel anti-infectives and antimicrobials it is of interest to investigate host-pathogen interactions and learn from the complexity of host defense strategies that have evolved over millennia. A myriad of host defense molecules are now known to play a role in protection against human infection. However, the interaction between host and pathogen is recognized to be a multifaceted one, involving countless host proteins, including several families of peptides. The regulation of infection and inflammation by multiple peptide families may represent an evolutionary failsafe in terms of functional degeneracy and emphasizes the significance of host defense in survival. One such family is the neuropeptides (NPs), which are conventionally defined as peptide neurotransmitters but have recently been shown to be pleiotropic molecules that are integral components of the nervous and immune systems. In this review we address the antimicrobial and anti-infective effects of NPs both in vitro and in vivo and discuss their potential therapeutic usefulness in overcoming infectious diseases. With improved understanding of the efficacy of NPs, these molecules could become an important part of our arsenal of weapons in the treatment of infection and inflammation. It is envisaged that targeted therapy approaches that selectively exploit the anti-infective, antimicrobial and immunomodulatory properties of NPs could become useful adjuncts to our current therapeutic modalities. PMID:23305360

MicroRNA's impact on neurotransmitter and neuropeptide systems: small but mighty mediators of anxiety.

PubMed

Martinetz, Stefanie

2016-06-01

Psychiatric disorders rank among the most common severe diseases worldwide, with millions of people affected worldwide every year. The symptoms are manifold, and the outcome for the patients is often unclear. As a high and yearly rising cost burden for society, anxiety disorders, depression and their related mental disorders are currently a well-researched topic in order to develop new functional pharmacological therapies as alternatives to those that are in use and bear many unpleasant side effects. Brain circuitries, such as those underlying anxiety formations, are mainly driven by the interplay of various neurotransmitter systems and the interaction of different brain loci, as well as the modulating impact of neuropeptides. Targeting those networks is a complex but promising way to regulate mood. Alterations on molecular level of the neuronal cell in response to respective receptor activation, especially at post-transcriptional level via the highly regulatory function of non-coding RNAs such as microRNAs (miRNAs) seem to hold a promising future in the development of novel therapeutic strategies and are therefore under intensified investigation. This review focusses on the impact of miRNAs on the neurotransmitter and neuropeptide systems of the central nervous system relevant for the formation of anxiety disorders and discusses the potential of miRNAs for the development of new therapeutic strategies for anxiety and mood disorders.

Widespread receptivity to neuropeptide PDF throughout the neuronal circadian clock network of Drosophila revealed by real-time cyclic AMP imaging.

PubMed

Shafer, Orie T; Kim, Dong Jo; Dunbar-Yaffe, Richard; Nikolaev, Viacheslav O; Lohse, Martin J; Taghert, Paul H

2008-04-24

The neuropeptide PDF is released by sixteen clock neurons in Drosophila and helps maintain circadian activity rhythms by coordinating a network of approximately 150 neuronal clocks. Whether PDF acts directly on elements of this neural network remains unknown. We address this question by adapting Epac1-camps, a genetically encoded cAMP FRET sensor, for use in the living brain. We find that a subset of the PDF-expressing neurons respond to PDF with long-lasting cAMP increases and confirm that such responses require the PDF receptor. In contrast, an unrelated Drosophila neuropeptide, DH31, stimulates large cAMP increases in all PDF-expressing clock neurons. Thus, the network of approximately 150 clock neurons displays widespread, though not uniform, PDF receptivity. This work introduces a sensitive means of measuring cAMP changes in a living brain with subcellular resolution. Specifically, it experimentally confirms the longstanding hypothesis that PDF is a direct modulator of most neurons in the Drosophila clock network.

Regulation of neuropeptide Y gene expression in rat brain.

PubMed

Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H

1990-01-01

NPY mRNA expression was studied in rat brain using in situ hybridization and RNA blot analysis. Transsynaptic regulation of NPY gene expression was specifically studied in caudate-putamen and frontoparietal (somatosensory) cortex of rats with unilateral lesion of midbrain dopamine neurons and in sham-injected animals. NPY mRNA expression in these two brain regions and the regulation of midbrain dopamine neurons were compared with that of SOM, PPT, CCK and GAD mRNA expression. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a unilateral dopamine deafferentation, the numerical density of both NPY and SOM mRNA expressing neurons almost doubled in the lesioned rat caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to normally suppress expression of these two neuropeptide genes. An activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons is seen when the level of dopamine is decreased. In the frontoparietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. RNA blot analysis shows clear-cut changes of NPY mRNA levels in both caudate-putamen and frontoparietal cortex consistent with the changes observed using in situ hybridization. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions. Indirect evidence is also presented indicating that dopamine regulates NPY mRNA expression in a subpopulation of neurons that possibly also express GAD mRNA, both in caudate-putamen and in frontoparietal cortex.

Alterations of peptide metabolism and neuropeptidase activity in senile dementia of the Alzheimer's type.

PubMed

Waters, S M; Davis, T P

1997-04-24

Work in our laboratory has shown that in addition to previously characterized changes in the level of neuropeptides in SDAT brain, the activity of degradative enzymes responsible for peptide metabolism is also affected. In addition to other reported alterations in peptide metabolism, we have observed that SS-28 degradation is increased in Brodmann area 22 whereas substance P degradation is increased in temporal cortex. Changes in the degradation of these neuropeptides known to be affected in SDAT correlate well with alterations in the activity of specific neuropeptidases. Trypsin-like serine protease activity is increased in SDAT Brodmann area 22 which parallels the increased degradation of SS-28. The activity of MEP 24.15 is decreased in temporal cortex which corresponds to the decreased degradation of substance P. Changes in the activity of these degradative enzymes in SDAT brain can potentially affect the action of other neuropeptide substrates because the neuropeptidases discussed here terminate the action of several neuropeptides. As more neuropeptide and degradative peptidase alterations are discovered in SDAT, greater emphasis may be placed on the role that peptides and neuropeptidases play in the progression of SDAT.

Neuromedin B and gastrin releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong renilla GFP in NPY neurons

PubMed Central

van den Pol, Anthony N.; Yao, Yang; Fu, Li-Ying; Foo, Kylie; Huang, Hao; Coppari, Roberto; Lowell, Brad; Broberger, Christian

2009-01-01

Neuropeptide Y (NPY) is one of the most widespread neuropeptides in the brain. Transgenic mice were generated that expressed bright renilla GFP in most or all of the known NPY cells in the brain, which otherwise were not identifiable. GFP expression in NPY cells was confirmed with immunocytochemistry and single cell RT-PCR. NPY neurons in the hypothalamic arcuate nucleus play an important role in energy homeostasis and endocrine control. Whole cell patch clamp recording was used to study identified arcuate NPY cells. Primary agents that regulate energy balance include melanocortin receptor agonists, AgRP, and cannabinoids; none of these substances substantially influenced electrical properties of NPY neurons. In striking contrast, neuropeptides of the bombesin family, including gastrin releasing peptide and neuromedin B which are found in axons in the arcuate nucleus and may also be released from the gut to signal the brain, showed strong direct excitatory actions at nanomolar levels on the NPY neurons, stronger than the actions of ghrelin and hypocretin/orexin. Bombesin-related peptides reduced input resistance and depolarized the membrane potential. The depolarization was attenuated by several factors: substitution of choline for sodium, extracellular Ni2+, inclusion of BAPTA in the pipette, KB-R7943 and SKF96365. Reduced extracellular calcium enhanced the current, which reversed around − 20 mV. Together, these data suggest two mechanisms, activation of non-selective cation channels and the sodium/calcium exchanger. Since both NPY and POMC neurons, which we also studied, are similarly directly excited by bombesin-like peptides, the peptides may function to initiate broad activation, rather than the cell-type selective activation or inhibition reported for many other compounds that modulate energy homeostasis. PMID:19357287

Analgesic effect of the neuropeptide cortistatin in murine models of arthritic inflammatory pain.

PubMed

Morell, Maria; Souza-Moreira, Luciana; Caro, Marta; O'Valle, Francisco; Forte-Lago, Irene; de Lecea, Luis; Gonzalez-Rey, Elena; Delgado, Mario

2013-05-01

To investigate the role of the antiinflammatory neuropeptide cortistatin in chronic pain evoked by joint inflammation. Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in cortistatin-deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo. Expression of cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit Gαi , impairment of ERK signaling, and decreased production of calcitonin gene-related peptide in primary nociceptors. These findings indicate that cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory

Conformational and receptor-binding properties of the insect neuropeptide proctolin and its analogues

NASA Astrophysics Data System (ADS)

Odell, Barbara; Hammond, Stephen J.; Osborne, Richard; Goosey, Michael W.

1996-04-01

Proctolin (Arg-Tyr-Leu-Pro-Thr) was the first insect neuropeptide to be chemically characterised. It plays an essential role in insect neurophysiology and is involved in muscular contraction and neuromodulation. Elements of secondary structure in solution have been studied by comparing data obtained from NMR and molecular dynamics simulations. Different secondary structural requirements are associated with agonist and antagonist activities. A favoured conformation of proctolin has an inverse γ-turn, comprising an intramolecular hydrogen bond near the C-terminal end between Thr NH and Leu CO. Antagonists have a more compact structure resembling a `paperclip' loop, containing an intramolecular hydrogen bond between Tyr NH and Pro CO, possibly stabilised by a salt bridge between the N- and C-terminal groups. A cyclic analogue retains antagonist activity and resembles a β-bulge loop, also comprising intramolecular hydrogen bonds between Tyr NH and Pro CO and Thr CO. These models may offer feasible starting points for designing novel compounds with proctolinergic activity.

Spinal neuropeptide modulation, functional assessment and cartilage lesions in a monosodium iodoacetate rat model of osteoarthritis.

PubMed

Otis, Colombe; Guillot, Martin; Moreau, Maxim; Martel-Pelletier, Johanne; Pelletier, Jean-Pierre; Beaudry, Francis; Troncy, Eric

2017-10-01

Characterising the temporal evolution of changes observed in pain functional assessment, spinal neuropeptides and cartilage lesions of the joint after chemical osteoarthritis (OA) induction in rats. On day (D) 0, OA was induced by an IA injection of monosodium iodoacetate (MIA). Rats receiving 2mg MIA were temporally assessed at D3, D7, D14 and D21 for the total spinal cord concentration of substance P (SP), calcitonin gene related-peptide (CGRP), bradykinin (BK) and somatostatin (STT), and for severity of cartilage lesions. At D21, the same outcomes were compared with the IA 1mg MIA, IA 2mg MIA associated with punctual IA injection of lidocaine at D7, D14 and D21, sham (sterile saline) and naïve groups. Tactile allodynia was sequentially assessed using a von Frey anaesthesiometer. Non-parametric and mixed models were applied for statistical analysis. Tactile allodynia developed in the 2mg MIA group as soon as D3 and was maintained up to D21. Punctual IA treatment with lidocaine counteracted it at D7 and D14. Compared to naïve, [STT], [BK] and [CGRP] reached a maximum as early as D7, which plateaued up to D21. For [SP], the increase was delayed up to D14 and maintained at D21. No difference in levels of neuropeptides was observed between MIA doses, except for higher [STT] in the 2mg MIA group (P=0.029). Neuropeptides SP and BK were responsive to lidocaine treatment. The increase in severity of cartilage lesions was significant only in the 2mg MIA groups (P=0.01). In the MIA OA pain model, neuropeptide modulation appears early, and confirms the central nervous system to be an attractive target for OA pain quantification. The relationship of neuropeptide release with severity of cartilage lesions and functional assessment are promising and need further validation. Copyright © 2017 Elsevier Ltd. All rights reserved.

The α-Helical Structure of Prodomains Promotes Translocation of Intrinsically Disordered Neuropeptide Hormones into the Endoplasmic Reticulum*

PubMed Central

Dirndorfer, Daniela; Seidel, Ralf P.; Nimrod, Guy; Miesbauer, Margit; Ben-Tal, Nir; Engelhard, Martin; Zimmermann, Richard; Winklhofer, Konstanze F.; Tatzelt, Jörg

2013-01-01

Different neuropeptide hormones, which are either too small to adopt a stable conformation or are predicted to be intrinsically disordered, are synthesized as larger precursors containing a prodomain in addition to an N-terminal signal peptide. We analyzed the biogenesis of three unstructured neuropeptide hormones and observed that translocation of these precursors into the lumen of the endoplasmic reticulum (ER) is critically dependent on the presence of the prodomain. The hormone domains could be deleted from the precursors without interfering with ER import and secretion, whereas constructs lacking the prodomain remained in the cytosol. Domain-swapping experiments revealed that the activity of the prodomains to promote productive ER import resides in their ability to adopt an α-helical structure. Removal of the prodomain from the precursor did not interfere with co-translational targeting of the nascent chain to the Sec61 translocon but with its subsequent productive translocation into the ER lumen. Our study reveals a novel function of prodomains to enable import of small or intrinsically disordered secretory proteins into the ER based on their ability to adopt an α-helical conformation. PMID:23532840

Modification of caffeine effects on the affect-modulated startle by neuropeptide S receptor gene variation.

PubMed

Domschke, Katharina; Klauke, Benedikt; Winter, Bernward; Gajewska, Agnes; Herrmann, Martin J; Warrings, Bodo; Mühlberger, Andreas; Wosnitza, Katherina; Dlugos, Andrea; Naunin, Swantje; Nienhaus, Kathrin; Fobker, Manfred; Jacob, Christian; Arolt, Volker; Pauli, Paul; Reif, Andreas; Zwanzger, Peter; Deckert, Jürgen

2012-08-01

Both the neuropeptide S (NPS) system and antagonism at the adenosine A2A receptor (e.g., by caffeine) were found to play a crucial role in the mediation of arousal and anxiety/panic in animal and human studies. Furthermore, a complex interaction of the neuropeptide S and the adenosinergic system has been suggested with administration of the adenosine A2A receptor antagonist caffeine downregulating NPS levels (Lage et al., 2006) and attenuating the stimulatory effects of NPS in rodents (Boeck et al., 2010). Thus, in the present study, the impact of the functional neuropeptide S receptor (NPSR) A/T (Asn(107)Ile; rs324981) variant on affect-modulated (neutral, unpleasant, and pleasant IAPS pictures) startle response depending on the administration of 300 mg caffeine citrate was investigated in a sample of 124 (m = 58, f = 66) healthy probands using a double-blind, placebo-controlled design. ANOVA revealed a significant interaction between NPSR genotype, challenge condition, and picture valence. Comparing startle magnitudes upon stimulation with neutral or emotional pictures between the placebo and caffeine condition, in AA/AT non-risk genotype carriers no significant difference was discerned, while TT risk genotype carriers showed a significantly increased startle magnitude in response to neutral stimuli (p = .02) and a significantly decreased startle magnitude in response to unpleasant stimuli (p = .02) in the caffeine condition as compared to the placebo condition. In summary, the present findings - extending previous evidence from rodent studies - for the first time provide support for a complex, non-linear interaction of the neuropeptide S and adenosinergic systems affecting the affect-modulated startle response as an intermediate phenotype of anxiety in humans.

Neuropeptides in the desert ant Cataglyphis fortis: Mass spectrometric analysis, localization, and age-related changes.

PubMed

Schmitt, Franziska; Vanselow, Jens T; Schlosser, Andreas; Wegener, Christian; Rössler, Wolfgang

2017-03-01

Cataglyphis desert ants exhibit an age-related polyethism, with ants performing tasks in the dark nest for the first ∼4 weeks of their adult life before they switch to visually based long-distance navigation to forage. Although behavioral and sensory aspects of this transition have been studied, the internal factors triggering the behavioral changes are largely unknown. We suggest the neuropeptide families allatostatin A (AstA), allatotropin (AT), short neuropeptide F (sNPF), and tachykinin (TK) as potential candidates. Based on a neuropeptidomic analysis in Camponotus floridanus, nano-LC-ESI MS/MS was used to identify these neuropeptides biochemically in Cataglyphis fortis. Furthermore, we show that all identified peptide families are present in the central brain and ventral ganglia of C. fortis whereas in the retrocerebral complex only sNPF could be detected. Immunofluorescence staining against AstA, AT, and TK in the brain revealed arborizations of AstA- and TK-positive neurons in primary sensory processing centers and higher order integration centers, whereas AT immunoreactivity was restricted to the central complex, the antennal mechanosensory and motor center, and the protocerebrum. For artificially dark-kept ants, we found that TK distribution changed markedly in the central complex from days 1 and 7 to day 14 after eclosion. Based on functional studies in Drosophila, this age-related variation of TK is suggestive of a modulatory role in locomotion behavior in C. fortis. We conclude that the general distribution and age-related changes in neuropeptides indicate a modulatory role in sensory input regions and higher order processing centers in the desert ant brain. J. Comp. Neurol. 525:901-918, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Phylogenetic appearance of Neuropeptide S precursor proteins in tetrapods

PubMed Central

Reinscheid, Rainer K.

2007-01-01

Sleep and emotional behavior are two hallmarks of vertebrate animal behavior, implying that specialized neuronal circuits and dedicated neurochemical messengers may have been developed during evolution to regulate such complex behaviors. Neuropeptide S (NPS) is a newly identified peptide transmitter that activates a typical G protein-coupled receptor. Central administration of NPS produces profound arousal, enhances wakefulness and suppresses all stages of sleep. In addition, NPS can alleviate behavioral responses to stress by producing anxiolytic-like effects. A bioinformatic analysis of current genome databases revealed that the NPS peptide precursor gene is present in all vertebrates with the exception of fish. A high level of sequence conservation, especially of aminoterminal structures was detected, indicating stringent requirements for agonist-induced receptor activation. Duplication of the NPS precursor gene was only found in one out of two marsupial species with sufficient genome coverage (Monodelphis domestica; opossum), indicating that the duplicated opossum NPS sequence might have arisen as an isolated event. Pharmacological analysis of both Monodelphis NPS peptides revealed that only the closely related NPS peptide retained agonistic activity at NPS receptors. The duplicated precursor might be either a pseudogene or could have evolved different receptor selectivity. Together, these data show that NPS is a relatively recent gene in vertebrate evolution whose appearance might coincide with its specialized physiological functions in terrestrial vertebrates. PMID:17293003

Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin.

PubMed

Kapan, Neval; Lushchak, Oleh V; Luo, Jiangnan; Nässel, Dick R

2012-12-01

Insulin/IGF-like signaling regulates the development, growth, fecundity, metabolic homeostasis, stress resistance and lifespan in worms, flies and mammals. Eight insulin-like peptides (DILP1-8) are found in Drosophila. Three of these (DILP2, 3 and 5) are produced by a set of median neurosecretory cells (insulin-producing cells, IPCs) in the brain. Activity in the IPCs of adult flies is regulated by glucose and several neurotransmitters and neuropeptides. One of these, short neuropeptide F (sNPF), regulates food intake, growth and Dilp transcript levels in IPCs via the sNPF receptor (sNPFR1) expressed on IPCs. Here we identify a set of brain neurons that utilizes sNPF to activate the IPCs. These sNPF-expressing neurons (dorsal lateral peptidergic neurons, DLPs) also produce the neuropeptide corazonin (CRZ) and have axon terminations impinging on IPCs. Knockdown of either sNPF or CRZ in DLPs extends survival in flies exposed to starvation and alters carbohydrate and lipid metabolism. Expression of sNPF in DLPs in the sNPF mutant background is sufficient to rescue wild-type metabolism and response to starvation. Since CRZ receptor RNAi in IPCs affects starvation resistance and metabolism, similar to peptide knockdown in DLPs, it is likely that also CRZ targets the IPCs. Knockdown of sNPF, but not CRZ in DLPs decreases transcription of Dilp2 and 5 in the brain, suggesting different mechanisms of action on IPCs of the two co-released peptides. Our findings indicate that sNPF and CRZ co-released from a small set of neurons regulate IPCs, stress resistance and metabolism in adult Drosophila.

The Role of Salivary Neuropeptides in Pediatrics: Potential Biomarkers for Integrated Therapies.

PubMed

Gershan, Lynn A; Durham, Paul L; Skidmore, Jaci; Shimizu, Joshua; Cady, Ryan J; Sheng, Xiaoming; Maloney, Christopher G

2015-08-01

Objective measures of symptom response to integrated complementary approaches in pediatrics are evolving. The purpose of this study was to document the concentration range of salivary neuropeptides in healthy controls and in children with cancer, to explore correlations between serum and salivary measurements for Calcitonin Gene-Related Peptide (CGRP) and Vasoactive Intestinal Polypeptide (VIP), and to determine whether there is a change in these salivary neuropeptide levels in response to integrated mind-body therapies. A non-randomized pragmatic study with three phases: Phase 1- Healthy Control Saliva-10 healthy controls provided saliva samples; Phase 2- Cancer Diagnosis Serum-Saliva- 16 mixed-type cancer patients provided blood and saliva samples; Phase 3- Acute Lymphocytic Leukemia (ALL) Saliva Intervention- 12 patients with ALL provided pre- and post-complementary intervention saliva samples. 20-minutes of structured touch or scripted relaxation breathing were administered to patients in Phase 3; Phase 1 and 2 patients did not receive this intervention. cortisol, CGRP, VIP, State/Trait Anxiety Scale, visual analogue scale, vital signs. Salivary CGRP and VIP were similar for children in Phases 1 and 2. There was a correlation between serum and salivary VIP in the mixed cancer group, though not between serum and salivary CGRP. In Phase 3 children, following a complementary intervention, salivary CGRP, heart rate, and systolic blood pressure decreased. These data provide evidence of a decrease in sympathetic output after integrative/complementary therapy intervention in children with cancer. The study underscores the potential role of salivary neuropeptides as non-invasive biomarkers for integrated therapies in pediatrics.

Monoamines and neuropeptides interact to inhibit aversive behaviour in Caenorhabditis elegans.

PubMed

Mills, Holly; Wragg, Rachel; Hapiak, Vera; Castelletto, Michelle; Zahratka, Jeffrey; Harris, Gareth; Summers, Philip; Korchnak, Amanda; Law, Wenjing; Bamber, Bruce; Komuniecki, Richard

2012-02-01

Pain modulation is complex, but noradrenergic signalling promotes anti-nociception, with α(2)-adrenergic agonists used clinically. To better understand the noradrenergic/peptidergic modulation of nociception, we examined the octopaminergic inhibition of aversive behaviour initiated by the Caenorhabditis elegans nociceptive ASH sensory neurons. Octopamine (OA), the invertebrate counterpart of norepinephrine, modulates sensory-mediated reversal through three α-adrenergic-like OA receptors. OCTR-1 and SER-3 antagonistically modulate ASH signalling directly, with OCTR-1 signalling mediated by Gα(o). In contrast, SER-6 inhibits aversive responses by stimulating the release of an array of 'inhibitory' neuropeptides that activate receptors on sensory neurons mediating attraction or repulsion, suggesting that peptidergic signalling may integrate multiple sensory inputs to modulate locomotory transitions. These studies highlight the complexity of octopaminergic/peptidergic interactions, the role of OA in activating global peptidergic signalling cascades and the similarities of this modulatory network to the noradrenergic inhibition of nociception in mammals, where norepinephrine suppresses chronic pain through inhibitory α(2)-adrenoreceptors on afferent nociceptors and stimulatory α(1)-receptors on inhibitory peptidergic interneurons.

Monoamines and neuropeptides interact to inhibit aversive behaviour in Caenorhabditis elegans

PubMed Central

Mills, Holly; Wragg, Rachel; Hapiak, Vera; Castelletto, Michelle; Zahratka, Jeffrey; Harris, Gareth; Summers, Philip; Korchnak, Amanda; Law, Wenjing; Bamber, Bruce; Komuniecki, Richard

2012-01-01

Pain modulation is complex, but noradrenergic signalling promotes anti-nociception, with α2-adrenergic agonists used clinically. To better understand the noradrenergic/peptidergic modulation of nociception, we examined the octopaminergic inhibition of aversive behaviour initiated by the Caenorhabditis elegans nociceptive ASH sensory neurons. Octopamine (OA), the invertebrate counterpart of norepinephrine, modulates sensory-mediated reversal through three α-adrenergic-like OA receptors. OCTR-1 and SER-3 antagonistically modulate ASH signalling directly, with OCTR-1 signalling mediated by Gαo. In contrast, SER-6 inhibits aversive responses by stimulating the release of an array of ‘inhibitory' neuropeptides that activate receptors on sensory neurons mediating attraction or repulsion, suggesting that peptidergic signalling may integrate multiple sensory inputs to modulate locomotory transitions. These studies highlight the complexity of octopaminergic/peptidergic interactions, the role of OA in activating global peptidergic signalling cascades and the similarities of this modulatory network to the noradrenergic inhibition of nociception in mammals, where norepinephrine suppresses chronic pain through inhibitory α2-adrenoreceptors on afferent nociceptors and stimulatory α1-receptors on inhibitory peptidergic interneurons. PMID:22124329

The neuropeptide oxytocin modulates consumer brand relationships

PubMed Central

Fürst, Andreas; Thron, Jesko; Scheele, Dirk; Marsh, Nina; Hurlemann, René

2015-01-01

Each year, companies invest billions of dollars into marketing activities to embellish brands as valuable relationship partners assuming that consumer brand relationships (CBRs) and interpersonal relationships rest upon the same neurobiological underpinnings. Given the crucial role of the neuropeptide oxytocin (OXT) in social bonding, this study tests whether OXT-based mechanisms also determine the bond between consumers and brands. We conducted a randomized, placebo-controlled study involving 101 subjects and analyzed the effect of intranasal OXT on consumers’ attribution of relationship qualities to brands, brands paired with human celebrity endorsers, and familiar persons. OXT indeed promoted the attribution of relationship qualities not only in the case of social and semi-social stimuli, but also brands. Intriguingly, for subjects scoring high on autistic-like traits, the effect of OXT was completely reversed, evident in even lower relationship qualities across all stimulus categories. The importance of OXT in a CBR context is further corroborated by a three-fold increase in endogenous release of OXT following exposure to one’s favorite brand and positive associations between baseline peripheral OXT concentrations and brand relationship qualities. Collectively, our findings indicate that OXT not only plays a fundamental role in developing interpersonal relationships, but also enables relationship formation with objects such as brands. PMID:26449882

The neuropeptide oxytocin modulates consumer brand relationships.

PubMed

Fürst, Andreas; Thron, Jesko; Scheele, Dirk; Marsh, Nina; Hurlemann, René

2015-10-09

Each year, companies invest billions of dollars into marketing activities to embellish brands as valuable relationship partners assuming that consumer brand relationships (CBRs) and interpersonal relationships rest upon the same neurobiological underpinnings. Given the crucial role of the neuropeptide oxytocin (OXT) in social bonding, this study tests whether OXT-based mechanisms also determine the bond between consumers and brands. We conducted a randomized, placebo-controlled study involving 101 subjects and analyzed the effect of intranasal OXT on consumers' attribution of relationship qualities to brands, brands paired with human celebrity endorsers, and familiar persons. OXT indeed promoted the attribution of relationship qualities not only in the case of social and semi-social stimuli, but also brands. Intriguingly, for subjects scoring high on autistic-like traits, the effect of OXT was completely reversed, evident in even lower relationship qualities across all stimulus categories. The importance of OXT in a CBR context is further corroborated by a three-fold increase in endogenous release of OXT following exposure to one's favorite brand and positive associations between baseline peripheral OXT concentrations and brand relationship qualities. Collectively, our findings indicate that OXT not only plays a fundamental role in developing interpersonal relationships, but also enables relationship formation with objects such as brands.

Neuropeptide Y and sleep.

PubMed

Dyzma, Michal; Boudjeltia, Karim Z; Faraut, Brice; Kerkhofs, Myriam

2010-06-01

Neuropeptide Y (NPY), a 36-amino-acid peptide from the pancreatic polypeptide family, is one of the more abundant peptides in the central nervous system. It acts as a neurohormone and as a neuromodulator. NPY is widely distributed in the brain, particularly the hypothalamus, the amygdala, the locus coeruleus and the cerebral cortex. At least six NPY receptors subtypes have been identified. NPY is involved in the regulation of several physiological functions such as food intake, hormonal release, circadian rhythms, cardiovascular disease, thermoregulation, stress response, anxiety and sleep. Sleep promoting effects of NPY as well as wakefulness effects of NPY were found in animals, depending on the site of injection as well as on the functional state of the structure. In humans, NPY was found to have hypnotic properties, possibly acting as a physiological antagonist of corticotropin-releasing hormone (CRH). In conclusion, NPY participates in sleep regulation in humans, particularly in the timing of sleep onset and may as such play a role in the integration of sleep regulation, food intake and metabolism. Copyright 2009 Elsevier Ltd. All rights reserved.

A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice.

PubMed

Takayasu, Shinobu; Sakurai, Takeshi; Iwasaki, Satoshi; Teranishi, Hitoshi; Yamanaka, Akihiro; Williams, S Clay; Iguchi, Haruhisa; Kawasawa, Yuka Imamura; Ikeda, Yukio; Sakakibara, Iori; Ohno, Kousaku; Ioka, Ryoichi X; Murakami, Saori; Dohmae, Naoshi; Xie, Jian; Suda, Toshihiro; Motoike, Toshiyuki; Ohuchi, Takashi; Yanagisawa, Masashi; Sakai, Juro

2006-05-09

Here, we report the isolation and characterization of an endogenous peptide ligand of GPR103 from rat brains. The purified peptide was found to be the 43-residue RF-amide peptide QRFP. We also describe two mouse homologues of human GPR103, termed mouse GPR103A and GPR103B. QRFP binds and activates the human GPR103, as well as mouse GPR103A and GPR103B, with nanomolar affinities in transfected cells. Systematic in situ hybridization analysis in mouse brains showed that QRFP is expressed exclusively in the periventricular and lateral hypothalamus, whereas the two receptor mRNAs are distinctly localized in various brain areas without an overlap to each other. When administered centrally in mice, QRFP induced feeding behavior, accompanied by increased general locomotor activity and metabolic rate. QRFP-induced food intake was abolished by preadministration of BIBP3226, a specific antagonist for the Y1 neuropeptide Y receptor. Hypothalamic prepro-QRFP mRNA expression was up-regulated upon fasting and in genetically obese ob/ob and db/db mice. Central QRFP administration also evoked highly sustained elevation of blood pressure and heart rate. Our findings suggest that QRFP and GPR103A/B may regulate diverse neuroendocrine and behavioral functions and implicate this neuropeptide system in metabolic syndrome.

Central and peripheral clocks are coupled by a neuropeptide pathway in Drosophila

PubMed Central

Selcho, Mareike; Millán, Carola; Palacios-Muñoz, Angelina; Ruf, Franziska; Ubillo, Lilian; Chen, Jiangtian; Bergmann, Gregor; Ito, Chihiro; Silva, Valeria; Wegener, Christian; Ewer, John

2017-01-01

Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals. PMID:28555616

Neuromedin B and gastrin-releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong Renilla green fluorescent protein in NPY neurons.

PubMed

van den Pol, Anthony N; Yao, Yang; Fu, Li-Ying; Foo, Kylie; Huang, Hao; Coppari, Roberto; Lowell, Bradford B; Broberger, Christian

2009-04-08

Neuropeptide Y (NPY) is one of the most widespread neuropeptides in the brain. Transgenic mice were generated that expressed bright Renilla green fluorescent protein (GFP) in most or all of the known NPY cells in the brain, which otherwise were not identifiable. GFP expression in NPY cells was confirmed with immunocytochemistry and single-cell reverse transcription-PCR. NPY neurons in the hypothalamic arcuate nucleus play an important role in energy homeostasis and endocrine control. Whole-cell patch clamp recording was used to study identified arcuate NPY cells. Primary agents that regulate energy balance include melanocortin receptor agonists, AgRP, and cannabinoids; none of these substances substantially influenced electrical properties of NPY neurons. In striking contrast, neuropeptides of the bombesin family, including gastrin-releasing peptide and neuromedin B, which are found in axons in the mediobasal hypothalamus and may also be released from the gut to signal the brain, showed strong direct excitatory actions at nanomolar levels on the NPY neurons, stronger than the actions of ghrelin and hypocretin/orexin. Bombesin-related peptides reduced input resistance and depolarized the membrane potential. The depolarization was attenuated by several factors: substitution of choline for sodium, extracellular Ni(2+), inclusion of BAPTA in the pipette, KB-R7943, and SKF96365. Reduced extracellular calcium enhanced the current, which reversed around -20 mV. Together, these data suggest two mechanisms, activation of nonselective cation channels and the sodium/calcium exchanger. Since both NPY and POMC neurons, which we also studied, are similarly directly excited by bombesin-like peptides, the peptides may function to initiate broad activation, rather than the cell-type selective activation or inhibition reported for many other compounds that modulate energy homeostasis.

The Role of Salivary Neuropeptides in Pediatrics: Potential Biomarkers for Integrated Therapies

PubMed Central

Gershan, Lynn A; Durham, Paul L; Skidmore, Jaci; Shimizu, Joshua; Cady, Ryan J; Sheng, Xiaoming; Maloney, Christopher G

2015-01-01

Introduction Objective measures of symptom response to integrated complementary approaches in pediatrics are evolving. The purpose of this study was to document the concentration range of salivary neuropeptides in healthy controls and in children with cancer, to explore correlations between serum and salivary measurements for Calcitonin Gene-Related Peptide (CGRP) and Vasoactive Intestinal Polypeptide (VIP), and to determine whether there is a change in these salivary neuropeptide levels in response to integrated mind-body therapies. Methods A non-randomized pragmatic study with three phases: Phase 1- Healthy Control Saliva-10 healthy controls provided saliva samples; Phase 2- Cancer Diagnosis Serum-Saliva- 16 mixed-type cancer patients provided blood and saliva samples; Phase 3- Acute Lymphocytic Leukemia (ALL) Saliva Intervention- 12 patients with ALL provided pre- and post-complementary intervention saliva samples. Interventions 20-minutes of structured touch or scripted relaxation breathing were administered to patients in Phase 3; Phase 1 and 2 patients did not receive this intervention. Outcome Measures cortisol, CGRP, VIP, State/Trait Anxiety Scale, visual analogue scale, vital signs. Results Salivary CGRP and VIP were similar for children in Phases 1 and 2. There was a correlation between serum and salivary VIP in the mixed cancer group, though not between serum and salivary CGRP. In Phase 3 children, following a complementary intervention, salivary CGRP, heart rate, and systolic blood pressure decreased. Discussion/Conclusions These data provide evidence of a decrease in sympathetic output after integrative/complementary therapy intervention in children with cancer. The study underscores the potential role of salivary neuropeptides as non-invasive biomarkers for integrated therapies in pediatrics. PMID:26388958

Specific Activation of the G Protein-coupled Receptor BNGR-A21 by the Neuropeptide Corazonin from the Silkworm, Bombyx mori, Dually Couples to the Gq and Gs Signaling Cascades*

PubMed Central

Yang, Jingwen; Huang, Haishan; Yang, Huipeng; He, Xiaobai; Jiang, Xue; Shi, Ying; Alatangaole, Damirin; Shi, Liangen; Zhou, Naiming

2013-01-01

Corazonin, an undecapeptide neurohormone sharing a highly conserved amino acid sequence across Insecta, plays different physiological roles in the regulation of heart contraction rates, silk spinning rates, the induction of dark color and morphometric phase changes, and ecdysis. Corazonin receptors have been identified in Drosophila melanogaster, Manduca sexta, and Musca domestica. However, detailed information on the signaling and major physiological functions of corazonin and its receptor is largely unknown. In the current study, using both the mammalian cell line HEK293 and insect cell lines BmN and Sf21, we paired the Bombyx corazonin neuropeptide as a specific endogenous ligand for the Bombyx neuropeptide G protein-coupled receptor A21 (BNGR-A21), and we therefore designated this receptor as BmCrzR. Further characterization indicated that synthetic BmCrz demonstrated a high affinity for and activated BmCrzR, resulting in intracellular cAMP accumulation, Ca2+ mobilization, and ERK1/2 phosphorylation via the Gq- and Gs-coupled signaling pathways. The direct interaction of BmCrzR with BmCrz was confirmed by a rhodamine-labeled BmCrz peptide. Moreover, experiments with double-stranded RNA and synthetic peptide injection suggested a possible role of BmCrz/BmCrzR in the regulation of larval growth and spinning rate. Our present results provide the first in-depth information on BmCrzR-mediated signaling for further elucidation of the BmCrz/BmCrzR system in the regulation of fundamental physiological processes. PMID:23457297

Non-pharmacological treatment affects neuropeptide expression in neuropathic pain model.

PubMed

Santos, Fabio Martinez; Silva, Joyce Teixeira; Rocha, Igor Rafael Correia; Martins, Daniel Oliveira; Chacur, Marucia

2018-05-15

Chronic constriction injury (CCI) of the sciatic nerve elicits changes in neuropeptide expression on the dorsal root ganglia (DRG). The neural mobilization (NM) technique is a noninvasive method that has been proven clinically effective in reducing pain. The aim of this study was to analyze the expression of substance P, transient receptor potential vanilloid 1 (TRPV1) and opioid receptors in the DRG of rats with chronic constriction injury and to compare it to animals that received NM treatment. CCI was performed on adult male rats. Each animal was submitted to 10 sessions of neural mobilization every other day, starting 14 days after the CCI injury. At the end of the sessions, the DRG (L4-L6) were analyzed using Western blot assays for substance P, TRPV1 and opioid receptors (µ-opioid receptor, δ-opioid receptor and κ-opioid receptor). We observed a decreased substance P and TRPV1 expression (48% and 35%, respectively) and an important increase of µ-opioid receptor expression (200%) in the DRG after NM treatment compared to control animals. The data provide evidence that NM promotes substantial changes in neuropeptide expression in the DRG; these results may provide new options for treating neuropathic pain. Copyright © 2018 Elsevier B.V. All rights reserved.

Bronchial mucosal immunoreactivity of sensory neuropeptides in severe airway diseases.

PubMed

Chanez, P; Springall, D; Vignola, A M; Moradoghi-Hattvani, A; Polak, J M; Godard, P; Bousquet, J

1998-09-01

Neuropeptides act on most of the components of the bronchial environment. They influence bronchomotor tone and bronchial vascular caliber and permeability. To investigate the nonadrenergic, noncholinergic system within the airways in asthma and chronic bronchitis, we performed endobronchial biopsies in 16 normal human volunteers, 49 patients with asthma of varying severity, including 16 patients treated with oral corticosteroids, and 13 patients with chronic bronchitis. Frozen sections of biopsies stained with specific antibodies against the neural marker PGP 9.5, vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were analyzed for the presence of nerves through indirect immunofluorescence. Nerves were present in most of the biopsies and were found within and below the epithelium and adjacent to smooth muscle, glands, and blood vessels. By comparison with those in normal subjects, the numbers of VIP-immunoreactive nerves were not significantly decreased in patients with asthma and chronic bronchitis, but NPY-immunoreactive nerves were significantly decreased in the smooth muscle of these latter two groups of patients (p < 0.005). There was no correlation between disease severity and the number of nerves found in the biopsies. This study does not confirm previous findings in autopsy material of some defects in sensory and VIP-containing nerves in severe asthma.

Intermittent hypoxia activates peptidylglycine α-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing

PubMed Central

Sharma, Suresh D.; Raghuraman, Gayatri; Lee, Myeong-Seon; Prabhakar, Nanduri R.; Kumar, Ganesh K.

2009-01-01

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine α-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the α-amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O2-sensitive peptidylglycine α-hydroxylating monooxygenase (PHM) and peptidyl-α-hydroxyglycine α-amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O2 for 15 s followed by 21% O2 for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of α-amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM (∼1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases Vmax but has no effect on Km. IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic neurotransmission in rat brain stem

Intermittent hypoxia activates peptidylglycine alpha-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing.

PubMed

Sharma, Suresh D; Raghuraman, Gayatri; Lee, Myeong-Seon; Prabhakar, Nanduri R; Kumar, Ganesh K

2009-01-01

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the alpha-amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O(2)-sensitive peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O(2) for 15 s followed by 21% O(2) for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of alpha-amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM ( approximately 1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases V(max) but has no effect on K(m). IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic

Neuropeptide Y, resilience, and PTSD therapeutics.

PubMed

Kautz, Marin; Charney, Dennis S; Murrough, James W

2017-05-10

Resilience to traumatic stress is a complex psychobiological process that protects individuals from developing posttraumatic stress disorder (PTSD) or other untoward consequences of exposure to extreme stress, including depression. Progress in translational research points toward the neuropeptide Y (NPY) system - among others - as a key mediator of stress response and as a potential therapeutic focus for PTSD. Substantial preclinical evidence supports the role of NPY in the modulation of stress response and in the regulation of anxiety in animal models. Clinical studies testing the safety and efficacy of modulating the NPY system in humans, however, have lagged behind. In the current article, we review the evidence base for targeting the NPY system as a therapeutic approach in PTSD, and consider impediments and potential solutions to therapeutic development. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Development of mimetic analogs of pyrokinin-like neuropeptides to disrupt pest insect physiology/behavior

USDA-ARS?s Scientific Manuscript database

Pyrokinin (FXPRLamide) neuropeptides regulate a variety of critical processes and behaviors in insects, though they are unsuitable as tools to arthropod endocrinologists and/or as pest management agents due to sub-optimal biostability and/or bioavailability characteristics. Peptidomimetic analogs c...

Evaluation of a PK/PBAN Analog with an (E)-Alkene, trans-Pro Isostere Identifies the Pro Orientation for Activity in Four Diverse PK/PBAN Bioassays

DTIC Science & Technology

2009-01-01

member of the family, leucopyrokinin (LPK), was isolated from the cockroach Leucophaea maderae [12] with over 30members of this peptide class...myotropic bioassays The results of an evaluation of trans-Pro isosteric analog PK- Etz in the larval pupariation assay of N. bullata and isolated ...001-01R) (RJN). References [1] Abernathy RL, Nachman RJ, Teal PEA , Yamashita O, Tumlinson JH. Pheromo- notropic activity of naturally-occurring

Drosophila GPCR Han is a receptor for the circadian clock neuropeptide PDF.

PubMed

Hyun, Seogang; Lee, Youngseok; Hong, Sung-Tae; Bang, Sunhoe; Paik, Donggi; Kang, Jongkyun; Shin, Jinwhan; Lee, Jaejung; Jeon, Keunhye; Hwang, Seungyoon; Bae, Eunkyung; Kim, Jaeseob

2005-10-20

The pigment-dispersing factor (PDF) is a neuropeptide controlling circadian behavioral rhythms in Drosophila, but its receptor is not yet known. From a large-scale temperature preference behavior screen in Drosophila, we isolated a P insertion mutant that preferred different temperatures during the day and night. This mutation, which we named han, reduced the transcript level of CG13758. We found that Han was expressed specifically in 13 pairs of circadian clock neurons in the adult brain. han null flies showed arrhythmic circadian behavior in constant darkness. The behavioral characteristics of han null mutants were similar to those of pdf null mutants. We also found that PDF binds specifically to S2 cells expressing Han, which results in the elevation of cAMP synthesis. Therefore, we herein propose that Han is a PDF receptor regulating circadian behavioral rhythm through coordination of activities of clock neurons.

Serotonin and the Neuropeptide PDF Initiate and Extend Opposing Behavioral States in C. elegans

PubMed Central

Flavell, Steven W.; Pokala, Navin; Macosko, Evan Z.; Albrecht, Dirk R.; Larsch, Johannes; Bargmann, Cornelia I.

2013-01-01

SUMMARY Foraging animals have distinct exploration and exploitation behaviors that are organized into discrete behavioral states. Here we characterize a neuromodulatory circuit that generates long-lasting roaming and dwelling states in Caenorhabditis elegans. We find that two opposing neuromodulators, serotonin and the neuropeptide pigment dispersing factor (PDF), each initiate and extend one behavioral state. Serotonin promotes dwelling states through the MOD-1 serotonin-gated chloride channel. The spontaneous activity of serotonergic neurons correlates with dwelling behavior, and optogenetic modulation of the critical MOD-1-expressing targets induces prolonged dwelling states. PDF promotes roaming states through a Gαs-coupled PDF receptor; optogenetic activation of cAMP production in PDF receptor-expressing cells induces prolonged roaming states. The neurons that produce and respond to each neuromodulator form a distributed circuit orthogonal to the classical wiring diagram, with several essential neurons that express each molecule. The slow temporal dynamics of this neuromodulatory circuit supplement fast motor circuits to organize long-lasting behavioral states. PMID:23972393

Characterization of tachykinin receptors mediating bronchomotor and vasodepressor responses to neuropeptide gamma and substance P in the anaesthetized rabbit.

PubMed

Yuan, L; Burcher, E; Nail, B S

1998-02-01

The effects of i.v. injections of two endogenous tachykinins, substance P (SP) and neuropeptide gamma and the highly selective tachykinin agonists [Sar9,Met(O2)11]-SP, [Lys5,MeLeu9, Nle10]-NKA(4-10) and senktide, on total lung resistance (RL), dynamic lung compliance (Cdyn) and systemic blood pressure, were compared in the anaesthetized rabbit. Senktide, the NK-3 receptor selective agonist, had no effect on RL, Cdyn or blood pressure. The other four agonists caused dose-dependent increases in RL and Cdyn, with [Sar9,Met(O2)11]-SP being the most potent agonist in producing changes in the absence of phosphoramidon. This suggested that NK-1 receptors play an important role in these responses. [Sar9, Met(O2)11]-SP, SP and neuropeptide gamma also decreased blood pressure. Phosphoramidon (1 mg/kg) potentiated the changes in RL and Cdyn evoked by [Sar9,Met(O2)11]-SP and SP, with very marked enhancement of responses to neuropeptide gamma. Responses to [Lys5, MeLeu9,Nle10]-NKA(4-10) were unaffected, suggesting that this NK-2 selective agonist may not be catabolized by neutral endopeptidase (NEP). In the presence of phosphoramidon, the non-peptide tachykinin NK-1 receptor selective antagonist CP 96345 (80 nmol/kg) reduced all responses to [Sar9,Met(O2)11]-SP and SP, whereas the NK-2 selective antagonist SR 48968 (40 nmol/kg) inhibited the bronchomotor but not the vasodepressor responses to neuropeptide gamma and [Lys5,MeLeu9, Nle10]-NKA(4-10). The fall in blood pressure induced by neuropeptide gamma was diminished by CP 96345, whereas bronchoconstriction was unaffected, indicating possible differences in NK-1 receptors in the vasculature and airways. Electrical stimulation of the distal ends of vagus nerves caused increases in RL which were abolished by atropine (1 mg/kg). Copyright 1998 Academic Press Limited

Peripheral axotomy of the rat mandibular trigeminal nerve leads to an increase in VIP and decrease of other primary afferent neuropeptides in the spinal trigeminal nucleus.

PubMed

Atkinson, M E; Shehab, S A

1986-12-01

In the vasoactive intestinal polypeptide (VIP)-rich lumbosacral spinal cord, VIP increases at the expense of other neuropeptides after primary sensory nerve axotomy. This study was undertaken to ascertain whether similar changes occur in peripherally axotomised cranial sensory nerves. VIP immunoreactivity increased in the terminal region of the mandibular nerve in the trigeminal nucleus caudalis following unilateral section of the sensory root of the mandibular trigeminal nerve at the foramen orale. Other primary afferent neuropeptides (substance P, cholecystokinin and somatostatin) were depleted and fluoride-resistant acid phosphatase activity was abolished in the same circumscribed areas of the nucleus caudalis. The rise in VIP and depletion of other markers began 4 days postoperatively and was maximal by 10 days, these levels remaining unchanged up to 1 year postoperatively. VIP-immunoreactive cell bodies were absent from trigeminal ganglia from the unoperated side but small and medium cells stained intensely in the ganglia of the operated side after axotomy. These observations indicate that increase of VIP in sensory nerve terminals is a general phenomenon occurring in both cranial and spinal sensory terminal areas. The intense VIP immunoreactivity in axotomised trigeminal ganglia suggests that the increased levels of VIP in the nucleus caudalis are of peripheral origin, indicating a change in expression of neuropeptides within primary afferent neurons following peripheral axotomy.

Neuropeptide S interacts with the basolateral amygdala noradrenergic system in facilitating object recognition memory consolidation.

PubMed

Han, Ren-Wen; Xu, Hong-Jiao; Zhang, Rui-San; Wang, Pei; Chang, Min; Peng, Ya-Li; Deng, Ke-Yu; Wang, Rui

2014-01-01

The noradrenergic activity in the basolateral amygdala (BLA) was reported to be involved in the regulation of object recognition memory. As the BLA expresses high density of receptors for Neuropeptide S (NPS), we investigated whether the BLA is involved in mediating NPS's effects on object recognition memory consolidation and whether such effects require noradrenergic activity. Intracerebroventricular infusion of NPS (1nmol) post training facilitated 24-h memory in a mouse novel object recognition task. The memory-enhancing effect of NPS could be blocked by the β-adrenoceptor antagonist propranolol. Furthermore, post-training intra-BLA infusions of NPS (0.5nmol/side) improved 24-h memory for objects, which was impaired by co-administration of propranolol (0.5μg/side). Taken together, these results indicate that NPS interacts with the BLA noradrenergic system in improving object recognition memory during consolidation. Copyright © 2013 Elsevier Inc. All rights reserved.

Association analysis between feed efficiency studies and expression of hypothalamic neuropeptide genes in laying ducks.

PubMed

Zeng, T; Chen, L; Du, X; Lai, S J; Huang, S P; Liu, Y L; Lu, L Z

2016-10-01

Residual feed intake (RFI) is now considered a more reasonable metric to evaluate animal feed efficiency. In this study, the correlation between RFI and other feed efficiency traits was investigated and gene expression within the hypothalamus was determined in low RFI (LRFI) and high RFI (HRFI) ducks. Further, several hypothalamic neuropeptide genes were measured using quantitative real-time PCR. The mean feed intake value was 160 g/day, whereas the egg mass laid (EML) and body weight were approximately 62.4 g/day and 1.46 kg respectively. Estimates for heritability of RFI, feed conversion ratio (FCR) and feed intake were 0.26, 0.18 and 0.23 respectively. RFI is phenotypically positively correlated with feed intake and FCR (P < 0.01). The expression of neuropeptide Y (NPY) and neuropeptide Y receptor Y5 (NPY5R) mRNA was higher in HRFI ducks compared with LRFI ducks (P < 0.05), whereas that of proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R) and cholecystokinin (CCK) was lower (P < 0.05). The mRNA expression of gonadotropin-releasing hormone 1 (luteinizing-releasing hormone) (GNRH1) and prolactin receptor (PRLR) was unchanged between LRFI and HRFI ducks. The results indicate that selection for LRFI could reduce feed intake without significant changes in EML, whereas selection on FCR will increase EML. © 2016 Stichting International Foundation for Animal Genetics.

Crustose Coralline Algae and a Cnidarian Neuropeptide Trigger Larval Settlement in Two Coral Reef Sponges

PubMed Central

Whalan, Steve; Webster, Nicole S.; Negri, Andrew P.

2012-01-01

In sessile marine invertebrates, larval settlement is fundamental to population maintenance and persistence. Cues contributing to the settlement choices and metamorphosis of larvae have important implications for the success of individuals and populations, but cues mediating larval settlement for many marine invertebrates are largely unknown. This study assessed larval settlement in two common Great Barrier Reef sponges, Coscinoderma matthewsi and Rhopaloeides odorabile, to cues that enhance settlement and metamorphosis in various species of scleractinian coral larvae. Methanol extracts of the crustose coralline algae (CCA), Porolithon onkodes, corresponding to a range of concentrations, were used to determine the settlement responses of sponge larvae. Cnidarian neuropeptides (GLW-amide neuropeptides) were also tested as a settlement cue. Settlement in both sponge species was approximately two-fold higher in response to live chips of CCA and optimum concentrations of CCA extract compared to 0.2 µm filtered sea water controls. Metamorphosis also increased when larvae were exposed to GLW-amide neuropeptides; R. odorabile mean metamorphosis reached 42.0±5.8% compared to 16.0±2.4% in seawater controls and in C. matthewsi mean metamorphosis reached 68.3±5.4% compared to 36.7±3.3% in seawater controls. These results demonstrate the contributing role chemosensory communication plays in the ability of sponge larvae to identify suitable habitat for successful recruitment. It also raises the possibility that larvae from distinct phyla may share signal transduction pathways involved in metamorphosis. PMID:22295083

Drosulfakinin activates CCKLR-17D1 and promotes larval locomotion and escape response in Drosophila

USDA-ARS?s Scientific Manuscript database

Neuropeptides are ubiquitous in both mammals and invertebrates and play essential roles in regulation and modulation of many developmental and physiological processes through activation of G-protein-coupled-receptors (GPCRs). However, the mechanisms by which many of the neuropeptides regulate speci...

Pancreatic Beta Cells Synthesize Neuropeptide Y and Can Rapidly Release Peptide Co-Transmitters

PubMed Central

Whim, Matthew D.

2011-01-01

Background In addition to polypeptide hormones, pancreatic endocrine cells synthesize a variety of bioactive molecules including classical transmitters and neuropeptides. While these co-transmitters are thought to play a role in regulating hormone release little is known about how their secretion is regulated. Here I investigate the synthesis and release of neuropeptide Y from pancreatic beta cells. Methodology/Principal Findings NPY appears to be an authentic co-transmitter in neonatal, but not adult, beta cells because (1) early in mouse post-natal development, many beta cells are NPY-immunoreactive whereas no staining is observed in beta cells from NPY knockout mice; (2) GFP-expressing islet cells from an NPY(GFP) transgenic mouse are insulin-ir; (3) single cell RT-PCR experiments confirm that the NPY(GFP) cells contain insulin mRNA, a marker of beta cells. The NPY-immunoreactivity previously reported in alpha and delta cells is therefore likely to be due to the presence of NPY-related peptides. INS-1 cells, a beta cell line, are also NPY-ir and contain NPY mRNA. Using the FMRFamide tagging technique, NPY secretion was monitored from INS-1 beta cells with high temporal resolution. Peptide release was evoked by brief depolarizations and was potentiated by activators of adenylate cyclase and protein kinase A. Following a transient depolarization, NPY-containing dense core granules fused with the cell membrane and discharged their contents within a few milliseconds. Conclusions These results indicate that after birth, NPY expression in pancreatic islets is restricted to neonatal beta cells. The presence of NPY suggests that peptide co-transmitters could mediate rapid paracrine or autocrine signaling within the endocrine pancreas. The FMRFamide tagging technique may be useful in studying the release of other putative islet co-transmitters in real time. PMID:21559341

Comparison of the therapeutic effects of sildenafil citrate, heparin and neuropeptides in a rat model of acetic acid-induced gastric ulcer.

PubMed

Kalayci, Mehmet; Kocdor, Mehmet Ali; Kuloglu, Tuncay; Sahin, İbrahim; Sarac, Mehmet; Aksoy, Aziz; Yardim, Meltem; Dalkilic, Semih; Gursu, Onur; Aydin, Suna; Akkoc, Ramazan Fazil; Ugras, Meltem; Artas, Gokhan; Ozercan, İbrahim Hanifi; Ugur, Kader; Aydin, Suleyman

2017-10-01

The purpose of our investigative work has been to determine whether there can be therapeutic roles in the administration of sildenafil citrate, heparin and several neuropeptides on an animal model where gastric ulcers were induced with acetic acid, and to compare their efficacy. The animals were divided into 13 groups, with 4 animals in each. Gastric ulcers was induced in the animals of 12 groups with one untreated group being left as the control (Group I - control; given normal saline (NS)). The other groups were: Group II (ulcer+NS); Group III (5mg/kg sildenafil citrate, low dose); Group IV (10mg/kg sildenafil citrate, high dose); Group V (0.6mg/kg heparin, low dose); Group VI (6mg/kg heparin, high dose); Group VII (20nmol/kg des-acyl ghrelin); Group VIII (40nmol/kg des-acyl ghrelin); Group IX (4nmol/kg acyl ghrelin); Group X (8nmol/kg acly ghrelin); Group XI (20pmol/kg Nesfatin-1); Group XII (15nmol/kg Obestatin) and Group XIII (5nmol/kg Neuropeptide Y). Gastric neuropeptide expression was measured using an immunohistochemical method, and the amount in circulation was detected using ELISA. To compare with no treatment, the controls and other treatment groups, we recorded loss of the surface epithelium of the stomach, erosion, bleeding and inflammatory cell infiltration in the upper halves of the gastric glands. The muscularis and the layers beneath it were, however, apparently normal. The gastric mucosa healed with little or no inflammation when sildenafil citrate, low dose heparin, ghrelin, NUCB2/Nesfatin-1, obestatin, Neuropeptide Y were administered. Overall the data indicate that low dose heparin, and especially sildenafil citrate and neuropeptides, can be used clinically as an alternative approach in the treatment of the gastric ulcer. Copyright © 2017 Elsevier Inc. All rights reserved.

Localisation of the neuropeptide PACAP and its receptors in the rat parathyroid and thyroid glands.

PubMed

Fahrenkrug, Jan; Hannibal, Jens

2011-03-01

PACAP (pituitary adenylate cyclase activating polypeptide) is widely distributed neuropeptide acting via three subtypes of receptors, PAC(1), VPAC(1) and VPAC(2). Here we examined the localisation and nature of PACAP-immunoreactive nerves in the rat thyroid and parathyroid glands and defined the distribution of PAC(1), VPAC(1) and VPAC(2) receptor mRNA's. In the parathyroid gland a large number of nerve fibres displaying PACAP-immunoreactivity were distributed beneath the capsule, around blood vessels and close to glandular cells. Most of the PACAP-nerves were sensory, since they co-stored CGRP (calcitonin-gene-related peptide) and were sensitive to capsaicin-treatment. mRNA's for PAC(1) and VPAC(2) receptors occurred in the parathyroid gland, mainly located in the glandular cells. In the thyroid gland PACAP-immunoreactive nerve fibres were associated with blood vessels, thyroid follicles and parafollicular C-cells. A high degree of co-existence between PACAP and VIP (vasoactive intestinal polypeptide) was observed in the intrathyroid nerve fibres and cell bodies of the thyroid ganglion indicating a common origin for the two peptides. A minor population of PACAP-immunoreactive nerve fibres with relation to blood vessels co-stored NPY (neuropeptide Y), whereas only a few fibres co-stored CGRP. PAC(1) and VPAC(1) receptor mRNA's occurred in follicular cells and blood vessels, whereas the expression of the VPAC(2) receptor was low. The findings suggest that PACAP plays a role in the regulation of parathyroid and thyroid blood flow and hormone secretion. Copyright © 2010 Elsevier Inc. All rights reserved.

24-hour variation in content and release of hypothalamic neuropeptides in the rat.

PubMed

Nicholson, S A; Adrian, T E; Bacarese-Hamilton, A J; Gillham, B; Jones, M T; Bloom, S R

1983-12-01

The tissue content of up to eight neuropeptides, viz bombesin (BOM), cholecystokinin (CCK-8), neurotensin (NT), neuropeptide Y (NPY), peptide histidine isoleucine amide (PHI), somatostatin (SRIF), substance P (SP) and vasoactive intestinal polypeptide (VIP), in rat hypothalami removed at various times of the day, was measured using specific radioimmunoassays. There was significant variation in the content of BOM, CCK-8, NT, PHI, SP and VIP across a 24-h period. The levels of BOM, CCK-8 and NT were lowest around the onset of darkness (1900 h) and rose throughout the night to reach a peak around the time of lights on. Hypothalamic content of all eight peptides fell between 0700 h and 1300 h by an average of 45 +/- 4%. Basal release of these peptides, as well as that in the presence of 48 mM potassium (K+), was measured from hypothalami removed between 0700 and 1900 h and incubated in vitro in a CSF-like medium. Basal secretion of NT significantly increased, whilst that of CCK-8 significantly decreased over the same period. There was no significant change in the basal release of the other neuropeptides. The release in the presence of 48 mM K+ of SP decreased significantly during the day, whilst that of VIP significantly increased. There was also a significant change in the stimulated release of BOM, levels falling during the morning and rising again at 1900 h. 48 mM K+ caused a significant increase in the release of SRIF and SP at all times tested. Whilst 48 mM K+ induced a significantly higher release of CCK-8 and NT in the morning, this stimulus was ineffective in the evening. The contrary was true in the case of BOM, NPY and VIP, where a significant stimulation was induced only at 1900 h. The possible implications of these findings are discussed.

Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation.

PubMed

Ferreira-Marques, Marisa; Aveleira, Célia A; Carmo-Silva, Sara; Botelho, Mariana; Pereira de Almeida, Luís; Cavadas, Cláudia

2016-07-01

Caloric restriction is an anti-aging intervention known to extend lifespan in several experimental models, at least in part, by stimulating autophagy. Caloric restriction increases neuropeptide Y (NPY) in the hypothalamus and plasma ghrelin, a peripheral gut hormone that acts in hypothalamus to modulate energy homeostasis. NPY and ghrelin have been shown to be neuroprotective in different brain areas and to induce several physiological modifications similar to those induced by caloric restriction. However, the effect of NPY and ghrelin in autophagy in cortical neurons is currently not known. Using a cell culture of rat cortical neurons we investigate the involvement of NPY and ghrelin in caloric restriction-induced autophagy. We observed that a caloric restriction mimetic cell culture medium stimulates autophagy in rat cortical neurons and NPY or ghrelin receptor antagonists blocked this effect. On the other hand, exogenous NPY or ghrelin stimulate autophagy in rat cortical neurons. Moreover, NPY mediates the stimulatory effect of ghrelin on autophagy in rat cortical neurons. Since autophagy impairment occurs in aging and age-related neurodegenerative diseases, NPY and ghrelin synergistic effect on autophagy stimulation may suggest a new strategy to delay aging process.

Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation

PubMed Central

Carmo-Silva, Sara; Botelho, Mariana; de Almeida, Luís Pereira; Cavadas, Cláudia

2016-01-01

Caloric restriction is an anti-aging intervention known to extend lifespan in several experimental models, at least in part, by stimulating autophagy. Caloric restriction increases neuropeptide Y (NPY) in the hypothalamus and plasma ghrelin, a peripheral gut hormone that acts in hypothalamus to modulate energy homeostasis. NPY and ghrelin have been shown to be neuroprotective in different brain areas and to induce several physiological modifications similar to those induced by caloric restriction. However, the effect of NPY and ghrelin in autophagy in cortical neurons is currently not known. Using a cell culture of rat cortical neurons we investigate the involvement of NPY and ghrelin in caloric restriction-induced autophagy. We observed that a caloric restriction mimetic cell culture medium stimulates autophagy in rat cortical neurons and NPY or ghrelin receptor antagonists blocked this effect. On the other hand, exogenous NPY or ghrelin stimulate autophagy in rat cortical neurons. Moreover, NPY mediates the stimulatory effect of ghrelin on autophagy in rat cortical neurons. Since autophagy impairment occurs in aging and age-related neurodegenerative diseases, NPY and ghrelin synergistic effect on autophagy stimulation may suggest a new strategy to delay aging process. PMID:27441412

Mas-allatotropin in the developing antennal lobe of the sphinx moth Manduca sexta: distribution, time course, developmental regulation, and colocalization with other neuropeptides.

PubMed

Utz, Sandra; Huetteroth, Wolf; Vömel, Matthias; Schachtner, Joachim

2008-01-01

The paired antennal lobes (ALs) of the sphinx moth Manduca sexta serve as a well-established model for studying development of the primary integration centers for odor information in the brain. To further reveal the role of neuropeptides during AL development, we have analyzed cellular distribution, developmental time course, and regulation of the neuropeptide M. sexta allatotropin (Mas-AT). On the basis of morphology and appearance during AL formation, seven major types of Mas-AT-immunoreactive (ir) cells could be distinguished. Mas-AT-ir cells are identified as local, projection, and centrifugal neurons, which are either persisting larval or newly added adult-specific neurons. Complementary immunostaining with antisera against two other neuropeptide families (A-type allatostatins, RFamides) revealed colocalization within three of the Mas-AT-ir cell types. On the basis of this neurochemistry, the most prominent type of Mas-AT-ir neurons, the local AT neurons (LATn), could be divided in three subpopulations. The appearance of the Mas-AT-ir cell types occurring during metamorphosis parallels the rising titer of the developmental hormone 20-hydroxyecdysone (20E). Artificially shifting the 20E titer to an earlier developmental time point resulted in the precocious occurrence of Mas-AT immunostaining. This result supports the hypothesis that the pupal rise of 20E is causative for Mas-AT expression during AL development. Comparing localization and developmental time course of Mas-AT and other neuropeptides with the time course of AL formation suggests various functions for these neuropeptides during development, including an involvement in the formation of the olfactory glomeruli.

The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system.

PubMed

Schéle, Erik; Grahnemo, Louise; Anesten, Fredrik; Hallén, Anna; Bäckhed, Fredrik; Jansson, John-Olov

2013-10-01

The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood. To investigate whether the gut microbiota affects hypothalamic and brainstem body fat-regulating circuits, we compared gene expression of food intake-regulating neuropeptides between germ-free and conventionally raised (CONV-R) mice. We found that CONV-R mice had decreased expression of the antiobesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in the brainstem. Moreover, in both the hypothalamus and the brainstem, CONV-R mice had decreased expression of the antiobesity neuropeptide brain-derived neurotrophic factor (Bdnf). CONV-R mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the antiobesity peptides proopiomelanocortin (Pomc) and cocaine- and amphetamine-regulated transcript (Cart) in the hypothalamus. The latter changes in neuropeptide expression could be secondary to elevated fat mass in CONV-R mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in CONV-R mice compared with germ-free mice. The hypothalamic expression of leptin resistance-associated suppressor of cytokine signaling 3 (Socs-3) was increased in CONV-R mice. In conclusion, the gut microbiota reduces the expression of 2 genes coding for body fat-suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat-inducing gut microbiota is associated with hypothalamic signs of Socs-3-mediated leptin resistance, which may be linked to failed compensatory body fat reduction.

Endogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors.

PubMed

Wultsch, T; Painsipp, E; Thoeringer, C K; Herzog, H; Sperk, G; Holzer, P

2005-01-01

Vagal afferents signal gastric acid challenge to the nucleus tractus solitarii of the rat brainstem. This study investigated whether nucleus tractus solitarii neurons in the mouse also respond to gastric acid challenge and whether this chemonociceptive input is modified by neuropeptide Y acting via neuropeptide Y receptors of type Y2 or Y4. The gastric mucosa of female mice was exposed to different concentrations of HCl or saline, excitation of neurons in the nucleus tractus solitarii visualized by c-Fos immunohistochemistry, gastric emptying deduced from the gastric volume recovery, and gastric lesion formation evaluated by planimetry. Relative to saline, intragastric HCl (0.15-0.35 M) increased the number of c-Fos-expressing cells in the nucleus tractus solitarii in a concentration-dependent manner, inhibited gastric emptying but failed to cause significant hemorrhagic injury in the stomach. Mice in which the Y2 or Y4 receptor gene had been deleted responded to gastric acid challenge with a significantly higher expression of c-Fos in the nucleus tractus solitarii, the increases amounting to 39 and 31%, respectively. The HCl-induced inhibition of gastric emptying was not altered by deletion of the Y2 or Y4 receptor gene. BIIE0246 ((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e] azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl] acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide; 0.03 mmol/kg s.c.), a Y2 receptor antagonist which does not cross the blood-brain barrier, did not modify the c-Fos response to gastric acid challenge. The Y2 receptor agonist peptide YY-(3-36) (0.1 mg/kg intraperitoneally) likewise failed to alter the gastric HCl-evoked expression of c-Fos in the nucleus tractus solitarii. BIIE0246, however, prevented the effect of peptide YY-(3-36) to inhibit gastric acid secretion as deduced from measurement of intragastric pH. The current data indicate that gastric challenge with acid

Effects of random food deprivation and refeeding on energy metabolism, behavior and hypothalamic neuropeptide expression in Apodemus chevrieri.

PubMed

Wan-Long, Zhu; Zheng-Kun, Wang

2016-11-01

Maintaining adaptive control of behavior and physiology is the main strategy used by animals in responding to changes of food resources. To investigate the effects of random food deprivation (FD) and refeeding on energy metabolism and behavior in Apodemus chevrieri, we acclimated adult males to FD for 4weeks, then refed them ad libitum for 4weeks (FD-Re group). During the period of FD, animals were fed ad libitum for 4 randomly assigned days each week, and deprived of food the other 3days. A control group was fed ad libitum for 8weeks. At 4 and 8weeks we measured body mass, thermogenesis, serum leptin levels, body composition, gastrointestinal tract morphology, behavior and hypothalamic neuropeptide expression. At 4weeks, food intake, gastrointestinal mass, neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expressions increased and thermogenesis, leptin levels, pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) expressions decreased in FD compared with controls. FD also showed more resting behavior and less activity than the controls on ad libitum day. There were no differences between FD-Re and controls at 8weeks, indicating significant plasticity. These results suggested that animals can compensate for unpredictable reduction in food availability by increasing food intake and reducing energy expended through thermogenesis and activity. Leptin levels, NPY, AgRP, POMC, and CART mRNA levels may also regulate energy metabolism. Significant plasticity in energy metabolism and behavior was shown by A. chevrieri over a short timescale, allowing them to adapt to food shortages in nutritionally unpredictable environments. Copyright © 2016 Elsevier Inc. All rights reserved.

Neuropeptide Y inhibits cholangiocarcinoma cell growth and invasion

PubMed Central

DeMorrow, Sharon; Onori, Paolo; Venter, Julie; Invernizzi, Pietro; Frampton, Gabriel; White, Mellanie; Franchitto, Antonio; Kopriva, Shelley; Bernuzzi, Francesca; Francis, Heather; Coufal, Monique; Glaser, Shannon; Fava, Giammarco; Meng, Fanyin; Alvaro, Domenico; Carpino, Guido; Gaudio, Eugenio

2011-01-01

No information exists on the role of neuropeptide Y (NPY) in cholangiocarcinoma growth. Therefore, we evaluated the expression and secretion of NPY and its subsequent effects on cholangiocarcinoma growth and invasion. Cholangiocarcinoma cell lines and nonmalignant cholangiocytes were used to assess NPY mRNA expression and protein secretion. NPY expression was assessed by immunohistochemistry in human liver biopsies. Cell proliferation and migration were evaluated in vitro by MTS assays and matrigel invasion chambers, respectively, after treatment with NPY or a neutralizing NPY antibody. The effect of NPY or NPY depletion on tumor growth was assessed in vivo after treatment with NPY or the neutralizing NPY antibody in a xenograft model of cholangiocarcinoma. NPY secretion was upregulated in cholangiocarcinoma compared with normal cholangiocytes. Administration of exogenous NPY decreased proliferation and cell invasion in all cholangiocarcinoma cell lines studied and reduced tumor cell growth in vivo. In vitro, the effects of NPY on proliferation were blocked by specific inhibitors for NPY receptor Y2, but not Y1 or Y5, and were associated with an increase in intracellular d-myo-inositol 1,4,5-trisphosphate and PKCα activation. Blocking of NPY activity using a neutralizing antibody promoted cholangiocarcinoma growth in vitro and in vivo and increased the invasiveness of cholangiocarcinoma in vitro. Increased NPY immunoreactivity in human tumor tissue occurred predominantly in the center of the tumor, with less expression toward the invasion front of the tumor. We demonstrated that NPY expression is upregulated in cholangiocarcinoma, which exerts local control on tumor cell proliferation and invasion. Modulation of NPY secretion may be important for the management of cholangiocarcinoma. PMID:21270292

Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans.

PubMed

Heinrichs, Markus; Domes, Gregor

2008-01-01

The fundamental ability to form attachment is indispensable for human social relationships. Impairments in social behaviour are associated with decreased quality of life and psychopathological states. In non-human mammals, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are key mediators of complex social behaviours, including attachment, social recognition and aggression. In particular, OXT reduces behavioural and neuroendocrine responses to social stress and seems both to enable animals to overcome their natural avoidance of proximity and to inhibit defensive behaviour, thereby facilitating approach behaviour. AVP has primarily been implicated in male-typical social behaviours, including aggression and pair-bond formation, and mediates anxiogenic effects. Initial studies in humans suggest behavioural, neural, and endocrine effects of both neuropeptides, similar to those found in animal studies. This review focuses on advances made to date in the effort to understand the role of OXT and AVP in human social behaviour. First, the literature on OXT and AVP and their involvement in social stress and anxiety, social cognition, social approach, and aggression is reviewed. Second, we discuss clinical implications for mental disorders that are associated with social deficits (e.g. autism spectrum disorder, borderline personality disorder). Finally, a model of the interactions of anxiety and stress, social approach behaviour, and the oxytocinergic system is presented, which integrates the novel approach of a psychobiological therapy in psychopathological states.

Neuropeptide Y and peptide YY: important regulators of energy metabolism.

PubMed

Nguyen, Amy D; Herzog, Herbert; Sainsbury, Amanda

2011-02-01

An overview of recent developments documenting the neuropeptide Y (NPY) family's role in energy metabolism. Specifically focusing on site-specific functions of NPY and increasing evidence of peptide YY (PYY) as a weight loss therapeutic. Studying the NPY family in hypothalamic nuclei, other than the arcuate and paraventricular nuclei, is a recent shift in metabolic research. NPY overexpression in the dorsomedial hypothalamus increases food intake whereas its ablation in this area reduces hyperphagia and obesity. Similarly, NPY exerts orexigenic effects in the ventromedial nucleus. However, specific arcuate Y2 receptor ablation leads to positive energy balance, suggesting the NPY family demonstrates location-specific functions. Peripherally, dual blockade of cannabinoid and NPY pathways has synergistic effects on weight loss, as does combined administration of PYY3-36 and oxyntomodulin in reducing food intake, perhaps due to the recently discovered role of PYY in mediating intestinal Gpr119 activity and controlling glucose tolerance. Conditional Y receptor knockout models have provided deeper insights on NPY's functions according to location. Further study of PYY appears vital, due to recent evidence of its role in intestinal motility, with exercise positively influencing PYY levels.

Developmental and sex-specific differences in expression of neuropeptides derived from allatotropin gene in the silkmoth Bombyx mori.

PubMed

Bednár, Branislav; Roller, Ladislav; Čižmár, Daniel; Mitrová, Diana; Žitňan, Dušan

2017-05-01

Allatotropin (AT) and related neuropeptides are widespread bioactive molecules that regulate development, food intake and muscle contractions in insects and other invertebrates. In moths, alternative splicing of the at gene generates three mRNA precursors encoding AT with different combinations of three structurally similar AT-like peptides (ATLI-III). We used in situ hybridization and immunohistochemistry to map the differential expression of these transcripts during the postembryonic development of Bombyx mori. Transcript encoding AT alone was expressed in numerous neurons of the central nervous system and frontal ganglion, whereas transcripts encoding AT with ATLs were produced by smaller specific subgroups of neurons in larval stages. Metamorphosis was associated with considerable developmental changes and sex-specific differences in the expression of all transcripts. The most notable was the appearance of AT/ATL transcripts (1) in the brain lateral neurosecretory cells producing prothoracicotropic hormone; (2) in the male-specific cluster of about 20 neurons in the posterior region of the terminal abdominal ganglion; (3) in the female-specific medial neurons in the abdominal ganglia AG2-7. Immunohistochemical staining showed that these neurons produced a mixture of various neuropeptides and innervated diverse peripheral organs. Our data suggest that AT/ATL neuropeptides are involved in multiple stage- and sex-specific functions during the development of B. mori.

Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors.

PubMed

Furlong, Michael; Seong, Jae Young

2017-01-01

Seven transmembrane receptors (7TMRs), also known as G protein-coupled receptors, are popular targets of drug development, particularly 7TMR systems that are activated by peptide ligands. Although many pharmaceutical drugs have been discovered via conventional bulk analysis techniques the increasing availability of structural and evolutionary data are facilitating change to rational, targeted drug design. This article discusses the appeal of neuropeptide-7TMR systems as drug targets and provides an overview of concepts in the evolution of vertebrate genomes and gene families. Subsequently, methods that use evolutionary concepts and comparative analysis techniques to aid in gene discovery, gene function identification, and novel drug design are provided along with case study examples.

Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors

PubMed Central

Furlong, Michael; Seong, Jae Young

2017-01-01

Seven transmembrane receptors (7TMRs), also known as G protein-coupled receptors, are popular targets of drug development, particularly 7TMR systems that are activated by peptide ligands. Although many pharmaceutical drugs have been discovered via conventional bulk analysis techniques the increasing availability of structural and evolutionary data are facilitating change to rational, targeted drug design. This article discusses the appeal of neuropeptide-7TMR systems as drug targets and provides an overview of concepts in the evolution of vertebrate genomes and gene families. Subsequently, methods that use evolutionary concepts and comparative analysis techniques to aid in gene discovery, gene function identification, and novel drug design are provided along with case study examples. PMID:28035082

The hypothalamic neuropeptide oxytocin is required for formation of the neurovascular interface of the pituitary.

PubMed

Gutnick, Amos; Blechman, Janna; Kaslin, Jan; Herwig, Lukas; Belting, Heinz-Georg; Affolter, Markus; Bonkowsky, Joshua L; Levkowitz, Gil

2011-10-18

The hypothalamo-neurohypophyseal system (HNS) is the neurovascular structure through which the hypothalamic neuropeptides oxytocin and arginine-vasopressin exit the brain into the bloodstream, where they go on to affect peripheral physiology. Here, we investigate the molecular cues that regulate the neurovascular contact between hypothalamic axons and neurohypophyseal capillaries of the zebrafish. We developed a transgenic system in which both hypothalamic axons and neurohypophyseal vasculature can be analyzed in vivo. We identified the cellular organization of the zebrafish HNS as well as the dynamic processes that contribute to formation of the HNS neurovascular interface. We show that formation of this interface is regulated during development by local release of oxytocin, which affects endothelial morphogenesis. This cell communication process is essential for the establishment of a tight axovasal interface between the neurons and blood vessels of the HNS. We present a unique example of axons affecting endothelial morphogenesis through secretion of a neuropeptide. Copyright © 2011 Elsevier Inc. All rights reserved.

Serotonin and the neuropeptide PDF initiate and extend opposing behavioral states in C. elegans.

PubMed

Flavell, Steven W; Pokala, Navin; Macosko, Evan Z; Albrecht, Dirk R; Larsch, Johannes; Bargmann, Cornelia I

2013-08-29

Foraging animals have distinct exploration and exploitation behaviors that are organized into discrete behavioral states. Here, we characterize a neuromodulatory circuit that generates long-lasting roaming and dwelling states in Caenorhabditis elegans. We find that two opposing neuromodulators, serotonin and the neuropeptide pigment dispersing factor (PDF), each initiate and extend one behavioral state. Serotonin promotes dwelling states through the MOD-1 serotonin-gated chloride channel. The spontaneous activity of serotonergic neurons correlates with dwelling behavior, and optogenetic modulation of the critical MOD-1-expressing targets induces prolonged dwelling states. PDF promotes roaming states through a Gαs-coupled PDF receptor; optogenetic activation of cAMP production in PDF receptor-expressing cells induces prolonged roaming states. The neurons that produce and respond to each neuromodulator form a distributed circuit orthogonal to the classical wiring diagram, with several essential neurons that express each molecule. The slow temporal dynamics of this neuromodulatory circuit supplement fast motor circuits to organize long-lasting behavioral states. Copyright © 2013 Elsevier Inc. All rights reserved.

Autism and urinary exogenous neuropeptides: development of an on-line SPE-HPLC-tandem mass spectrometry method to test the opioid excess theory.

PubMed

Dettmer, K; Hanna, D; Whetstone, P; Hansen, R; Hammock, B D

2007-08-01

Autism is a complex neurodevelopmental disorder with unknown etiology. One hypothesis regarding etiology in autism is the "opioid peptide excess" theory that postulates that excessive amounts of exogenous opioid-like peptides derived from dietary proteins are detectable in urine and that these compounds may be pathophysiologically important in autism. A selective LC-MS/MS method was developed to analyze gliadinomorphin, beta-casomorphin, deltorphin 1, and deltorphin 2 in urine. The method is based on on-line SPE extraction of the neuropeptides from urine, column switching, and subsequent HPLC analysis. A limit of detection of 0.25 ng/mL was achieved for all analytes. Analyte recovery rates from urine ranged between 78% and 94%, with relative standard deviations of 0.2-6.8%. The method was used to screen 69 urine samples from children with and without autism spectrum disorders for the occurrence of neuropeptides. The target neuropeptides were not detected above the detection limit in either sample set.

Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol.

PubMed

Anderson, Rachel I; Moorman, David E; Becker, Howard C

2018-03-11

Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders. These systems are also closely interrelated with one another - dynorphin/kappa opioid receptors and orexin/hypocretin receptors are found in similar regions and hypocretin/orexin neurons also express dynorphin - suggesting that these two systems may work together in the regulation of alcohol seeking and may be mutually disrupted in alcohol use disorders. This chapter reviews studies demonstrating a role for each of these systems in motivated behavior, with a focus on their roles in regulating alcohol-seeking and self-administration behaviors. Consideration is also given to evidence indicating that these neuropeptide systems may be viable targets for the development of potential treatments for alcohol use disorders.

Remote control of renal physiology by the intestinal neuropeptide pigment-dispersing factor in Drosophila.

PubMed

Talsma, Aaron D; Christov, Christo P; Terriente-Felix, Ana; Linneweber, Gerit A; Perea, Daniel; Wayland, Matthew; Shafer, Orie T; Miguel-Aliaga, Irene

2012-07-24

The role of the central neuropeptide pigment-dispersing factor (PDF) in circadian timekeeping in Drosophila is remarkably similar to that of vasoactive intestinal peptide (VIP) in mammals. Like VIP, PDF is expressed outside the circadian network by neurons innervating the gut, but the function and mode of action of this PDF have not been characterized. Here we investigate the visceral roles of PDF by adapting cellular and physiological methods to the study of visceral responses to PDF signaling in wild-type and mutant genetic backgrounds. We find that intestinal PDF acts at a distance on the renal system, where it regulates ureter contractions. We show that PdfR, PDF's established receptor, is expressed by the muscles of the excretory system, and present evidence that PdfR-induced cAMP increases underlie the myotropic effects of PDF. These findings extend the similarities between PDF and VIP beyond their shared central role as circadian regulators, and uncover an unexpected endocrine mode of myotropic action for an intestinal neuropeptide on the renal system.

Remote control of renal physiology by the intestinal neuropeptide pigment-dispersing factor in Drosophila

PubMed Central

Talsma, Aaron D.; Christov, Christo P.; Terriente-Felix, Ana; Linneweber, Gerit A.; Perea, Daniel; Wayland, Matthew; Shafer, Orie T.; Miguel-Aliaga, Irene

2012-01-01

The role of the central neuropeptide pigment-dispersing factor (PDF) in circadian timekeeping in Drosophila is remarkably similar to that of vasoactive intestinal peptide (VIP) in mammals. Like VIP, PDF is expressed outside the circadian network by neurons innervating the gut, but the function and mode of action of this PDF have not been characterized. Here we investigate the visceral roles of PDF by adapting cellular and physiological methods to the study of visceral responses to PDF signaling in wild-type and mutant genetic backgrounds. We find that intestinal PDF acts at a distance on the renal system, where it regulates ureter contractions. We show that PdfR, PDF's established receptor, is expressed by the muscles of the excretory system, and present evidence that PdfR-induced cAMP increases underlie the myotropic effects of PDF. These findings extend the similarities between PDF and VIP beyond their shared central role as circadian regulators, and uncover an unexpected endocrine mode of myotropic action for an intestinal neuropeptide on the renal system. PMID:22778427

Neuropeptides in Heteroptera: Identification of allatotropin-related peptide and tachykinin-related peptides using MALDI-TOF mass spectrometry

USDA-ARS?s Scientific Manuscript database

Recently, the peptidomic analysis of neuropeptides from the retrocerebral complex and abdominal perisympathetic organs of polyphagous stinkbugs (Pentatomidae) revealed the group-specific sequences of pyrokinins, CAPA peptides (CAPA-periviscerokinins/PVKs and CAPA-pyrokinin), myosuppressin, corazonin...

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

PubMed Central

Maurer, Verena; Murphy, Conor; Schmuckermair, Claudia; Muigg, Patrick; Neumann, Inga D.; Whittle, Nigel

2016-01-01

Background: Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. Methods: The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. Results: Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. Conclusions: By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. PMID:26625894

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches.

PubMed

Sartori, Simone B; Maurer, Verena; Murphy, Conor; Schmuckermair, Claudia; Muigg, Patrick; Neumann, Inga D; Whittle, Nigel; Singewald, Nicolas

2016-06-01

Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. © The Author 2015. Published by Oxford University Press on behalf of CINP.

The Neuropeptide Y system regulates both mechanical and histaminergic itch.

PubMed

Gao, Tianle; Ma, Haisha; Xu, Bo; Bergman, Jessica; Larhammar, Dan; Lagerström, Malin Charlotta

2018-05-24

Itch is a somatosensory modality that serves to alert the organism to harmful elements removable by scratching, such as parasites and chemical irritants. Recently, ablation or silencing of neuropeptide Y (NPY)-expressing spinal interneurons was reported to selectively enhance mechanical itch whereas chemical itch was unaffected. We have examined the effect of activating the NPY/Y 1 receptor system on scratch behavior in mouse. We found that intrathecal administration of the Y 1 agonist [Leu 31 ,Pro 34 ]-NPY (LP-NPY) attenuated itch behavior induced by application of 0.07 g von Frey filament in the nape of the neck, compared to saline treatment, indicating that activation of the spinal NPY/Y 1 system dampens mechanical itch. However, intrathecal administration of LP-NPY also attenuated chemically induced scratching provoked by intradermal application of histamine or the mast cell degranulator 48/80 (histaminergic itch), and the latter effect could be reversed by administration of the Y 1 antagonist BIBO3304. Intrathecal application of the native non-selective agonist NPY also attenuated histamine or 48/80-induced scratching. Our analyses emphasize the importance of including additional quantitative parameters to characterize the full spectrum of itch behavior and show that the NPY/Y 1 system dampens both mechanically and chemically induced scratching and hence is shared by the two sub-modalities of itch. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Neuropeptide Y stimulates retinal neural cell proliferation--involvement of nitric oxide.

PubMed

Alvaro, Ana Rita; Martins, João; Araújo, Inês M; Rosmaninho-Salgado, Joana; Ambrósio, António F; Cavadas, Cláudia

2008-06-01

Neuropeptide Y (NPY) is a 36 amino acid peptide widely present in the CNS, including the retina. Previous studies have demonstrated that NPY promotes cell proliferation of rat post-natal hippocampal and olfactory epithelium precursor cells. The aim of this work was to investigate the role of NPY on cell proliferation of rat retinal neural cells. For this purpose, primary retinal cell cultures expressing NPY, and NPY Y(1), Y(2), Y(4) and Y(5) receptors [Alvaro et al., (2007) Neurochem. Int., 50, 757] were used. NPY (10-1000 nM) stimulated cell proliferation through the activation of NPY Y(1), Y(2) and Y(5) receptors. NPY also increased the number of proliferating neuronal progenitor cells (BrdU(+)/nestin(+) cells). The intracellular mechanisms coupled to NPY receptors activation that mediate the increase in cell proliferation were also investigated. The stimulatory effect of NPY on cell proliferation was reduced by L-nitroarginine-methyl-esther (L-NAME; 500 microM), a nitric oxide synthase inhibitor, 1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ; 20 microM), a soluble guanylyl cyclase inhibitor or U0126 (1 microM), an inhibitor of the extracellular signal-regulated kinase 1/2 (ERK 1/2). In conclusion, NPY stimulates retinal neural cell proliferation, and this effect is mediated through nitric oxide-cyclic GMP and ERK 1/2 pathways.

Feed intake of gilts following intracerebroventicular injection of the novel hypothalamic RFamide (RFa) neuropeptide, 26RFa

USDA-ARS?s Scientific Manuscript database

RFamide (RFa) peptides have been implicated in a broad spectrum of biological processes including energy expenditure and feed intake. 26RFa is a recently discovered hypothalamic neuropeptide that altered the release of pituitary hormones and stimulated feed intake via a NPY-specific mechanism in rat...

The Neuropeptide Oxytocin Induces a Social Altruism Bias.

PubMed

Marsh, Nina; Scheele, Dirk; Gerhardt, Holger; Strang, Sabrina; Enax, Laura; Weber, Bernd; Maier, Wolfgang; Hurlemann, René

2015-11-25

Current psychological concepts of social and ecological responsibility emphasize the relevance of altruism, suggesting that more altruistic individuals are more likely to engage in sustainable behaviors. Emerging evidence indicates a central role of the neuropeptide oxytocin in promoting altruism. Whether this influence extends to ecological responsibility or is limited to the social domain remains unknown. In two independent experiments involving 172 human participants, we addressed this question by exposing subjects to a sustainability-related monetary donation task, with the option to support either socially or ecologically framed charities. We found that oxytocin induced a context-dependent change in altruistic behavior away from pro-environmental toward pro-social donations, while keeping constant the overall proportion of donated money. This pro-social bias transcended to the domain of sustainable consumption. Collectively, our findings demonstrate that altruistic priorities vary as a function of oxytocin system activity, which has implications for the promotion of pro-environmental attitudes and eco-friendly behaviors. Individual responses to ecological and social sustainability require a shift in personal priorities away from selfish to more altruistic behaviors. Emerging evidence indicates a central role of the hypothalamic peptide oxytocin in promoting altruism, but whether the influence of oxytocin benefits altruistic decision-making in the context of ecological and social sustainability is unclear. In two independent behavioral experiments involving 172 human subjects, we show that heightened oxytocin system activity induces a social altruism bias at the cost of ecological responsibility. Our results have fundamental implications for policy interventions and business strategies designed to sustain ecological resources by suggesting that a social framing may attract more individuals to engage in pro-environmental and eco-friendly behaviors. Copyright �

Neuropeptides and seizures.

PubMed

Snead, O C

1986-11-01

There are four lines of evidence for or against a role of neuropeptides in epilepsy: Administration of a variety of opiate agonists into the ventricles or brain of animals produces a constellation of electrical and behavioral changes, seemingly receptor-specific, both sensitive to the specific opiate antagonist naloxone as well as certain anticonvulsant drugs. The primary reservation concerning these data in terms of their relevance to epilepsy regards the fact that the peptides are exogenously administered in relatively high doses. Hence, these data may reflect neurotoxic effects of peptides rather than physiologic function. A variety of opiate agonists are anticonvulsant and naloxone shortens the postictal state in some experimental seizure models. One could attempt to reconcile these data with those in No. 1 by hypothesizing that the spikes and behavioral changes examined in the latter experimental parodynes represented a sort of isolated model of the postictal state. Naloxone has little effect in clinical epilepsy. These data are far from conclusive for two reasons. First, few patients have been studied. Second, because of the issue of opiate receptor heterogeneity and the high doses of naloxone needed experimentally to block non-mu opiate effects, the doses of naloxone used clinically to date are too low to rule out possible delta- or epsilon-mediated effects. The negative clinical data are illustrative of the dangers and difficulties of extrapolating data generated in animal models of seizures to the human condition. ACTH, a peptide that is derived from the same precursor molecule as beta-endorphin, is clearly an effective anticonvulsant in certain childhood seizure states. However, whether this is due to a direct or indirect (that is, cortisol) effect on brain is far from clear. Paradoxically, in contradistinction to other data concerning pro- and anticonvulsant properties of various opioid peptides, there is no animal model of infantile spasms to help

The gut peptide neuropeptide Y and post-traumatic stress disorder.

PubMed

Rasmusson, Ann M

2017-02-01

This article reviews the role of neuropeptide Y (NPY) in the pathophysiology of post-traumatic stress disorder (PTSD) and gastrointestinal disorders such as irritable bowel syndrome (IBS) with which PTSD is highly comorbid. NPY is low in the cerebrospinal fluid and plasma of male combat veterans with PTSD and correlates negatively with sympathetic nervous system (SNS) hyperreactivity, PTSD symptoms and time to recovery. NPY regulation has not yet been evaluated in women with PTSD. NPY levels in bowel tissue are low in IBS with diarrhea (IBS-D) versus IBS with constipation. The density of ghrelin containing cells of the gastric oxyntic mucosa is markedly increased in IBS-D. PTSD-related SNS hyperreactivity may interact with this substrate to increase ghrelin release, which activates receptors in the lumbosacral spinal cord and basolateral amygdala to increase colonic motility and amygdala hyperreactivity, respectively. Loss of function gene polymorphisms in adrenergic α2-autoreceptors and increased corticotropin-releasing hormone, as observed in PTSD, are also thought to contribute to IBS-D. Knowledge of shared underlying NPY system-related neurobiological factors that contribute to the comorbidity of PTSD and gastrointestinal disorders may help guide research, development and prescription of targeted and more effective individualized therapeutic interventions.

Acute heat stress up-regulates neuropeptide Y precursor mRNA expression and alters brain and plasma concentrations of free amino acids in chicks.

PubMed

Ito, Kentaro; Bahry, Mohammad A; Hui, Yang; Furuse, Mitsuhiro; Chowdhury, Vishwajit S

2015-09-01

Heat stress causes an increase in body temperature and reduced food intake in chickens. Several neuropeptides and amino acids play a vital role in the regulation of food intake. However, the responses of neuropeptides and amino acids to heat-stress-induced food-intake regulation are poorly understood. In the current study, the hypothalamic mRNA expression of some neuropeptides related to food intake and the content of free amino acids in the brain and plasma was examined in 14-day-old chicks exposed to a high ambient temperature (HT; 40±1 °C for 2 or 5 h) or to a control thermoneutral temperature (CT; 30±1 °C). HT significantly increased rectal temperature and plasma corticosterone level and suppressed food intake. HT also increased the expression of neuropeptide Y (NPY) and agouti-signaling protein (ASIP) precursor mRNA, while no change was observed in pro-opiomelanocortin, cholecystokinin, ghrelin, or corticotropin-releasing hormone precursor mRNA. It was further found that the diencephalic content of free amino acids - namely, tryptophan, leucine, isoleucine, valine and serine - was significantly higher in HT chicks with some alterations in their plasma amino acids in comparison with CT chicks. The induction of NPY and ASIP expression and the alteration of some free amino acids during HT suggest that these changes can be the results or causes the suppression of food intake. Copyright © 2015. Published by Elsevier Inc.

Possible involvement of neuropeptide Y Y1 receptors in antidepressant like effect of agmatine in rats.

PubMed

Kotagale, Nandkishor R; Paliwal, Nikhilesh P; Aglawe, Manish M; Umekar, Milind J; Taksande, Brijesh G

2013-09-01

Agmatine and neuropeptide Y (NPY) are widely distributed in central nervous system and critically involved in modulation of depressive behavior in experimental animals. However their mutual interaction, if any, in regulation of depression remain largely unexplored. In the present study we explored the possible interaction between agmatine and neuropeptide Y in regulation of depression like behavior in forced swim test. We found that acute intracerebroventricular (i.c.v.) administration of agmatine (20-40μg/rat), NPY (5 and 10μg/rat) and NPY Y1 receptor agonist, [Leu(31), Pro(34)]-NPY (0.4 and 0.8ng/rat) dose dependently decreased immobility time in forced swim test indicating their antidepressant like effects. In combination studies, the antidepressant like effect of agmatine (10μg/rat) was significantly potentiated by NPY (1 and 5μg/rat, icv) or [Leu(31), Pro(34)]-NPY (0.2 and 0.4ng/rat, icv) pretreatment. Conversely, pretreatment of animals with NPY Y1 receptor antagonist, BIBP3226 (0.1ng/rat, i.c.v.) completely blocked the antidepressant like effect of agmatine (20-40μg/rat) and its synergistic effect with NPY (1μg/rat, icv) or [Leu(31), Pro(34)]-NPY (0.2ng/rat, icv). The results of the present study showed that, agmatine exerts antidepressant like effects via NPYergic system possibly mediated by the NPY Y1 receptor subtypes and suggest that interaction between agmatine and neuropeptide Y may be relevant to generate the therapeutic strategies for the treatment of depression. Copyright © 2013 Elsevier Inc. All rights reserved.

Increase of long-term 'diabesity' risk, hyperphagia, and altered hypothalamic neuropeptide expression in neonatally overnourished 'small-for-gestational-age' (SGA) rats.

PubMed

Schellong, Karen; Neumann, Uta; Rancourt, Rebecca C; Plagemann, Andreas

2013-01-01

Epidemiological data have shown long-term health adversity in low birth weight subjects, especially concerning the metabolic syndrome and 'diabesity' risk. Alterations in adult food intake have been suggested to be causally involved. Responsible mechanisms remain unclear. By rearing in normal (NL) vs. small litters (SL), small-for-gestational-age (SGA) rats were neonatally exposed to either normal (SGA-in-NL) or over-feeding (SGA-in-SL), and followed up into late adult age as compared to normally reared appropriate-for-gestational-age control rats (AGA-in-NL). SGA-in-SL rats displayed rapid neonatal weight gain within one week after birth, while SGA-in-NL growth caught up only at juvenile age (day 60), as compared to AGA-in-NL controls. In adulthood, an increase in lipids, leptin, insulin, insulin/glucose-ratio (all p<0.05), and hyperphagia under normal chow as well as high-energy/high-fat diet, modelling modern 'westernized' lifestyle, were observed only in SGA-in-SL as compared to both SGA-in-NL and AGA-in-NL rats (p<0.05). Lasercapture microdissection (LMD)-based neuropeptide expression analyses in single neuron pools of the arcuate hypothalamic nucleus (ARC) revealed a significant shift towards down-regulation of the anorexigenic melanocortinergic system (proopiomelanocortin, Pomc) in SGA-in-SL rats (p<0.05). Neuropeptide expression within the orexigenic system (neuropeptide Y (Npy), agouti-related-peptide (Agrp) and galanin (Gal)) was not significantly altered. In essence, the 'orexigenic index', proposed here as a neuroendocrine 'net-indicator', was increased in SGA-in-SL regarding Npy/Pomc expression (p<0.01), correlated to food intake (p<0.05). Adult SGA rats developed increased 'diabesity' risk only if exposed to neonatal overfeeding. Hypothalamic malprogramming towards decreased anorexigenic activity was involved into the pathophysiology of this neonatally acquired adverse phenotype. Neonatal overfeeding appears to be a critical long-term risk factor in

Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats.

PubMed

Dhillo, W S; Small, C J; Stanley, S A; Jethwa, P H; Seal, L J; Murphy, K G; Ghatei, M A; Bloom, S R

2002-09-01

A number of neuropeptides implicated in the hypothalamic regulation of appetite are synthesized in the arcuate nucleus (Arc). Neuropeptide Y (NPY) and agouti-related protein (Agrp) are orexigenic. The pro-opiomelanocortin (POMC) product alpha-melanocyte-stimulating hormone (alpha-MSH) is anorectic. Intracerebroventricular administration of cocaine- and amphetamine-regulated transcript (CART) decreases food intake. However, recent results show that CART is orexigenic when injected into discrete hypothalamic nuclei. There is almost complete coexpression of NPY and Agrp mRNA in Arc neurones, and the majority of CART-containing neurones in the Arc also contain POMC mRNA. We investigated possible interactions between these neuropeptides in vitro using a rat hypothalamic explant system. Administration of 1, 10 and 100 nm of NPY to hypothalamic explants significantly increased release of Agrp(83-132)-immunoreactivity (IR). NPY (10 and 100 nm) significantly increased the release of CART(55-102)-IR and alpha-MSH-IR from hypothalamic explants. Agrp(83-132) (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. Agrp(83-132) (10 and 100 nm) significantly decreased the release of CART(55-102)-IR from hypothalamic explants. Administration of 1, 10 and 100 nm CART(55-102) to hypothalamic explants resulted in a significant increase in NPY-IR release. Administration of 10 nm CART(55-102) to hypothalamic explants significantly increased the release of Agrp(83-132)-IR. NDP-MSH (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. NDP-MSH (10 and 100 nm) significantly increased the release of Agrp(83-132)-IR from hypothalamic explants. These data suggest that orexigenic neuropeptides in the arcuate nucleus stimulate the release of each other, perhaps reinforcing orexigenic behaviour via a positive-feedback loop. Our results are also in keeping with the possibility that the melanocortin-3 receptor in the

Axonal outgrowth, neuropeptides expression and receptors tyrosine kinase phosphorylation in 3D organotypic cultures of adult dorsal root ganglia

PubMed Central

Alves, Cecília J.; Leitão, Luís; Sousa, Daniela M.; Alencastre, Inês S.; Conceição, Francisco; Lamghari, Meriem

2017-01-01

Limited knowledge from mechanistic studies on adult sensory neuronal activity was generated, to some extent, in recapitulated adult in vivo 3D microenvironment. To fill this gap there is a real need to better characterize the adult dorsal root ganglia (aDRG) organotypic cultures to make these in vitro systems exploitable for different approaches, ranging from basic neurobiology to regenerative therapies, to address the sensory nervous system in adult stage. We conducted a direct head-to-head comparison of aDRG and embryonic DRG (eDRG) organotypic culture focusing on axonal growth, neuropeptides expression and receptors tyrosine kinase (RTK) activation associated with neuronal survival, proliferation and differentiation. To identify alterations related to culture conditions, these parameters were also addressed in retrieved aDRG and eDRG and compared with organotypic cultures. Under similar neurotrophic stimulation, aDRG organotypic cultures displayed lower axonal outgrowth rate supported by reduced expression of growth associated protein-43 and high levels of RhoA and glycogen synthase kinase 3 beta mRNA transcripts. In addition, differential alteration in sensory neuropeptides expression, namely calcitonin gene-related peptide and substance P, was detected and was mainly pronounced at gene expression levels. Among 39 different RTK, five receptors from three RTK families were emphasized: tropomyosin receptor kinase A (TrkA), epidermal growth factor receptors (EGFR, ErbB2 and ErbB3) and platelet-derived growth factor receptor (PDGFR). Of note, except for EGFR, the phosphorylation of these receptors was dependent on DRG developmental stage and/or culture condition. In addition, EGFR and PDGFR displayed alterations in their cellular expression pattern in cultured DRG. Overall we provided valuable information particularly important when addressing in vitro the molecular mechanisms associated with development, maturation and regeneration of the sensory nervous system

A pharmacological study of NLP-12 neuropeptide signaling in free-living and parasitic nematodes.

PubMed

Peeters, Lise; Janssen, Tom; De Haes, Wouter; Beets, Isabel; Meelkop, Ellen; Grant, Warwick; Schoofs, Liliane

2012-03-01

NLP-12a and b have been identified as cholecystokinin/sulfakinin-like neuropeptides in the free-living nematode Caenorhabditis elegans. They are suggested to play an important role in the regulation of digestive enzyme secretion and fat storage. This study reports on the identification and characterization of an NLP-12-like peptide precursor gene in the rat parasitic nematode Strongyloides ratti. The S. ratti NLP-12 peptides are able to activate both C. elegans CKR-2 receptor isoforms in a dose-dependent way with affinities in the same nanomolar range as the native C. elegans NLP-12 peptides. The C-terminal RPLQFamide sequence motif of the NLP-12 peptides is perfectly conserved between free-living and parasitic nematodes. Based on systemic amino acid replacements the Arg-, Leu- and Phe- residues appear to be critical for high-affinity receptor binding. Finally, a SAR analysis revealed the essential pharmacophore in C. elegans NLP-12b to be the pentapeptide RPLQFamide. Copyright © 2011 Elsevier Inc. All rights reserved.

The distribution of neuropeptide Y and dynorphin immunoreactivity in the brain and pituitary gland of the platyfish, Xiphophorus maculatus, from birth to sexual maturity

NASA Technical Reports Server (NTRS)

Cepriano, L. M.; Schreibman, M. P.

1993-01-01

Immunoreactive neuropeptide Y and dynorphin have been localized in the brain and pituitary gland of the platyfish, Xiphophorus maculatus, at different ages and stages of development from birth to sexual maturity. Immunoreactive neuropeptide Y was found in perikarya and tracts of the nucleus olfactoretinalis, telencephalon, ventral tegmentum and in the neurohypophysis and in the three regions of the adenohypophysis. Immunoreactive dynorphin was found in nerve tracts in the olfactory bulb and in cells of the pars intermedia and the rostral pars distalis of the pituitary gland.

RAB-5 and RAB-10 cooperate to regulate neuropeptide release in Caenorhabditis elegans

PubMed Central

Sasidharan, Nikhil; Sumakovic, Marija; Hannemann, Mandy; Hegermann, Jan; Liewald, Jana F.; Olendrowitz, Christian; Koenig, Sabine; Grant, Barth D.; Rizzoli, Silvio O.; Gottschalk, Alexander; Eimer, Stefan

2012-01-01

Neurons secrete neuropeptides from dense core vesicles (DCVs) to modulate neuronal activity. Little is known about how neurons manage to differentially regulate the release of synaptic vesicles (SVs) and DCVs. To analyze this, we screened all Caenorhabditis elegans Rab GTPases and Tre2/Bub2/Cdc16 (TBC) domain containing GTPase-activating proteins (GAPs) for defects in DCV release from C. elegans motoneurons. rab-5 and rab-10 mutants show severe defects in DCV secretion, whereas SV exocytosis is unaffected. We identified TBC-2 and TBC-4 as putative GAPs for RAB-5 and RAB-10, respectively. Multiple Rabs and RabGAPs are typically organized in cascades that confer directionality to membrane-trafficking processes. We show here that the formation of release-competent DCVs requires a reciprocal exclusion cascade coupling RAB-5 and RAB-10, in which each of the two Rabs recruits the other’s GAP molecule. This contributes to a separation of RAB-5 and RAB-10 domains at the Golgi–endosomal interface, which is lost when either of the two GAPs is inactivated. Taken together, our data suggest that RAB-5 and RAB-10 cooperate to locally exclude each other at an essential stage during DCV sorting. PMID:23100538

Neuropeptide cycloprolylglycine increases the levels of brain-derived neurotrophic factor in neuronal cells.

PubMed

Gudasheva, T A; Koliasnikova, K N; Antipova, T A; Seredenin, S B

2016-07-01

It was shown for the first time that the endogenous cyclic dipeptide cycloprolylglycine (CPG) at concentrations of 10(-7) and 10(-3) M and piracetam at a concentration of 10(-3) M increased the content of brainderived neurotrophic factor (BDNF) in the culture of neuronal cells in normal state and under conditions of glutamate and 6-oxydopamine neurotoxicity. This may indicate the possible involvement of BDNF in the mechanism of action of neuropeptide CPG and piracetam.

The possible role of neuropeptide Y after spontaneous subarachnoid hemorrhage.

PubMed

Schebesch, Karl-Michael; Brawanski, Alexander; Kagerbauer, Simone Maria; Martin, Jan; Bele, Sylvia; Herbst, Andreas; Feigl, Günther; Stoerr, Eva-Maria; Lohmeier, Anette; Proescholdt, Martin

2011-08-01

Neuropeptide Y (NPY), a highly potent vasoconstrictive neuropeptide, is widely expressed in the human brain, regulating vessel diameter and cerebral blood flow. Earlier studies focusing on the possible role of NPY in the context of aneurismal subarachnoid hemorrhage (SAH) and vasospasm have produced conflicting results. However, despite extensive research efforts, the pathophysiological mechanisms underlying the SAH-related vasospasm and delayed cerebral ischemia (DCI) have not been clarified. We, therefore, attempted to investigate the role of NPY in SAH-induced vasospasm in a larger, well documented patient population utilizing modern analytical tools. We focused on the release of the potent vasoconstrictor NPY in cerebrospinal fluid (CSF) and blood, and its correlation to vasospasm and stroke in the early clinical stage. Thirty-seven patients with SAH and a control group consisting of 29 patients were included. Eighteen patients developed stroke, 21 patients met the Doppler sonographical criteria for vasospasm. Twenty-nine patients had aneurysms of the anterior circulation and four patients of the posterior circulation. All patients had ventricular drainage inserted and an arterial catheter. Blood and CSF were drawn daily for NPY analysis during a 10-day interval. The levels of NPY in CSF and plasma were significantly higher after SAH than in the control group (p = 0.001). The vasospasm group showed NPY levels in CSF which continuously ranged above the NPY levels of the non-vasospasm group (p = 0.001). Patients with stroke caused by vasospasm had significantly higher levels of NPY (p = 0.001). NPY is released excessively into blood and CSF following SAH. Patients with cerebral infarction caused by vasospasm had significantly higher levels of NPY. Our results indicate a certain role for NPY in the pathophysiology of vasospasm due to SAH and justify further studies in this area of research.

Appetite-associated responses to central neuropeptide Y injection in quail.

PubMed

McConn, Betty R; Gilbert, Elizabeth R; Cline, Mark A

2018-06-01

The appetite-associated effects of neuropeptide Y (NPY) have been extensively studied in mammalian models. Less knowledge exists for other vertebrate species including birds. The aim of this study was to determine the effects of central injection of NPY on feeding behavior and hypothalamic physiology in 7 day-old Japanese quail (Coturnix japonica). During the light cycle, intracerebroventricular injection of 1.9 pmol, 0.5, and 1.0 nmol doses of NPY did not affect food intake, 0.031 to 0.13 nmol increased food intake, and 2.0 nmol NPY decreased food intake, in comparison to vehicle injection. Multiple doses of NPY stimulated water intake, but when food was not available, water intake was not affected. When injected during the dark cycle, NPY did not influence food intake. NPY-injected chicks had more c-Fos immunoreactive cells in the arcuate nucleus of the hypothalamus (ARC) and greater hypothalamic agouti-related peptide and neuropeptide Y receptors 1 and 2 (NPYR1 and NPYR2, respectively) mRNA than vehicle-injected chicks. Within the ventromedial hypothalamus, NPY-treated chicks expressed less NPYR1 mRNA, within the dorsomedial hypothalamus less NPY mRNA, and in the ARC greater NPYR2 mRNA than vehicle-injected chicks. Lastly, quail injected with NPY increased feeding pecks, escape attempts, and time spent preening, while locomotion, the number of steps, and time spent perching decreased compared to chicks injected with the vehicle. Results demonstrate that NPY stimulates food intake in quail, consistent with mammals and other avian species, but with some unique responses at the molecular level that are not documented in other species. Copyright © 2018 Elsevier Ltd. All rights reserved.

Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection.

PubMed

Woods, Tyson A; Du, Min; Carmody, Aaron; Peterson, Karin E

2015-12-30

Monocyte infiltration into the CNS is a hallmark of several viral infections of the central nervous system (CNS), including retrovirus infection. Understanding the factors that mediate monocyte migration in the CNS is essential for the development of therapeutics that can alter the disease process. In the current study, we found that neuropeptide Y (NPY) suppressed monocyte recruitment to the CNS in a mouse model of polytropic retrovirus infection. NPY(-/-) mice had increased incidence and kinetics of retrovirus-induced neurological disease, which correlated with a significant increase in monocytes in the CNS compared to wild-type mice. Both Ly6C(hi) inflammatory and Ly6C(lo) alternatively activated monocytes were increased in the CNS of NPY(-/-) mice following virus infection, suggesting that NPY suppresses the infiltration of both cell types. Ex vivo analysis of myeloid cells from brain tissue demonstrated that infiltrating monocytes expressed high levels of the NPY receptor Y2R. Correlating with the expression of Y2R on monocytes, treatment of NPY(-/-) mice with a truncated, Y2R-specific NPY peptide suppressed the incidence of retrovirus-induced neurological disease. These data demonstrate a clear role for NPY as a negative regulator of monocyte recruitment into the CNS and provide a new mechanism for suppression of retrovirus-induced neurological disease. Monocyte recruitment to the brain is associated with multiple neurological diseases. However, the factors that influence the recruitment of these cells to the brain are still not well understood. In the current study, we found that neuropeptide Y, a protein produced by neurons, affected monocyte recruitment to the brain during retrovirus infection. We show that mice deficient in NPY have increased influx of monocytes into the brain and that this increase in monocytes correlates with neurological-disease development. These studies provide a mechanism by which the nervous system, through the production of NPY

Intranasal Neuropeptide Administration To Target the Human Brain in Health and Disease.

PubMed

Spetter, Maartje S; Hallschmid, Manfred

2015-08-03

Central nervous system control of metabolic function relies on the input of endocrine messengers from the periphery, including the pancreatic hormone insulin and the adipokine leptin. This concept primarily derives from experiments in animals where substances can be directly applied to the brain. A feasible approach to study the impact of peptidergic messengers on brain function in humans is the intranasal (IN) route of administration, which bypasses the blood-brain barrier and delivers neuropeptides to the brain compartment, but induces considerably less, if any, peripheral uptake than other administration modes. Experimental IN insulin administration has been extensively used to delineate the role of brain insulin signaling in the control of energy homeostasis, but also cognitive function in healthy humans. Clinical pilot studies have found beneficial effects of IN insulin in patients with memory deficits, suggesting that the IN delivery of this and other peptides bears some promise for new, selectively brain-targeted pharmaceutical approaches in the treatment of metabolic and cognitive disorders. More recently, experiments relying on the IN delivery of the hypothalamic hormone oxytocin, which is primarily known for its involvement in psychosocial processes, have provided evidence that oxytocin influences metabolic control in humans. The IN administration of leptin has been successfully tested in animal models but remains to be investigated in the human setting. We briefly summarize the literature on the IN administration of insulin, leptin, and oxytocin, with a particular focus on metabolic effects, and address limitations and perspectives of IN neuropeptide administration.

Neuropeptides shaping the central nervous system development: Spatiotemporal actions of VIP and PACAP through complementary signaling pathways.

PubMed

Maduna, Tando; Lelievre, Vincent

2016-12-01

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are neuropeptides with wide, complementary, and overlapping distributions in the central and peripheral nervous systems, where they exert important regulatory roles in many physiological processes. VIP and PACAP display a large range of biological cellular targets and functions in the adult nervous system including regulation of neurotransmission and neuroendocrine secretion and neuroprotective and neuroimmune responses. As the main focus of the present review, VIP and PACAP also have been long implicated in nervous system development and maturation through their interaction with the seven transmembrane domain G protein-coupled receptors, PAC1, VPAC1, and VPAC2, initiating multiple signaling pathways. Compared with PAC1, which solely binds PACAP with very high affinity, VPACs exhibit high affinities for both VIP and PACAP but differ from each other because of their pharmacological profile for both natural accessory peptides and synthetic or chimeric molecules, with agonistic and antagonistic properties. Complementary to initial pharmacological studies, transgenic animals lacking these neuropeptides or their receptors have been used to further characterize the neuroanatomical, electrophysiological, and behavioral roles of PACAP and VIP in the developing central nervous system. In this review, we recapitulate the critical steps and processes guiding/driving neurodevelopment in vertebrates and superimposing the potential contribution of PACAP and VIP receptors on the given timeline. We also describe how alterations in VIP/PACAP signaling may contribute to both (neuro)developmental and adult pathologies and suggest that tuning of VIP/PACAP signaling in a spatiotemporal manner may represent a novel avenue for preventive therapies of neurological and psychiatric disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice.

PubMed

Bo, E; Farinetti, A; Marraudino, M; Sterchele, D; Eva, C; Gotti, S; Panzica, G

2016-07-01

Tributyltin (TBT), a pesticide used in antifouling paints, is toxic for aquatic invertebrates. In vertebrates, TBT may act in obesogen- inducing adipogenetic gene transcription for adipocyte differentiation. In a previous study, we demonstrated that acute administration of TBT induces c-fos expression in the arcuate nucleus. Therefore, in this study, we tested the hypothesis that adult exposure to TBT may alter a part of the nervous pathways controlling animal food intake. In particular, we investigated the expression of neuropeptide Y (NPY) immunoreactivity. This neuropeptide forms neural circuits dedicated to food assumption and its action is mediated by Y1 receptors that are widely expressed in the hypothalamic nuclei responsible for the regulation of food intake and energy homeostasis. To this purpose, TBT was orally administered at a dose of 0.025 mg/kg/day/body weight to adult animals [male and female C57BL/6 (Y1-LacZ transgenic mice] for 4 weeks. No differences were found in body weight and fat deposition, but we observed a significant increase in feed efficiency in TBT-treated male mice and a significant decrease in circulating leptin in both sexes. Computerized quantitative analysis of NPY immunoreactivity and Y1-related β-galactosidase activity demonstrated a statistically significant reduction in NPY and Y1 transgene expression in the hypothalamic circuit controlling food intake of treated male mice in comparison with controls. In conclusion, the present results indicate that adult exposure to TBT is profoundly interfering with the nervous circuits involved in the stimulation of food intake. © 2016 American Society of Andrology and European Academy of Andrology.

The Use of Neuropeptide Y as a Measurement of the Effectiveness of Stress Inoculation

DTIC Science & Technology

2011-04-01

Allen, Adrian , Allen, Tatemoto, Crow, Bloom , & Polak, 1983). One of the roles of NPY is related to eating behavior. Clark, Kalra, Crowley, & Kalra (1984...ultimately contribute to a more effective fighting force. 16 Annotated References Allen, Y.S., Adrian , T.E., Allen, J.M., Tatemoto, K...Crow, T.J., Bloom , S.R., & Polak, J.M. (1983). Neuropeptide Y distribution in the rat brain. Science, 221(4613), 877-879. This experiment determined

Analysis of mouse brain peptides using mass spectrometry-based peptidomics: Implications for novel functions ranging from non-classical neuropeptides to microproteins

PubMed Central

Fricker, Lloyd D.

2010-01-01

Peptides are known to play many important physiological roles in signaling. A large number of peptides have been detected in mouse brain extracts using mass spectrometry-based peptidomics studies, and 850 peptides have been identified. Half of these peptides are derived from secretory pathway proteins and many are known bioactive neuropeptides which activate G protein-coupled receptors; these are termed “classical neuropeptides.” In addition, 427 peptides were identified that are derived from non-secretory pathway proteins; the majority are cystosolic, and the remainder are mitochondrial, nuclear, lysosomal, or membrane proteins. Many of these peptides represent the N- or C-terminus of the protein, rather than internal fragments, raising the possibility that they are formed by selective processing rather than protein degradation. In addition to consideration of the cleavage site required to generate the intracellular peptides, their potential functions are discussed. Several of the cytosolic peptides were previously found to interact with receptors and/or otherwise influence cellular activity; examples include hemophins, hemopressins, diazepam binding inhibitor, and hippocampal cholinergic neurostimulating peptide. The possibility that these peptides are secreted from cells and function in cell-cell signaling is discussed. If these intracellular peptides can be shown to be secreted in levels sufficient to produce a biological effect, they would appropriately be called “non-classical neuropeptides” by analogy with non-classical neurotransmitters such as nitric oxide and anandamide. It is also possible that intracellular peptides function as “microproteins” and modulate protein-protein interactions; evidence for this function is discussed, along with future directions that are needed to establish this and other possible functions for peptides. PMID:20428524

Effects of peptide YY and neuropeptide Y on gastric emptying in man.

PubMed

Allen, J M; Fitzpatrick, M L; Yeats, J C; Darcy, K; Adrian, T E; Bloom, S R

1984-01-01

Neuropeptide Y (NPY) and peptide YY (PYY) are two structurally related peptides. PYY has been identified within endocrine cells and NPY within nerves of the gastrointestinal tract. Infusion of PYY at a low dose at a nominal rate of 2 pmol/kg/min resulted in an increment of 59.2 +/- 7.1 pmol/1 in plasma concentration and a significant delay in gastric emptying of glucose. Infusion of NPY at the same rate produced similar plasma concentrations (52.5 +/- 1.1 pmol/1) and had no significant effect on the rate of gastric emptying.

Proliferation of prostate cancer cells and activity of neutral endopeptidase is regulated by bombesin and IL-1beta with IL-1beta acting as a modulator of cellular differentiation.

PubMed

Albrecht, Martin; Doroszewicz, Jolanta; Gillen, Sonja; Gomes, Iara; Wilhelm, Beate; Stief, Thomas; Aumüller, Gerhard

2004-01-01

Neutral endopeptidase (NEP) is a cell-surface bound enzyme that cleaves and inactivates neuropeptides such as bombesin and substance P and is involved in the transition from hormonally regulated androgen-dependent prostate cancer (PC) to androgen-independent PC. Neuropeptides are implicated in growth regulation of different cell types and function as transmitters between the neuroendocrine and the immune system. NEP-expression, enzymatic activity of the membrane bound protein, cell proliferation, procalcitonin (PCT) production, and secretion as well as changes in cell morphology of prostatic cells were evaluated after treatment with the immunomodulatory cytokine interleukin-1beta (IL-1beta), neuropeptides (bombesin, substance P), and neuropeptide-conditioned media derived from a human neuroendocrine cell line. Incubation of LNCaP tumor cells with IL-1beta resulted in a diminished proliferative activity, induction of neurite-like outgrowth which was accompanied by the formation of tubular-type mitochondria typical for neuronal/neuroendocrine cells, and an increased production and secretion of PCT. Conversely, proliferation of prostatic stromal cells was enhanced by the cytokine coming along with an increased number of Golgi-apparatuses and ER-cisternae. Bombesin had an antimitotic effect on LNCaP, but not on stromal cells. Substance P did not influence the growth of any of the cell types investigated, whereas neuropeptide-conditioned media exerted a slightly mitogenic effect on both cell types. The activity of LNCaP cell-surface bound NEP was enhanced by bombesin, but was diminished by substance P and neuropeptide-conditioned media. Proliferation and activity of neuropeptide degrading NEP is regulated differently by immunomodulatory substances in PC cells and cells derived from the prostatic stroma with IL-1beta being a potent modulator of cellular differentiation and a potential target for anticancer drug design in PC cells. Copyright 2003 Wiley-Liss, Inc.

The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders.

PubMed

Guan, Jian; Harris, Paul; Brimble, Margaret; Lei, Yang; Lu, Jun; Yang, Yang; Gunn, Alistair J

2015-06-01

Exogenous IGF-1 protects the brain from ischemic injury and improves function. However, its clinical application to neurological disorders is limited by its large molecular size, poor central uptake and mitogenic potential. In this review, the authors have discussed the efficacy, pharmacokinetics and mechanisms of IGF-1 derivatives on protecting acute brain injury, preventing memory impairment and improving recovery from neurological degenerative conditions evaluated in various animal models. We have included natural metabolites of IGF-1, glycine-proline-glutamate (GPE), cleaved from N-terminal IGF-1 and cyclic glycine-proline (cGP) as well as the structural analogues of GPE and cGP, glycine-2-methyl-proline-glutamate and cyclo-l-glycyl-l-2-allylproline, respectively. In addition, the regulatory role for cGP in bioavailability of IGF-1 has also been discussed. These small neuropeptides provide effective neuroprotection by offering an improved pharmacokinetic profile and more practical route of administration compared with IGF-1 administration. Developing modified neuropeptides to overcome the limitations of their endogenous counterparts represents a novel strategy of pharmaceutical discovery for neurological disorders. The mechanism of action may involve a regulation of IGF-1 bioavailability.

Timed food availability affects circadian behavior but not the neuropeptide Y expression in Indian weaverbirds exposed to atypical light environment.

PubMed

Singh, Devraj; Trivedi, Neerja; Malik, Shalie; Rani, Sangeeta; Kumar, Vinod

2016-07-01

We tested the hypothesis whether daily food availability period would restore rhythmicity in individuals with disrupted circadian behavior with no effect on appetite regulation. Particularly, we investigated the effects of timed food availability on activity behavior, and Fos and neuropeptide Y expressions in Indian weaverbirds (Ploceus philippinus) under atypical light conditions. Initially, weaverbirds in 3 groups of 7-8 each were entrained to 7L:17D (25: <0.3lx) with food ad libitum. Thereafter, food availability was restricted for 7h such that it overlapped with the light period. After a week, 7L:17D was replaced with 3.5L: 3.5D (T7, group 1), 3.5L: 20.5D (T24, group 2) or constant dim light, LLdim (<0.3lx, group 3) for 5weeks. Food cycles synchronized the circadian activity behavior, albeit with group differences, but did not affect body mass, blood glucose levels or testis size. Further, Fos, not NPY mRNA or peptide, expression measured at ZT2 and ZT14 (ZT0=time of food given) showed significant group differences in the hippocampus, dorsomedial hypothalamus and infundibular nuclear complex. Another identical experiment examined after-effects of the 3 light conditions on persistence of the circadian rhythms. Weaverbirds exposed for 4weeks to identical food but different light conditions, as above, were released into the free-running condition of food ad libitum and LLdim. Circadian rhythms were decayed in birds previously exposed to T7 LD cycle. Overall, these results show that timed meal restores rhythmicity in individuals with circadian rhythm disruptions without involving neuropeptide Y, the key appetite regulatory molecule. Copyright © 2016 Elsevier Inc. All rights reserved.

The Neuropeptide Allatostatin A Regulates Metabolism and Feeding Decisions in Drosophila

PubMed Central

Hentze, Julie L.; Carlsson, Mikael A.; Kondo, Shu; Nässel, Dick R.; Rewitz, Kim F.

2015-01-01

Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and energy mobilization are regulated by the glucagon-related adipokinetic hormone (AKH) and the Drosophila insulin-like peptides (DILPs). Here, we provide evidence that the Drosophila neuropeptide Allatostatin A (AstA) regulates AKH and DILP signaling. The AstA receptor gene, Dar-2, is expressed in both the insulin and AKH producing cells. Silencing of Dar-2 in these cells results in changes in gene expression and physiology associated with reduced DILP and AKH signaling and animals lacking AstA accumulate high lipid levels. This suggests that AstA is regulating the balance between DILP and AKH, believed to be important for the maintenance of nutrient homeostasis in response to changing ratios of dietary sugar and protein. Furthermore, AstA and Dar-2 are regulated differentially by dietary carbohydrates and protein and AstA-neuronal activity modulates feeding choices between these types of nutrients. Our results suggest that AstA is involved in assigning value to these nutrients to coordinate metabolic and feeding decisions, responses that are important to balance food intake according to metabolic needs. PMID:26123697

The Neuropeptide Oxytocin Enhances Information Sharing and Group Decision Making Quality.

PubMed

De Wilde, Tim R W; Ten Velden, Femke S; De Dreu, Carsten K W

2017-01-11

Groups can make better decisions than individuals when members cooperatively exchange and integrate their uniquely held information and insights. However, under conformity pressures group members are biased towards exchanging commonly known information, and away from exchanging unique information, thus undermining group decision-making quality. At the neurobiological level, conformity associates with the neuropeptide oxytocin. A double-blind placebo controlled study found no evidence for oxytocin induced conformity. Compared to placebo groups, three-person groups whose members received intranasal oxytocin, focused more on unique information (i) and repeated this information more often (ii). These findings reveal oxytocin as a neurobiological driver of group decision-making processes.

The Neuropeptide Oxytocin Enhances Information Sharing and Group Decision Making Quality

PubMed Central

De Wilde, Tim R. W.; Ten Velden, Femke S.; De Dreu, Carsten K. W.

2017-01-01

Groups can make better decisions than individuals when members cooperatively exchange and integrate their uniquely held information and insights. However, under conformity pressures group members are biased towards exchanging commonly known information, and away from exchanging unique information, thus undermining group decision-making quality. At the neurobiological level, conformity associates with the neuropeptide oxytocin. A double-blind placebo controlled study found no evidence for oxytocin induced conformity. Compared to placebo groups, three-person groups whose members received intranasal oxytocin, focused more on unique information (i) and repeated this information more often (ii). These findings reveal oxytocin as a neurobiological driver of group decision-making processes. PMID:28074896

Increase of Long-Term ‘Diabesity’ Risk, Hyperphagia, and Altered Hypothalamic Neuropeptide Expression in Neonatally Overnourished ‘Small-For-Gestational-Age’ (SGA) Rats

PubMed Central

Schellong, Karen; Neumann, Uta; Rancourt, Rebecca C.; Plagemann, Andreas

2013-01-01

Background Epidemiological data have shown long-term health adversity in low birth weight subjects, especially concerning the metabolic syndrome and ‘diabesity’ risk. Alterations in adult food intake have been suggested to be causally involved. Responsible mechanisms remain unclear. Methods and Findings By rearing in normal (NL) vs. small litters (SL), small-for-gestational-age (SGA) rats were neonatally exposed to either normal (SGA-in-NL) or over-feeding (SGA-in-SL), and followed up into late adult age as compared to normally reared appropriate-for-gestational-age control rats (AGA-in-NL). SGA-in-SL rats displayed rapid neonatal weight gain within one week after birth, while SGA-in-NL growth caught up only at juvenile age (day 60), as compared to AGA-in-NL controls. In adulthood, an increase in lipids, leptin, insulin, insulin/glucose-ratio (all p<0.05), and hyperphagia under normal chow as well as high-energy/high-fat diet, modelling modern ‘westernized’ lifestyle, were observed only in SGA-in-SL as compared to both SGA-in-NL and AGA-in-NL rats (p<0.05). Lasercapture microdissection (LMD)-based neuropeptide expression analyses in single neuron pools of the arcuate hypothalamic nucleus (ARC) revealed a significant shift towards down-regulation of the anorexigenic melanocortinergic system (proopiomelanocortin, Pomc) in SGA-in-SL rats (p<0.05). Neuropeptide expression within the orexigenic system (neuropeptide Y (Npy), agouti-related-peptide (Agrp) and galanin (Gal)) was not significantly altered. In essence, the ‘orexigenic index’, proposed here as a neuroendocrine ‘net-indicator’, was increased in SGA-in-SL regarding Npy/Pomc expression (p<0.01), correlated to food intake (p<0.05). Conclusion Adult SGA rats developed increased ‘diabesity’ risk only if exposed to neonatal overfeeding. Hypothalamic malprogramming towards decreased anorexigenic activity was involved into the pathophysiology of this neonatally acquired adverse phenotype. Neonatal

CDK-5 regulates the polarized trafficking of neuropeptide-containing dense-core vesicles in C. elegans motor neurons

PubMed Central

Goodwin, Patricia R.; Sasaki, Jennifer M.; Juo, Peter

2012-01-01

The polarized trafficking of axonal and dendritic proteins is essential for the structure and function of neurons. Cyclin-dependent kinase-5 (CDK-5) and its activator CDKA-1/p35 regulate diverse aspects of nervous system development and function. Here, we show that CDK-5 and CDKA-1/p35 are required for the polarized distribution of neuropeptide-containing dense-core vesicles (DCVs) in C. elegans cholinergic motor neurons. In cdk-5 or cdka-1/p35 mutants, the predominantly axonal localization of DCVs containing INS-22 neuropeptides was disrupted and DCVs accumulated in dendrites. Time-lapse microscopy in DB class motor neurons revealed decreased trafficking of DCVs in axons and increased trafficking and accumulation of DCVs in cdk-5 mutant dendrites. The polarized distribution of several axonal and dendritic markers, including synaptic vesicles, was unaltered in cdk-5 mutant DB neurons. We found that microtubule polarity is plus-end out in axons and predominantly minus-end out in dendrites of DB neurons. Surprisingly, cdk-5 mutants had increased amounts of plus-end-out microtubules in dendrites, suggesting that CDK-5 regulates microtubule orientation. However, these changes in microtubule polarity are not responsible for the increased trafficking of DCVs into dendrites. Genetic analysis of cdk-5 and the plus-end-directed axonal DCV motor unc-104/KIF1A suggest that increased trafficking of UNC-104 into dendrites cannot explain the dendritic DCV accumulation. Instead, we found that mutations in the minus-end-directed motor cytoplasmic dynein, completely block the increased DCVs observed in cdk-5 mutant dendrites without affecting microtubule polarity. We propose a model where CDK-5 regulates DCV polarity by both promoting DCV trafficking in axons and preventing dynein-dependent DCV trafficking into dendrites. PMID:22699897

Structural analysis of the starfish SALMFamide neuropeptides S1 and S2: the N-terminal region of S2 facilitates self-association.

PubMed

Otara, Claire B; Jones, Christopher E; Younan, Nadine D; Viles, John H; Elphick, Maurice R

2014-02-01

The neuropeptides S1 (GFNSALMFamide) and S2 (SGPYSFNSGLTFamide), which share sequence similarity, were discovered in the starfish Asterias rubens and are prototypical members of the SALMFamide family of neuropeptides in echinoderms. SALMFamide neuropeptides act as muscle relaxants and both S1 and S2 cause relaxation of cardiac stomach and tube foot preparations in vitro but S2 is an order of magnitude more potent than S1. Here we investigated a structural basis for this difference in potency using spectroscopic techniques. Circular dichroism spectroscopy showed that S1 does not have a defined structure in aqueous solution and this was supported by 2D nuclear magnetic resonance experiments. In contrast, we found that S2 has a well-defined conformation in aqueous solution. However, the conformation of S2 was concentration dependent, with increasing concentration inducing a transition from an unstructured to a structured conformation. Interestingly, this property of S2 was not observed in an N-terminally truncated analogue of S2 (short S2 or SS2; SFNSGLTFamide). Collectively, the data obtained indicate that the N-terminal region of S2 facilitates peptide self-association at high concentrations, which may have relevance to the biosynthesis and/or bioactivity of S2 in vivo. © 2013.

Adaptogens stimulate neuropeptide y and hsp72 expression and release in neuroglia cells.

PubMed

Panossian, Alexander; Wikman, Georg; Kaur, Punit; Asea, Alexzander

2012-01-01

The beneficial stress-protective effect of adaptogens is related to the regulation of homeostasis via mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of the stress response, such as molecular chaperones, stress-activated c-Jun N-terminal protein kinase, forkhead box O transcription factor, cortisol, and nitric oxide (NO). However, it still remains unclear what the primary upstream targets are in response to stimulation by adaptogens. The present study addresses this gap in our knowledge and suggests that an important target for adaptogen mediated stress-protective effector functions is the stress hormone neuropeptide Y (NPY). We demonstrated that ADAPT-232, a fixed combination of adaptogens Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract SHR-5, and its active constituent salidroside, stimulated the expression of NPY and 72 kDa heat shock protein (Hsp72) in isolated human neuroglia cells. The central role of NPY was validated in experiments in which pre-treatment of human neuroglia cells with NPY-siRNA and HSF1-siRNA resulted in the significant suppression of ADAPT-232-induced NPY and Hsp72 release. Taken together our studies suggest that the stimulation and release of the stress hormones, NPY and Hsp72, into systemic circulation is an innate defense response against mild stressors (ADAPT-232), which increase tolerance and adaptation to stress.

Neuropeptide Y - an early biomarker for cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

PubMed

Schebesch, Karl-Michael; Brawanski, Alexander; Bele, Sylvia; Schödel, Petra; Herbst, Andreas; Bründl, Elisabeth; Kagerbauer, Simone Maria; Martin, Jan; Lohmeier, Anette; Stoerr, Eva-Maria; Proescholdt, Martin

2013-12-01

In the human brain, the potent vasoconstrictive neuropeptide Y (NPY) is abundantly expressed. Neuropeptide Y, which is stored in perivascular nerve fibers of the cerebral arteries, regulates the cerebral vascular diameter as well as cerebral blood flow. However, the role of NPY in the pathogenesis of cerebral vasospasm (CV) related to subarachnoid hemorrhage (SAH) is unclear. We prospectively analyzed and compared the release of endogenous NPY in the cerebrospinal fluid (CSF) of 66 patients with SAH to NPY release in a control group. Additionally, we correlated the levels of NPY with CV and consecutive ischemic stroke. Sixty-six consecutive patients (40 women, 26 men; mean age 53·1 years) with aneurysmal SAH were included. In the SAH group, CSF was drawn daily from day 1 to day 10 after the onset of SAH. The CSF of 29 patients undergoing spinal anesthesia for orthopedic surgery served as control samples. The NPY levels were determined in duplicate CSF samples by means of a competitive enzyme immunoassay (EIA). The levels of NPY in CSF were correlated with the development of CV over the 10-day period after the onset of SAH and to the occurrence of consecutive ischemic stroke. To evaluate CSF NPY levels as a predictive biomarker for vasospasm, we calculated the sensitivity and specificity as well as the positive and negative predictive values. The NPY levels were significantly higher in the SAH group than in the control group (p < 0·001). The treatment modality (clip versus coil) did not influence the level of NPY in CSF (p > 0·05). Patients with CV showed significantly higher NPY levels than patients without CV during the entire observation period. The NPY levels of the non-CV group dissipated over time, whereas the CV group showed continuously increasing values. The NPY levels from day 4 to 10 were significantly higher in patients with CV-related stroke than in non-stroke patients. Using 0·3 ng/ml as a cut-off value, NPY levels on day 3 predicted the occurrence

Mmp1 processing of the PDF neuropeptide regulates circadian structural plasticity of pacemaker neurons.

PubMed

Depetris-Chauvin, Ana; Fernández-Gamba, Agata; Gorostiza, E Axel; Herrero, Anastasia; Castaño, Eduardo M; Ceriani, M Fernanda

2014-10-01

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior.

Mmp1 Processing of the PDF Neuropeptide Regulates Circadian Structural Plasticity of Pacemaker Neurons

PubMed Central

Depetris-Chauvin, Ana; Fernández-Gamba, Ágata; Gorostiza, E. Axel; Herrero, Anastasia; Castaño, Eduardo M.; Ceriani, M. Fernanda

2014-01-01

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior. PMID:25356918

The thioredoxin TRX-1 modulates the function of the insulin-like neuropeptide DAF-28 during dauer formation in Caenorhabditis elegans.

PubMed

Fierro-González, Juan Carlos; Cornils, Astrid; Alcedo, Joy; Miranda-Vizuete, Antonio; Swoboda, Peter

2011-01-27

Thioredoxins comprise a conserved family of redox regulators involved in many biological processes, including stress resistance and aging. We report that the C. elegans thioredoxin TRX-1 acts in ASJ head sensory neurons as a novel modulator of the insulin-like neuropeptide DAF-28 during dauer formation. We show that increased formation of stress-resistant, long-lived dauer larvae in mutants for the gene encoding the insulin-like neuropeptide DAF-28 requires TRX-1 acting in ASJ neurons, upstream of the insulin-like receptor DAF-2. Genetic rescue experiments demonstrate that redox-independent functions of TRX-1 specifically in ASJ neurons are needed for the dauer formation constitutive (Daf-c) phenotype of daf-28 mutants. GFP reporters of trx-1 and daf-28 show opposing expression patterns in dauers (i.e. trx-1 is up-regulated and daf-28 is down-regulated), an effect that is not observed in growing L2/L3 larvae. In addition, functional TRX-1 is required for the down-regulation of a GFP reporter of daf-28 during dauer formation, a process that is likely subject to DAF-28-mediated feedback regulation. Our findings demonstrate that TRX-1 modulates DAF-28 signaling by contributing to the down-regulation of daf-28 expression during dauer formation. We propose that TRX-1 acts as a fluctuating neuronal signaling modulator within ASJ neurons to monitor the adjustment of neuropeptide expression, including insulin-like proteins, during dauer formation in response to adverse environmental conditions.

The lysosomal degradation of neuromedin B is dependent on tripeptidyl peptidase-I: evidence for the impairment of neuropeptide degradation in late-infantile neuronal ceroid lipofuscinosis.

PubMed

Kopan, Sharmila; Sivasubramaniam, Uthayatharsini; Warburton, Michael J

2004-06-18

Late-infantile neuronal ceroid lipofuscinosis (CLN2), previously known as the late-infantile form of Batten disease, is a lysosomal storage disease which results from mutations in the gene that codes for tripeptidyl peptidase-I (TPP-I). This disease is characterised by progressive neurodegeneration in young children although the molecular mechanisms responsible for neuronal cell death are unclear. TPP-I is an exopeptidase which removes N-terminal tripeptides from small peptides, including several peptide hormones. We report that the degradation of the neuropeptide, neuromedin B, by mouse brain cells is restricted to lysosomes and that the pattern of degradation products is consistent with a predominant role for TPP-I. Neuromedin B is degraded by a similar pathway in a mouse neuronal cell line and also in cultured human fibroblasts. A specific inhibitor of TPP-I is able to abolish neuromedin B degradation in a variety of cell types. Fibroblasts from CLN2 patients, which are deficient in TPP-I activity, are unable to degrade neuromedin B. These observations suggest that TPP-I is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B. The inability of cells from CLN2 patients to degrade neuromedin B and other neuropeptides may contribute to the pathogenesis of the disease.

Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors

PubMed Central

Bahl, Ethan; Hannah, Claire; Hofammann, Dabney; Acevedo, Summer; Cui, Huxing; McAdams, Carrie J.

2017-01-01

Objective Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown. Methods To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating. Results An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of ‘binge-like’ eating. Conclusions These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating. PMID:28846695

Brain innate immunity regulates hypothalamic arcuate neuronal activity and feeding behavior.

PubMed

Reis, Wagner L; Yi, Chun-Xia; Gao, Yuanqing; Tschöp, Mathias H; Stern, Javier E

2015-04-01

Hypothalamic inflammation, involving microglia activation in the arcuate nucleus (ARC), is proposed as a novel underlying mechanism in obesity, insulin and leptin resistance. However, whether activated microglia affects ARC neuronal activity, and consequently basal and hormonal-induced food intake, is unknown. We show that lipopolysaccharide, an agonist of the toll-like receptor-4 (TLR4), which we found to be expressed in ARC microglia, inhibited the firing activity of the majority of orexigenic agouti gene-related protein/neuropeptide Y neurons, whereas it increased the activity of the majority of anorexigenic proopiomelanocortin neurons. Lipopolysaccharide effects in agouti gene-related protein/neuropeptide Y (but not in proopiomelanocortin) neurons were occluded by inhibiting microglia function or by blocking TLR4 receptors. Finally, we report that inhibition of hypothalamic microglia altered basal food intake, also preventing central orexigenic responses to ghrelin. Our studies support a major role for a TLR4-mediated microglia signaling pathway in the control of ARC neuronal activity and feeding behavior.

Role of hindbrain adenosine 5'-monophosphate-activated protein kinase (AMPK) in hypothalamic AMPK and metabolic neuropeptide adaptation to recurring insulin-induced hypoglycemia in the male rat.

PubMed

Mandal, Santosh K; Shrestha, Prem K; Alenazi, Fahaad S H; Shakya, Manita; Alhamami, Hussain; Briski, Karen P

2017-12-01

Glucose counter-regulatory dysfunction correlates with impaired activation of the hypothalamic metabolic sensor adenosine 5'-monophosphate-activated protein kinase (AMPK). Hypothalamic AMPK is controlled by hindbrain energy status; we examined here whether hindbrain AMPK regulates hypothalamic AMPK and metabolic neurotransmitter maladaptation to recurring insulin-induced hypoglycemia (RIIH). Brain tissue was harvested after single versus serial insulin (I) dosing for Western blot analysis of AMPK, phospho-AMPK (pAMPK), and relevant biosynthetic enzyme/neuropeptide expression in micro-punch dissected arcuate (ARH), ventromedial (VMH), dorsomedial (DMH) nuclei and lateral hypothalamic area (LHA) tissue. The AMPK inhibitor compound c (Cc) or vehicle was administered to the caudal fourth ventricle ahead of antecedent I injections. RIIH caused site-specific elevation (ARH, VMH, LHA) or reduction (DMH) of total AMPK protein versus acute hypoglycemia; Cc respectively exacerbated or attenuated this response in the ARH and VMH. Hindbrain AMPK correspondingly inhibited or stimulated LHA and DMH pAMPK expression during RIIH. RIIH elicited Cc-reversible augmentation of VMH glutamate decarboxylase profiles, but stimulated (ARH pro-opiomelanocortin; LHA orexin-A) or decreased (VMH nitric oxide synthase) other metabolic neurotransmitters without hindbrain sensor involvement. Results demonstrate acclimated up-regulation of total AMPK protein expression in multiple hypothalamic loci during RIIH, and document hindbrain sensor contribution to amplification of this protein profile in the VMH. Concurrent lack of net change in ARH and VMH tissue pAMPK implies adaptive reductions in local sensor activity, which may/may not reflect positive gain in energy state. It remains unclear if 'glucose-excited' VMH GABAergic and/or ARH pro-opiomelanocortin neurons exhibit AMPK habituation to RIIH, and whether diminished sensor activation in these and other mediobasal hypothalamic neurotransmitter

A new approach of light microscopic immunohistochemical triple-staining: combination of Fos labeling with diaminobenzidine-nickel and neuropeptides labeled with Alexa488 and Alexa555 fluorescent dyes.

PubMed

Majercikova, Z; Weering, H van; Scsukova, S; Mikkelsen, J D; Kiss, A

2012-10-01

The aim of the present study was to introduce a new approach of the light microscopic immunohistochemical triple-staining enabling to study the differences in the activity of at least two different phenotypes of neurons on the same histological section. For this purpose combination of Fos (a product of the immediate early gene) labeling with nickel intensified diaminobenzidine (DAB-Ni) and two neuropeptides labeled with Alexa488 and Alexa555 fluorescent dyes on cryo-processed 35-40 µm thick free-floating brain sections was selected. The parallel occurrence of three antibodies studied, i.e. Fos, hypocretin (HCRT), and melanin-concentrating hormone (MCH), was studied by a new methodic approach utilizing combination of Fos immunolabeled with DAB-Ni and HCRT and MCH labeled with Alexa488 and Alexa555 fluorescent dyes, respectively. Fos stimulation was induced by a single immobilization (IM0) for 120 min. Then, the rats were sacrificed, the brains removed, soaked with 30% sucrose in 0.1 M phosphate buffer (PB), cryo-sectioned throughout the hypothalamus into 35-40 μm thick coronal sections, collected, and washed in the same buffer for 10-15 min. Fos was revealed by avidin-biotin-peroxidase (ABC) complex and visualized by diaminobenzidine chromogen containing nickel chloride salt. HCRT and MCH neurons were visualized by the above mentioned fluorescent dyes. Evaluation of the Fos and fluorescent staining was performed in the computerized Axo Imager Carl Zeiss microscope using light and fluorescent illuminations. All the antibodies used showed clear immunoreactive staining. Fos staining occurred in the form of black color located in the cell nuclei. HCRH and MCH neuropeptides showed clear green and red fluorescence in the cell perikarya, respectively. The final merged picture showed Fos protein in the activated green HCRT or red MCH neurons in the form of white nuclei. The present study clearly demonstrate that the combination of Fos labeling with DAB-Ni and

The metabolic regulator PGC-1α directly controls the expression of the hypothalamic neuropeptide oxytocin.

PubMed

Blechman, Janna; Amir-Zilberstein, Liat; Gutnick, Amos; Ben-Dor, Shifra; Levkowitz, Gil

2011-10-19

The transcriptional coactivator PGC-1α is a key regulator of cellular energy expenditure in peripheral tissues. Recent studies report that PGC-1α-null mice develop late-onset obesity and that the neuronal inactivation of PGC-1α causes increased food intake. However, the exact role of PGC-1α in the CNS remains unclear. Here we show that PGC-1α directly regulates the expression of the hypothalamic neuropeptide oxytocin, a known central regulator of appetite. We developed a unique genetic approach in the zebrafish, allowing us to monitor and manipulate PGC-1α activity in oxytocinergic neurons. We found that PGC-1α is coexpressed with oxytocin in the zebrafish hypothalamus. Targeted knockdown of the zebrafish PGC-1α gene activity caused a marked decrease in oxytocin mRNA levels and inhibited the expression of a transgenic GFP reporter driven by the oxytocin promoter. The effect of PGC-1α loss of function on oxytocin gene activity was rescued by tissue-specific re-expression of either PGC-1α or oxytocin precursor in zebrafish oxytocinergic neurons. PGC-1α activated the oxytocin promoter in a heterologous cell culture system, and overexpression of PGC-1α induced ectopic expression of oxytocin in muscles and neurons. Finally, PGC-1α forms an in vivo complex with the oxytocin promoter in fed but not fasted animals. These findings demonstrate that PGC-1α is both necessary and sufficient for the production of oxytocin, implicating hypothalamic PGC-1α in the direct activation of a hypothalamic hormone known to control energy intake.

Secretoneurin, substance P and neuropeptide Y in the oxygen-induced retinopathy in C57Bl/6N mice.

PubMed

Schmid, Eduard; Nogalo, Marina; Bechrakis, Nikolaos E; Fischer-Colbrie, Reiner; Tasan, Ramon; Sperk, Günther; Theurl, Markus; Beer, Arno G E; Kirchmair, Rudolf; Herzog, Herbert; Troger, Josef

2012-10-01

In this study, we investigated whether the proangiogenic neuropeptides secretoneurin (SN), substance P (SP), and neuropeptide Y (NPY) contribute to the development of abnormal neovascularization in the oxygen-induced retinopathy (OIR) model in mice. By exposing litters of C57Bl/6N mice to 75% oxygen from postnatal day 7 (P7) until postnatal day 11 (P11) and then returning them to normoxic conditions, retinal ischemia and subsequent neovascularization on the retinal surface were induced. Retinae were dissected on P9, P11, P12-P14, P16 and P20, and the concentrations of SN, SP, NPY and VEGF determined by radioimmunoassay or ELISA. The levels of SN and SP increased in controls from P9 until P16 and from P9 until P14, respectively, whereas the levels of NPY were high at P9 and decreased thereafter until P20, suggesting that NPY may participate in the development of the retina. However, dipeptidyl peptidase IV (DPPIV) and the NPY-Y2 receptor were not detectable in the immature retina indicating that NPY is not involved in the physiological vascularization in the retina. Compared to controls, OIR had no effect on the levels of SN, whereas levels of both SP and NPY slightly decreased during hyperoxia. Normalization of the levels of SP, and to a more pronounced extent of NPY, was significantly delayed during relative hypoxia. This clearly indicates that these three neuropeptides are not involved in the pathogenesis of neovascularization in OIR. Moreover, since there were no differences in the expression of two vessel markers in the retina of NPY knockout mice versus controls at P14, NPY is also not involved in the delayed development of the intermediate and deep vascular plexus in the retina in this animal model. Copyright © 2012 Elsevier Inc. All rights reserved.

The Thioredoxin TRX-1 Modulates the Function of the Insulin-Like Neuropeptide DAF-28 during Dauer Formation in Caenorhabditis elegans

PubMed Central

Fierro-González, Juan Carlos; Cornils, Astrid; Alcedo, Joy

2011-01-01

Thioredoxins comprise a conserved family of redox regulators involved in many biological processes, including stress resistance and aging. We report that the C. elegans thioredoxin TRX-1 acts in ASJ head sensory neurons as a novel modulator of the insulin-like neuropeptide DAF-28 during dauer formation. We show that increased formation of stress-resistant, long-lived dauer larvae in mutants for the gene encoding the insulin-like neuropeptide DAF-28 requires TRX-1 acting in ASJ neurons, upstream of the insulin-like receptor DAF-2. Genetic rescue experiments demonstrate that redox-independent functions of TRX-1 specifically in ASJ neurons are needed for the dauer formation constitutive (Daf-c) phenotype of daf-28 mutants. GFP reporters of trx-1 and daf-28 show opposing expression patterns in dauers (i.e. trx-1 is up-regulated and daf-28 is down-regulated), an effect that is not observed in growing L2/L3 larvae. In addition, functional TRX-1 is required for the down-regulation of a GFP reporter of daf-28 during dauer formation, a process that is likely subject to DAF-28-mediated feedback regulation. Our findings demonstrate that TRX-1 modulates DAF-28 signaling by contributing to the down-regulation of daf-28 expression during dauer formation. We propose that TRX-1 acts as a fluctuating neuronal signaling modulator within ASJ neurons to monitor the adjustment of neuropeptide expression, including insulin-like proteins, during dauer formation in response to adverse environmental conditions. PMID:21304598

Effect of monensin on the levels of tachykinins and their processing enzyme activity in rat dorsal root ganglia.

PubMed

Chikuma, Toshiyuki; Inomata, Yuji; Tsuchida, Ken; Hojo, Hiroshi; Kato, Takeshi

2002-06-28

Th effect of monensin, which inhibits trans-Golgi function, on the levels of tachykinins and their processing enzyme activity was examined in organ-cultured rat dorsal root ganglia (DRG). Using an enzyme immunoassay method, we measured neurokinin A and substance P immunoreactivity in the DRG cultured for 72 h with and without 0.1 microM monensin. Both tachykinins were reduced in the DRG treated with monensin. Treatment with monensin also reduced the activity of carboxypeptidase E, which is one of the proteolytic processing enzymes of neuropeptides. These data suggest that proteolytic processing enzymes may in part modulate the biological activity of neuropeptides within a trans-Golgi apparatus.

Nanoparticulate anatase TiO2 (TiO2 NPs) upregulates the expression of silkworm (Bombyx mori) neuropeptide receptor and promotes silkworm feeding, growth, and silking.

PubMed

Ni, Min; Zhang, Hua; Li, Fan Chi; Wang, Bin Bin; Xu, Kai Zun; Shen, Wei De; Li, Bing

2015-06-01

Bombyx mori orphan G protein-coupled receptor, BNGR-A4, is the specific receptor of B. mori neuropeptide F (BmNPFR, neuropeptide F designated NPF). BmNPFR binds specifically and efficiently to B. mori neuropeptides BmNPF1a and BmNPF1b, which activates the ERK1/2 signaling pathway to regulate B. mori food intake and growth. Titanium dioxide nanoparticles (TiO2 NPs) can promote B. mori growth. However, whether the mechanisms of TiO2 NPs' effects are correlated with BmNPFR remains unknown. In this study, the effects of TiO2 NPs (5mg/L) feeding and BmNPFR-dsRNA injection on B. mori food intake and growth were investigated; after TiO2 NPs treatments, B. mori food intake, body weight, and cocoon shell weight were 5.82%, 4.64%, and 9.30% higher, respectively, than those of controls. The food intake, body weight, and cocoon shell weight of the BmNPFR-dsRNA injection group were reduced by 8.05%, 6.28%, and 6.98%, respectively, compared to the control. After TiO2 NPs treatment for 72h, the transcriptional levels of BmNPFR, BmNPF1a, and BmNPF1b in the midgut were 1.58, 1.43, and 1.34-folds, respectively, of those of the control, but 1.99, 2.26, and 2.19-folds, respectively, of the BmNPFR-dsRNA injection group; the phosphorylation level of MAPK was 24.03% higher than the control, while the phosphorylation level of BmNPFR-dsRNA injection group was 71.00% of control. The results indicated that TiO2 NPs affect B. mori feeding and growth through increasing the expression of BmNPFR. This study helps clarify the roles of BmNPF/BmNPFR system in TiO2 NPs' effects on B. mori feeding, growth, and development. Copyright © 2015 Elsevier Inc. All rights reserved.

Neuropeptide Y Has a Protective Role during Murine Retrovirus-Induced Neurological Disease▿

PubMed Central

Du, Min; Butchi, Niranjan B.; Woods, Tyson; Morgan, Timothy W.; Peterson, Karin E.

2010-01-01

Viral infections in the central nervous system (CNS) can lead to neurological disease either directly by infection of neurons or indirectly through activation of glial cells and production of neurotoxic molecules. Understanding the effects of virus-mediated insults on neuronal responses and neurotrophic support is important in elucidating the underlying mechanisms of viral diseases of the CNS. In the current study, we examined the expression of neurotrophin- and neurotransmitter-related genes during infection of mice with neurovirulent polytropic retrovirus. In this model, virus-induced neuropathogenesis is indirect, as the virus predominantly infects macrophages and microglia and does not productively infect neurons or astrocytes. Virus infection is associated with glial cell activation and the production of proinflammatory cytokines in the CNS. In the current study, we identified increased expression of neuropeptide Y (NPY), a pleiotropic growth factor which can regulate both immune cells and neuronal cells, as a correlate with neurovirulent virus infection. Increased levels of Npy mRNA were consistently associated with neurological disease in multiple strains of mice and were induced only by neurovirulent, not avirulent, virus infection. NPY protein expression was primarily detected in neurons near areas of virus-infected cells. Interestingly, mice deficient in NPY developed neurological disease at a faster rate than wild-type mice, indicating a protective role for NPY. Analysis of NPY-deficient mice indicated that NPY may have multiple mechanisms by which it influences virus-induced neurological disease, including regulating the entry of virus-infected cells into the CNS. PMID:20702619

Adaptogens Stimulate Neuropeptide Y and Hsp72 Expression and Release in Neuroglia Cells

PubMed Central

Panossian, Alexander; Wikman, Georg; Kaur, Punit; Asea, Alexzander

2011-01-01

The beneficial stress–protective effect of adaptogens is related to the regulation of homeostasis via mechanisms of action associated with the hypothalamic–pituitary–adrenal axis and the regulation of key mediators of the stress response, such as molecular chaperones, stress-activated c-Jun N-terminal protein kinase, forkhead box O transcription factor, cortisol, and nitric oxide (NO). However, it still remains unclear what the primary upstream targets are in response to stimulation by adaptogens. The present study addresses this gap in our knowledge and suggests that an important target for adaptogen mediated stress–protective effector functions is the stress hormone neuropeptide Y (NPY). We demonstrated that ADAPT-232, a fixed combination of adaptogens Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract SHR-5, and its active constituent salidroside, stimulated the expression of NPY and 72 kDa heat shock protein (Hsp72) in isolated human neuroglia cells. The central role of NPY was validated in experiments in which pre-treatment of human neuroglia cells with NPY-siRNA and HSF1-siRNA resulted in the significant suppression of ADAPT-232-induced NPY and Hsp72 release. Taken together our studies suggest that the stimulation and release of the stress hormones, NPY and Hsp72, into systemic circulation is an innate defense response against mild stressors (ADAPT-232), which increase tolerance and adaptation to stress. PMID:22347152

Attenuated plasma extravasation to sensory neuropeptides in diabetic rats.

PubMed

Mathison, R; Davison, J S

1993-01-01

The effects of either substance P (SP) or a metabolically stable SP analogue, [pGlu5,Me-Phe8,Sar9]SP(5-11), alone or in combination with calcitonin gene-related peptide (CGRP) on blood pressure (BP) and extravasation of serum albumin were examined in normal and diabetic rats. CGRP (12 ng/kg) modified neither BP nor vascular permeability in control and diabetic rats. Both SP and its analogue (74 ng/kg) produced hypotension, and increased plasma extravasation in the respiratory tissues, urinary bladder and skin. The simultaneous injection of CGRP and SP resulted in modest potentiation of the vascular permeability actions of SP in control and diabetic rats. However, extravasation induced by [pGlu5,Me-Phe8,Sar9]SP(5-11) was potentiated by CGRP in control animals, but not in diabetic rats. Defective neurogenic inflammatory responses in diabetic rats may result from decreased responses in the effector tissues of diabetic rats to the neuropeptides released from sensory nerves.

Sensory neuropeptides and the human lower airways: present state and future directions.

PubMed

Joos, G F; Germonpre, P R; Kips, J C; Peleman, R A; Pauwels, R A

1994-06-01

The sensory neuropeptides, substance P and neurokinin A, are present in human airway nerves, beneath and within the epithelium, around blood vessels and submucosal glands, and within the bronchial smooth muscle layer. Studies on autopsy tissue, bronchoalveolar lavage and sputum suggest that in asthma the substance P content of the airways may be increased. Neurokinin A is a more potent bronchoconstrictor than substance P. Asthmatics are hyperresponsive to neurokinin A and substance P. The neuropeptide degrading enzyme, neutral endopeptidase is present in the airways and is involved in the degradation of endogenously released and exogenously administered substance P and neurokinin A, both in normal and asthmatic subjects. As for other indirect bronchoconstrictor stimuli, the effect of neurokinin A on airway calibre in asthmatics can be inhibited by pretreatment with nedocromil sodium. Evidence is accumulating, not only from studies in animals but also from experiments on human airways, that tachykinins may also cause mucus secretion and plasma extravasation. They also have important proinflammatory effects, such as the chemoattraction of eosinophils and neutrophils, the adhesion of neutrophils, and the stimulation of lymphocytes, macrophages and mast cells. The tachykinins interact with the targets on the airways by specific tachykinin receptors. The NK1 and the NK2 receptor have been characterized in human airways, both pharmacologically and by cloning. The NK2 receptor is responsible for the in vitro contraction of normal airways, whilst the NK1 receptor is responsible for most of the other airway effects. Because of their presence in the airways and because of their ability to mimic the various pathophysiological features of asthma, substance P and neurokinin A are presently considered as possible mediators of asthma. The present development of potent and selective tachykinin antagonists will allow us to further define the role of tachykinins in the pathogenesis

BNGR-A25L and -A27 are two functional G protein-coupled receptors for CAPA periviscerokinin neuropeptides in the silkworm Bombyx mori.

PubMed

Shen, Zhangfei; Chen, Yu; Hong, Lingjuan; Cui, Zhenteng; Yang, Huipeng; He, Xiaobai; Shi, Ying; Shi, Liangen; Han, Feng; Zhou, Naiming

2017-10-06

CAPA peptides, such as periviscerokinin (PVK), are insect neuropeptides involved in many signaling pathways controlling, for example, metabolism, behavior, and reproduction. They are present in a large number of insects and, together with their cognate receptors, are important for research into approaches for improving insect control. However, the CAPA receptors in the silkworm ( Bombyx mori ) insect model are unknown. Here, we cloned cDNAs of two putative CAPA peptide receptor genes, BNGR-A27 and -A25, from the brain of B. mori larvae. We found that the predicted BNGR-A27 ORF encodes 450 amino acids and that one BNGR-A25 splice variant encodes a full-length isoform (BNGR-A25L) of 418 amino acid residues and another a short isoform (BNGR-A25S) of 341 amino acids with a truncated C-terminal tail. Functional assays indicated that both BNGR-A25L and -A27 are activated by the PVK neuropeptides Bom -CAPA-PVK-1 and -PVK-2, leading to a significant increase in cAMP-response element-controlled luciferase activity and Ca 2+ mobilization in a G q inhibitor-sensitive manner. In contrast, BNGR-A25S was not significantly activated in response to the PVK peptides. Moreover, Bom -CAPA-PVK-1 directly bound to BNGR-A25L and -A27, but not BNGR-A25S. Of note, CAPA-PVK-mediated ERK1/2 phosphorylation and receptor internalization confirmed that BNGR-A25L and -A27 are two canonical receptors for Bombyx CAPA-PVKs. However, BNGR-A25S alone is a nonfunctional receptor but serves as a dominant-negative protein for BNGR-A25L. These results provide evidence that BNGR-A25L and -A27 are two functional G q -coupled receptors for Bombyx CAPA-PVKs, enabling the further elucidation of the endocrinological roles of Bom -CAPA-PVKs and their receptors in insect biology. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis.

PubMed

Misawa, Kiyoshi; Mima, Masato; Imai, Atsushi; Mochizuki, Daiki; Misawa, Yuki; Endo, Shiori; Ishikawa, Ryuji; Kanazawa, Takeharu; Mineta, Hiroyuki

2018-01-01

Staging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Identifying biomarkers for HNSCC that will progress and cause death is a critical research area, particularly if the biomarker can be linked to selection of patients. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of five neuropeptide gene promoters. The promoter methylation status was determined by quantitative methylation-specific PCR in 230 cases of HNSCC; 58 hypopharynx, 45 larynx, 56 oropharynx, and 71 oral cavity tumor samples were studied. The somatostatin ( SST ), tachykinin precursor 1 ( TAC1 ), hypocretin neuropeptide precursor ( HCRT ), neuropeptide Y ( NPY ), and galanin ( GAL ) promoters were methylated in 84.3, 63.5, 32.6, 28.3, and 20.0%, respectively, of the samples. The mean number of methylated genes per sample was 2.29 (range, 0-5). Disease-free survival was lower in patients with 3-5 methylated genes than in those with 0-2 methylated genes (log-rank test, P  = 0.007). In multivariate Cox proportional hazards analysis, TAC1 and GAL promoter methylation independently predicted recurrence (odds ratios 1.620, 95% confidence interval [CI] 1.018-2.578, P  = 0.042, and odds ratios 1.692, 95% CI 1.063-2.694, P  = 0.027, respectively). In patients with oral cancer, TAC1 methylation showed the best correlation with poor survival (odds ratio 4.427, 95% CI 1.634-12.00, P  = 0.003). Similar findings were observed for HCRT and GAL in patients with laryngeal cancer and oropharyngeal cancer, respectively. In this study, we demonstrated the methylation status of the neuropeptide-encoding genes SST , TAC1 , HCRT , NPY , and GAL and its relationship with recurrence and survival in HNSCC. These methylation changes may serve as potential molecular markers for defining the risk and prognosis of HNSCC.

Sch 37224, an experimental antiallergy compound, inhibits the neuropeptide component of hyperventilation- and nicotine-induced bronchoconstriction in guinea pigs.

PubMed

Mauser, P J; Rasquinha, C; Hey, J A; Kreutner, W; Egan, R W; Sherwood, J E; Anthes, J; Greenfeder, S; Chapman, R W

1997-01-01

Sch 37224 is an experimental antiallergy compound that inhibits hyperventilation-induced bronchoconstriction (HIB) in guinea pigs and cold air bronchospasm in human asthmatics. HIB in guinea pigs may involve the release of tachykinins such as neurokinin A (NKA) and substance P (SP), and the action of Sch 37224 in this model may relate to inhibition of these neuropeptides. We studied the effect of Sch 37224 on the neuropeptide component of HIB that was enhanced in guinea pigs treated with the neutral endopeptidase inhibitors, thiorphan and phosphoramidon. Pulmonary resistance (RL) and dynamic lung compliance (CDyn) were measured in anesthetized, mechanically ventilated guinea pigs. RL and CDyn were measured at baseline (1 ml/100 g tidal volume and 50 breaths/min) and after a 10-min period of hyperventilation (1 ml/100 g, 150 breaths/min). Hyperventilation produced modest changes in RL (+41 +/- 12%) and CDyn (-12 +/- 3%) which were markedly enhanced by treatment with 3 mg/kg of either thiorphan or phosphoramidon (RL + 269 +/- 43% for thiorphan, + 292 +/- 63% for phosphoramidon and CDyn -65 +/- 3% for thiorphan, -51 +/- 13% for phosphoramidon). In the presence of thiorphan or phosphoramidon, the bronchospasm to hyperventilation was significantly reduced (> 70%) with 5 mg/kg, p.o., of Sch 37224. In other studies, the peptidergic (conducted in the presence of ipratropium bromide and phosphoramidon) bronchoconstrictor response to intravenous nicotine (1 mg/kg) was also inhibited by Sch 37224 (0.3-10 mg/kg, p.o.). However, Sch 37224 (5 mg/kg, p.o.) had no effect on the bronchoconstrictor response to intravenous NKA. These results indicate that Sch 37224 inhibits the neuropeptide component of HIB and nicotine in guinea pigs and this effect appears to be mediated by the inhibition of the release of tachykinins from airway C fibers.

Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior

PubMed Central

Wircer, Einav; Blechman, Janna; Borodovsky, Nataliya; Tsoory, Michael; Nunes, Ana Rita; Oliveira, Rui F; Levkowitz, Gil

2017-01-01

Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co-express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa−/− deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior. DOI: http://dx.doi.org/10.7554/eLife.22170.001 PMID:28094761

Gamma-aminobutyric acid (GABA) and neuropeptides in neural areas mediating motion-induced emesis

NASA Technical Reports Server (NTRS)

Damelio, F.; Daunton, Nancy G.; Fox, Robert A.

1991-01-01

Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid and the neuropeptides substance P and Met-enkephalin in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), dorsal motor nucleus of the vagus nerve (DMNV), and lateral vestibular nucleus (LVN). Glutamic acid decarboxylase immunoreactive (GAD-IR) terminals and fibers were observed in the AP and particularly in the ASP. A gradual decrease in the density of terminals was seen towards the solitary complex. The DMNV revealed irregularly scattered GAD-IR terminals within the neuropil or closely surrounding neuronal cell bodies. The LVN, particularly the dorsal division, showed numerous axon terminals which were mostly localize around large neurons and their proximal dendrites. Substance P immunoreactive (SP-IR) terminals and fibers showed high density in the solitary complex, in particular within the lateral division. The ASP showed medium to low density of SP-IR fibers and terminals. The AP exhibited a small number of fibers and terminals irregularly distributed. The DMNV revealed a high density of SP-IR terminals and fibers that were mainly concentrated in the periphery. Very few terminals were detected in the LVN. Met-enkephalin immunoreactive (Met-Enk-IR) fibers and terminals showed high density and uniform distribution in the DMNV. Scattered terminals and fibers were observed in the AP, ASP, and NTS (particularly the lateral division). The very few fibers were observed in the LVN surrounded the neuronal cell bodies. The present report is part of a study designed to investigate the interaction between neuropeptides and conventional neurotransmitters under conditions producing motion sickness and in the process of sensory-motor adaptation.

Stimulation of sensory neuropeptide release by nociceptin/orphanin FQ leads to hyperaemia in acutely inflamed rat knees

PubMed Central

Zhang, Chunfen; McDougall, Jason J

2006-01-01

The peripheral effect of the ‘opioid-like' peptide nociceptin/orphanin FQ (N/OFQ) on joint blood flow was investigated in acutely inflamed rats. Sensory neuropeptide release from capsaicin-sensitive nerves and the involvement of synovial mast cells and leukocytes on these vasomotor responses were also studied. Blood flow measurements of exposed knee joints were performed in urethane-anaesthetised rats (2 mg kg−1 intraperitoneal) using laser Doppler perfusion imaging. Topical administration of N/OFQ (10−13–10−8 mol) to acutely inflamed joints caused a dose-dependent increase in synovial perfusion with an ED50 of 4.0 × 10−10 mol. This vasodilatatory response was blocked by the selective NOP receptor antagonist [Phe1-(CH2-NH)-Gly2]-Nociceptin(1–13)-NH2 (10−9 mol) (P<0.0001). Co-administration of N/OFQ with the neurokinin-1 (NK1) receptor antagonist [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-Substance P (10−12 mol), the vasoactive intestinal peptide (VIP) receptor antagonist VIP6–28 (10−9 mol) or the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8–37 (10−9 mol) all blocked the hyperaemic effect of N/OFQ (P<0.0001). Treatment of acutely inflamed knees with capsaicin (8-methyl-N-vanillyl-6-noneamide) to destroy unmyelinated joint afferents also inhibited N/OFQ vasomotor activity. Stabilisation of synovial mast cells with disodium cromoglycate (cromolyn) ameliorated N/OFQ responses, whereas inactivation of circulating leukocytes with the pan-selectin inhibitor fucoidin completely blocked N/OFQ-induced hyperaemia in these joints. These experiments show that in acutely inflamed knee joints, N/OFQ acts on NOP receptors located on synovial mast cells and leukocytes leading to the secondary release of proinflammatory mediators into the joint. These agents subsequently stimulate sensory neuropeptide release from capsaicin-sensitive nerves culminating in vasodilatation and increased articular blood flow. PMID:16783411

Accelerated onset of the vesicovesical reflex in postnatal NGF-OE mice and the role of neuropeptides

PubMed Central

Girard, Beatrice; Peterson, Abbey; Malley, Susan; Vizzard, Margaret A.

2016-01-01

The mechanisms underlying the postnatal maturation of micturition from a somatovesical to a vesicovesical reflex are not known but may involve neuropeptides in the lower urinary tract. A transgenic mouse model with chronic urothelial overexpression (OE) of NGF exhibited increased voiding frequency, increased number of non-voiding contractions, altered morphology and hyperinnervation of the urinary bladder by peptidergic (e.g., Sub P and CGRP) nerve fibers in the adult. In early postnatal and adult NGF-OE mice we have now examined: (1) micturition onset using filter paper void assays and open-outlet, continuous fill, conscious cystometry; (2) innervation and neurochemical coding of the suburothelial plexus of the urinary bladder using immunohistochemistry and semi-quantitative image analyses; (3) neuropeptide protein and transcript expression in urinary bladder of postnatal and adult NGF-OE mice using Q-PCR and ELISAs and (4) the effects of intravesical instillation of a neurokinin (NK)-1 receptor antagonist on bladder function in postnatal and adult NGF-OE mice using conscious cystometry. Postnatal NGF-OE mice exhibit age-dependent (R2= 0.996–0.998; p ≤ 0.01) increases in Sub and CGRP expression in the urothelium and significantly (p ≤ 0.01) increased peptidergic hyperinnervation of the suburothelial nerve plexus. By as early as P7, NGF-OE mice exhibit a vesicovesical reflex in response to intravesical instillation of saline whereas littermate WT mice require perigenital stimulation to elicit a micturition reflex until P13 when vesicovesical reflexes are first observed. Intravesical instillation of a NK-1 receptor antagonist, netupitant (0.1 μg/ml), significantly (p ≤ 0.01) increased void volume and the interval between micturition events with no effects on bladder pressure (baseline, threshold, peak) in postnatal NGF-OE mice; effects on WT mice were few. NGF-induced pleiotropic effects on neuropeptide (e.g., Sub P) expression in the urinary bladder

Neuropeptide W acts in brain to control prolactin, corticosterone, and growth hormone release.

PubMed

Baker, Jennifer R; Cardinal, Kara; Bober, Cynthia; Taylor, Meghan M; Samson, Willis K

2003-07-01

The endogenous, peptide ligand for the orphan receptors GPR7 and GPR8 was identified to be neuropeptide W (NPW). Because these receptors are expressed in brain and in particular in hypothalamus, we hypothesized that NPW might interact with neuroendocrine systems that control hormone release from the anterior pituitary gland. No significant effects of NPW were observed on the in vitro releases of prolactin (PRL), ACTH, or GH when log molar concentrations ranging from 1 pM to 100 nM NPW were incubated with dispersed anterior pituitary cells. However, NPW, when injected into the lateral cerebroventricle of conscious, unrestrained male rats, in a dose-related fashion elevated PRL and corticosterone and lowered GH levels in circulation. The threshold dose for all three effects was 1.0 nmol. We conclude that endogenous NPW may play a regulatory role in the organization of neuroendocrine signals accessing the anterior pituitary gland but does not itself act as a true releasing or inhibiting factor in the gland. Central administration of NPW23 also stimulated water drinking and food intake. The ability of exogenous peptide to decrease GH but stimulate PRL secretion and activate the hypothalamo-pituitary adrenal axis, together with the observed behavioral effects, suggests that endogenous NPW may play a role in the hypothalamic response to stress.

Biostable aptamers with antagonistic properties to the neuropeptide nociceptin/orphanin FQ

PubMed Central

FAULHAMMER, DIRK; ESCHGFÄLLER, BERND; STARK, SANDRA; BURGSTALLER, PETRA; ENGLBERGER, WERNER; ERFURTH, JEANNETTE; KLEINJUNG, FRANK; RUPP, JOHANNA; VULCU, SEBASTIAN DAN; SCHRÖDER, WERNER; VONHOFF, STEFAN; NAWRATH, HERMANN; GILLEN, CLEMENS; KLUSSMANN, SVEN

2004-01-01

The neuropeptide nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor, has been shown to play a prominent role in the regulation of several biological functions such as pain and stress. Here we describe the isolation and characterization of N/OFQ binding biostable RNA aptamers (Spiegelmers) using a mirror-image in vitro selection approach. Spiegelmers are l-enantiomeric oligonucleotide ligands that display high affinity and specificity to their targets and high resistance to enzymatic degradation compared to d-oligonucleotides. A representative Spiegelmer from the selections performed was size-minimized to two distinct sequences capable of high affinity binding to N/OFQ. The Spiegelmers were shown to antagonize binding of N/OFQ to the ORL1 receptor in a binding-competition assay. The calculated IC50 values for the Spiegelmers NOX 2149 and NOX 2137a/b were 110 nM and 330 nM, respectively. The competitive antagonistic properties of these Spiegelmers were further demonstrated by their effective and specific inhibition of G-protein activation in two additional models. The Spiegelmers antagonized the N/OFQ-induced GTPγS incorporation into cell membranes of a CHO-K1 cell line expressing the human ORL1 receptor. In oocytes from Xenopus laevis, NOX 2149 showed an antagonistic effect to the N/OFQ-ORL 1 receptor system that was functionally coupled with G-protein-regulated inwardly rectifying K+ channels. PMID:14970396

Neuropeptides and epitheliopeptides: structural and functional diversity in an ancestral metazoan Hydra.

PubMed

Takahashi, Toshio

2013-06-01

Peptides are known to play important developmental and physiological roles in signaling. The rich diversity of peptides, with functions as diverse as intercellular communication, neurotransmission and signaling that spatially and temporally controls axis formation and cell differentiation, hints at the wealth of information passed between interacting cells. Little is known about peptides that control developmental processes such as cell differentiation and pattern formation in metazoans. The cnidarian Hydra is one of the most basic metazoans and is a key model system for study of the peptides involved in these processes. We developed a novel peptidomic approach for the isolation and identification of functional peptide signaling molecules from Hydra (the Hydra Peptide Project). Over the course of this project, a wide variety of novel neuropeptides were identified. Most of these peptides act directly on muscle cells and their functions include induction of contraction and relaxation. Some peptides are involved in cell differentiation and morphogenesis. Moreover, epitheliopeptides that are produced by epithelial cells were originally identified in Hydra. Some of these epitheliopeptides exhibit morphogen-like activities, whereas others are involved in regulating neuron differentiation, possibly through neuron-epithelial cell interactions. We also describe below our high-throughput reverse-phase nano-flow LCMALDI- TOF-MS/MS approach, which has proved a powerful tool for the discovery of novel peptide signaling molecules in Hydra.

Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness.

PubMed

Li, Shanru; Koziol-White, Cynthia; Jude, Joseph; Jiang, Meiqi; Zhao, Hengjiang; Cao, Gaoyuan; Yoo, Edwin; Jester, William; Morley, Michael P; Zhou, Su; Wang, Yi; Lu, Min Min; Panettieri, Reynold A; Morrisey, Edward E

2016-05-02

Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma.

The Response to High CO2 Levels Requires the Neuropeptide Secretion Component HID-1 to Promote Pumping Inhibition

PubMed Central

Sharabi, Kfir; Charar, Chayki; Friedman, Nurit; Mizrahi, Inbar; Zaslaver, Alon; Sznajder, Jacob I.; Gruenbaum, Yosef

2014-01-01

Carbon dioxide (CO2) is a key molecule in many biological processes; however, mechanisms by which organisms sense and respond to high CO2 levels remain largely unknown. Here we report that acute CO2 exposure leads to a rapid cessation in the contraction of the pharynx muscles in Caenorhabditis elegans. To uncover the molecular mechanisms underlying this response, we performed a forward genetic screen and found that hid-1, a key component in neuropeptide signaling, regulates this inhibition in muscle contraction. Surprisingly, we found that this hid-1-mediated pathway is independent of any previously known pathways controlling CO2 avoidance and oxygen sensing. In addition, animals with mutations in unc-31 and egl-21 (neuropeptide secretion and maturation components) show impaired inhibition of muscle contraction following acute exposure to high CO2 levels, in further support of our findings. Interestingly, the observed response in the pharynx muscle requires the BAG neurons, which also mediate CO2 avoidance. This novel hid-1-mediated pathway sheds new light on the physiological effects of high CO2 levels on animals at the organism-wide level. PMID:25101962

Nerve growth factor regulates galanin and neuropeptide Y expression in primary cultured superior cervical ganglion neurons.

PubMed

Liu, Huaxiang; Liu, Zhen; Xu, Xiaobo; Yang, Xiangdong; Wang, Huaijing; Li, Zhengzhong

2010-03-01

Both galanin and neuropeptide Y (NPY) are expressed in superior cervical ganglion (SCG) neurons. Following nerve transection or axotomy galanin is strongly upregulated and NPY is downregulated in SCG neurons because target-derived nerve growth factor (NGF) content decreased. It is not known whether or to what extent NGF affects both galanin and NPY expression in primary cultured SCG neurons. In the present study we examine whether exogenous NGF affects expression of neuropeptides for galanin and NPY in primary cultured SCG neurons. In addition, we explore whether mRNAs for galanin and NPY are affected by administration of exogenous NGF in SCG cultures. The significance of expression of galanin and NPY and their mRNAs was revealed by performing experiments without and with administration of exogenous NGF. Galanin and its mRNA expression was attenuated by administration of exogenous NGF in SCG cultures. The enhancement of NPY and its mRNA expression by administration of exogenous NGF in SCG cultures was dose-dependent. The physiological or pathophysiological mechanisms of the alterations of galanin and NPY expression affected by NGF in primary cultured SCG neurons are still unknown. The present data provide basic knowledge about the expression of galanin and NPY in primary cultured SCG neurons of rats, which may further improve our understanding of the functional significance of galanin and NPY expression affected by NGF.

Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome.

PubMed

Kuo, Lydia E; Kitlinska, Joanna B; Tilan, Jason U; Li, Lijun; Baker, Stephen B; Johnson, Michael D; Lee, Edward W; Burnett, Mary Susan; Fricke, Stanley T; Kvetnansky, Richard; Herzog, Herbert; Zukowska, Zofia

2007-07-01

The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.

Neuropeptide modulation of pattern-generating systems in crustaceans: comparative studies and approaches.

PubMed

Dickinson, Patsy S; Qu, Xuan; Stanhope, Meredith E

2016-12-01

Central pattern generators are subject to modulation by peptides, allowing for flexibility in patterned output. Current techniques used to characterize peptides include mass spectrometry and transcriptomics. In recent years, hundreds of neuropeptides have been sequenced from crustaceans; mass spectrometry has been used to identify peptides and to determine their levels and locations, setting the stage for comparative studies investigating the physiological roles of peptides. Such studies suggest that there is some evolutionary conservation of function, but also divergence of function even within a species. With current baseline data, it should be possible to begin using comparative approaches to ask fundamental questions about why peptides are encoded the way that they are and how this affects nervous system function. Copyright © 2016 Elsevier Ltd. All rights reserved.

Local neuropeptide signaling modulates serotonergic transmission to shape the temporal organization of C. elegans egg-laying behavior

PubMed Central

Banerjee, Navonil; Bhattacharya, Raja; Francis, Michael M.

2017-01-01

Animal behaviors are often composed of distinct alternating behavioral states. Neuromodulatory signals are thought to be critical for establishing stable behavioral states and for orchestrating transitions between them. However, we have only a limited understanding of how neuromodulatory systems act in vivo to alter circuit performance and shape behavior. To address these questions, we have investigated neuromodulatory signaling in the context of Caenorhabditis elegans egg-laying. Egg-laying activity cycles between discrete states–short bursts of egg deposition (active phases) that alternate with prolonged quiescent periods (inactive phases). Here using genetic, pharmacological and optogenetic approaches for cell-specific activation and inhibition, we show that a group of neurosecretory cells (uv1) located in close spatial proximity to the egg-laying neuromusculature direct the temporal organization of egg-laying by prolonging the duration of inactive phases. We demonstrate that the modulatory effects of the uv1 cells are mediated by peptides encoded by the nlp-7 and flp-11 genes that act locally to inhibit circuit activity, primarily by inhibiting vesicular release of serotonin from HSN motor neurons. This peptidergic inhibition is achieved, at least in part, by reducing synaptic vesicle abundance in the HSN motor neurons. By linking the in vivo actions of specific neuropeptide signaling systems with the generation of stable behavioral outcomes, our study reveals how cycles of neuromodulation emanating from non-neuronal cells can fundamentally shape the organization of a behavioral program. PMID:28384151

RNA-seq analysis of Drosophila clock and non-clock neurons reveals neuron-specific cycling and novel candidate neuropeptides.

PubMed

Abruzzi, Katharine C; Zadina, Abigail; Luo, Weifei; Wiyanto, Evelyn; Rahman, Reazur; Guo, Fang; Shafer, Orie; Rosbash, Michael

2017-02-01

Locomotor activity rhythms are controlled by a network of ~150 circadian neurons within the adult Drosophila brain. They are subdivided based on their anatomical locations and properties. We profiled transcripts "around the clock" from three key groups of circadian neurons with different functions. We also profiled a non-circadian outgroup, dopaminergic (TH) neurons. They have cycling transcripts but fewer than clock neurons as well as low expression and poor cycling of clock gene transcripts. This suggests that TH neurons do not have a canonical circadian clock and that their gene expression cycling is driven by brain systemic cues. The three circadian groups are surprisingly diverse in their cycling transcripts and overall gene expression patterns, which include known and putative novel neuropeptides. Even the overall phase distributions of cycling transcripts are distinct, indicating that different regulatory principles govern transcript oscillations. This surprising cell-type diversity parallels the functional heterogeneity of the different neurons.

Peptidase inhibitors reduce opiate narcotic withdrawal signs, including seizure activity, in the rat.

PubMed

Pinsky, C; Dua, A K; LaBella, F S

1982-07-15

Narcotic withdrawal was precipitated by administration of naloxone in a low dose at 2 h after the final dose of morphine in a 9-day dependency-inducing schedule. Withdrawal was characterized by leaps, increased nocifensor activity and by cerebral cortical epileptiform activity, the latter not generally reported to be prominent in narcotic withdrawal. Single large doses of morphine did not provoke epileptiform activity at 2 h postinjection but did induce an acute opioid dependency wherein a moderately high dose of naloxone, ineffective in non-dependent rats, provoked upward leaping and electrocortical epileptiform activity. Pretreatment of the 9-day dependent rats with peptidase inhibitors, administered intracerebroventricularly, significantly reduced withdrawal severity including the epileptiform activity. We propose that peptidase inhibitors protect certain species of endogenous opioids and/or other neuropeptides that tend to suppress expression of the narcotic withdrawal syndrome. Furthermore, our findings suggest that epileptiform activity is a nascent form of cerebral activity hitherto largely unnoticed in narcotic withdrawal and that neuropeptides may be involved in certain epileptic states.

Angiotensin II Reduces Food Intake by Altering Orexigenic Neuropeptide Expression in the Mouse Hypothalamus

PubMed Central

Yoshida, Tadashi; Semprun-Prieto, Laura; Wainford, Richard D.; Sukhanov, Sergiy; Kapusta, Daniel R.

2012-01-01

Angiotensin II (Ang II), which is elevated in many chronic disease states such as end-stage renal disease and congestive heart failure, induces cachexia and skeletal muscle wasting by increasing muscle protein breakdown and reducing food intake. Neurohormonal mechanisms that mediate Ang II-induced appetite suppression are unknown. Consequently, we examined the effect of Ang II on expression of genes regulating appetite. Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Ang II markedly reduced phosphorylation of AMP-activated protein kinase (AMPK), an enzyme that is known to regulate Npy expression. Intracerebroventricular Ang II infusion (50 ng/kg · min) caused a reduction of food intake, and Ang II dose dependently reduced Npy and orexin expression in the hypothalamus cultured ex vivo. The reduction of Npy and orexin in hypothalamic cultures was completely prevented by candesartan or the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated. PMID:22234465

Cell-specific expression of neuropeptide Y Y1 receptor immunoreactivity in the rat basolateral amygdala.

PubMed

Rostkowski, Amanda B; Teppen, Tara L; Peterson, Daniel A; Urban, Janice H

2009-11-10

Activation of neuropeptide Y (NPY) Y1 receptors (Y1r) in the rat basolateral nuclear complex of the amygdala (BLA) produces anxiolysis and interferes with the generation of conditioned fear. NPY is important in regulating the output of the BLA, yet the cell types involved in mediating this response are currently unknown. The current studies employed multiple label immunocytochemistry to determine the distribution of Y1r-immunoreactivity (-ir) in glutamatergic pyramidal and GABAergic cell populations in the BLA using scanning laser confocal stereology. Pyramidal neurons were identified by expression of calcium-calmodulin dependent kinase II (CaMKII-ir) and functionally distinct interneuron subpopulations were distinguished by peptide (cholecystokinin, somatostatin) or calcium-binding protein (parvalbumin, calretinin) content. Throughout the BLA, Y1r-ir was predominately on soma with negligible fiber staining. The high degree of coexpression of Y1r-ir (99.9%) in CaMKII-ir cells suggests that these receptors colocalize on pyramidal cells and that NPY could influence BLA output by directly regulating the activity of these projection neurons. Additionally, Y1r-ir was also colocalized with the interneuronal markers studied. Parvalbumin-ir interneurons, which participate in feedforward inhibition of BLA pyramidal cells, represented the largest number of Y1r expressing interneurons in the BLA ( approximately 4% of the total neuronal population). The anatomical localization of NPY receptors on different cell populations within the BLA provides a testable circuit whereby NPY could modulate the activity of the BLA via actions on both projection cells and interneuronal cell populations.

Terminal-Nerve-Derived Neuropeptide Y Modulates Physiological Responses in the Olfactory Epithelium of Hungry Axolotls (Ambystoma mexicanum)

PubMed Central

Mousley, Angela; Polese, Gianluca; Marks, Nikki J.; Eisthen, Heather L.

2007-01-01

The vertebrate brain actively regulates incoming sensory information, effectively filtering input and focusing attention toward environmental stimuli that are most relevant to the animal's behavioral context or physiological state. Such centrifugal modulation has been shown to play an important role in processing in the retina and cochlea, but has received relatively little attention in olfaction. The terminal nerve, a cranial nerve that extends underneath the lamina propria surrounding the olfactory epithelium, displays anatomical and neurochemical characteristics that suggest that it modulates activity in the olfactory epithelium. Using immunocytochemical techniques, we demonstrate that neuropeptide Y (NPY) is abundantly present in the terminal nerve in the axolotl (Ambystoma mexicanum), an aquatic salamander. Because NPY plays an important role in regulating appetite and hunger in many vertebrates, we investigated the possibility that NPY modulates activity in the olfactory epithelium in relation to the animal's hunger level. We therefore characterized the full length NPY gene from axolotls to enable synthesis of authentic axolotl NPY for use in electrophysiological experiments. We find that axolotl NPY modulates olfactory epithelial responses evoked by L-glutamic acid, a food-related odorant, but only in hungry animals. Similarly, whole-cell patch-clamp recordings demonstrate that bath application of axolotl NPY enhances the magnitude of a tetrodotoxin-sensitive inward current, but only in hungry animals. These results suggest that expression or activity of NPY receptors in the olfactory epithelium may change with hunger level, and that terminal nerve-derived peptides modulate activity in the olfactory epithelium in response to an animal's changing behavioral and physiological circumstances. PMID:16855098

Terminal nerve-derived neuropeptide y modulates physiological responses in the olfactory epithelium of hungry axolotls (Ambystoma mexicanum).

PubMed

Mousley, Angela; Polese, Gianluca; Marks, Nikki J; Eisthen, Heather L

2006-07-19

The vertebrate brain actively regulates incoming sensory information, effectively filtering input and focusing attention toward environmental stimuli that are most relevant to the animal's behavioral context or physiological state. Such centrifugal modulation has been shown to play an important role in processing in the retina and cochlea, but has received relatively little attention in olfaction. The terminal nerve, a cranial nerve that extends underneath the lamina propria surrounding the olfactory epithelium, displays anatomical and neurochemical characteristics that suggest that it modulates activity in the olfactory epithelium. Using immunocytochemical techniques, we demonstrate that neuropeptide Y (NPY) is abundantly present in the terminal nerve in the axolotl (Ambystoma mexicanum), an aquatic salamander. Because NPY plays an important role in regulating appetite and hunger in many vertebrates, we investigated the possibility that NPY modulates activity in the olfactory epithelium in relation to the animal's hunger level. We therefore characterized the full-length NPY gene from axolotls to enable synthesis of authentic axolotl NPY for use in electrophysiological experiments. We find that axolotl NPY modulates olfactory epithelial responses evoked by l-glutamic acid, a food-related odorant, but only in hungry animals. Similarly, whole-cell patch-clamp recordings demonstrate that bath application of axolotl NPY enhances the magnitude of a tetrodotoxin-sensitive inward current, but only in hungry animals. These results suggest that expression or activity of NPY receptors in the olfactory epithelium may change with hunger level, and that terminal nerve-derived peptides modulate activity in the olfactory epithelium in response to an animal's changing behavioral and physiological circumstances.

Neuropeptide AF Induces Piecemeal Degranulation in Murine Mucosal Mast Cells: A New Mediator in Neuro-Immune Communication in the Intestinal Lamina Propria?

PubMed

Abdellah, Nada; van Remoortel, Samuel; Mohey-Elsaeed, Omnia; Mustafa, Mohamed-Nabil; Ahmed, Yasser A; Timmermans, Jean-Pierre; Buckinx, Roeland

2018-06-01

Neuropeptides AF (NPAF), FF (NPFF) and SF (NPSF) are RFamide neuropeptides known to be widely expressed in the mammalian central nervous system, where they fulfill a wide range of functions with pain modulation being the most prominent one. Recent evidence indicates that RFamides act as mediators in mast cell-sensory nerve communications related to allergic disease. Previous work by our group has shown that the expression levels of some members of the Mas-related gene receptor (Mrgpr) family in both enteric neurons and mucosal mast cells change during intestinal inflammation. The Mrgpr subtypes C11 and A4 can be activated by NPAF, while A1 and C11 are triggered by NPFF. The aim of the present study was to investigate whether RFamides of the NPFF group are expressed in the gastrointestinal tract and to identify possible targets and receptors that might be involved in RFamide-associated mast cell modulation. To this end, the expression and distribution patterns of NPFF/AF receptors and the NPFF precursor protein were determined in bone marrow-derived mucosal mast cells (BMMCs) by immunocytochemistry and (RT-) PCR. BMMCs were found to express MrgprA4 and A1, and functional analysis of the effects of NPAF by means of a β-hexosaminidase assay, mMCP-1 ELISA, electron microscopy and live cell calcium imaging revealed a piecemeal degranulation induced by NPAF. However, knock-out of MrgprA4 and A1 did not reduce the effect of NPAF, indicating that the BMMC response to NPAF was receptor independent. ProNPFF was expressed in neurons and BMMCs, suggesting that both cell types are potential sources of NPAF in situ. Our results show that the RFamide NPAF can be considered as a novel modulator of BMMC activity in the neuro-immune communication in the gastrointestinal tract, although the exact signaling pathway remains to be elucidated. Anat Rec, 00:000-000, 2018. © 2018 Wiley Periodicals, Inc. Anat Rec, 301:1103-1114, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley

Estrogen receptors in neuropeptide Y neurons: at the crossroads of feeding and reproduction.

PubMed

Acosta-Martinez, Maricedes; Horton, Teresa; Levine, Jon E

2007-03-01

Hypothalamic neuropeptide Y (NPY) neurons function as physiological integrators in at least two different neuroendocrine systems - one governing feeding and the other controlling reproduction. Estrogen might modulate both systems by regulating NPY gene expression; it might reduce food intake by suppressing NPY expression, and evoke reproductive hormone surges by stimulating it. How can estrogen exert opposing effects in an ostensibly homogeneous NPY neuronal population? Recent work with immortalized NPY-producing cells suggests that the ratio of estrogen receptor alpha:estrogen receptor beta can determine the direction and temporal pattern of transcriptional responses to estrogen. Because this ratio might itself be physiologically regulated, these findings provide one explanation for multiple neuropeptidergic responses to a single steroid hormone.

Activation of p300 histone acetyltransferase activity and acetylation of the androgen receptor by bombesin in prostate cancer cells.

PubMed

Gong, J; Zhu, J; Goodman, O B; Pestell, R G; Schlegel, P N; Nanus, D M; Shen, R

2006-03-30

Androgen receptor signaling in prostate cancer cells is augmented by the androgen receptor (AR) coactivator p300, which transactivates and acetylates the AR in the presence of dihydrotestosterone (DHT). As prostate cancer (PC) cells progress to androgen independence, AR signaling remains intact, indicating that other factors stimulate AR activities in the absence of androgen. We previously reported that neuropeptide growth factors could transactivate the AR in the presence of very low concentrations of DHT. Here, we examine the involvement of p300 in neuropeptide activation of AR signaling. Transfection of increasing concentrations of p300 in the presence of bombesin into PC-3 cells resulted in a linear increase in AR transactivation, suggesting that p300 acts as a coactivator in neuropeptide-mediated AR transactivation. P300 is endowed with histone acetyltransferase (HAT) activity. Therefore, we examine the effect of bombesin on p300 HAT activity. At 4 h after the addition of bombesin, p300 HAT activity increased 2.0-fold (P<0.01). Incubation with neutral endopeptidase, which degrades bombesin, or bombesin receptor antagonists blocked bombesin-induced p300 HAT activity. To explore the potential signaling pathways involved in bombesin-induced p300 HAT activity, we examined Src and PKCdelta pathways that mediate bombesin signaling. Inhibitors of Src kinase activity or Src kinase siRNA blocked bombesin-induced p300 HAT activity, whereas PKCdelta inhibitors or PKCdelta siRNA significantly increased bombesin-induced p300 HAT activity suggesting that Src kinase and PKCdelta kinase are involved in the regulation of p300 HAT activity. As AR is acetylated in the presence of 100 nM DHT, we next examined whether bombesin-induced p300 HAT activity would result in enhanced AR acetylation. Bombesin-induced AR acetylation at the same motif KLKK observed in DHT-induced acetylation. Elimination of p300 using p300 siRNA reduced AR acetylation, demonstrating that AR acetylation was

Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia.

PubMed

Loktev, Alexander V; Jackson, Peter K

2013-12-12

Human monogenic obesity syndromes, including Bardet-Biedl syndrome (BBS), implicate neuronal primary cilia in regulation of energy homeostasis. Cilia in hypothalamic neurons have been hypothesized to sense and regulate systemic energy status, but the molecular mechanism of this signaling remains unknown. Here, we report a comprehensive localization screen of 42 G-protein-coupled receptors (GPCR) revealing seven ciliary GPCRs, including the neuropeptide Y (NPY) receptors NPY2R and NPY5R. We show that mice modeling BBS disease or obese tubby mice fail to localize NPY2R to cilia in the hypothalamus and that BBS mutant mice fail to activate c-fos or decrease food intake in response to the NPY2R ligand PYY3-36. We find that cells with ciliary NPY2R show augmented PYY3-36-dependent cAMP signaling. Our data demonstrate that ciliary targeting of NPY receptors is important for controlling energy balance in mammals, revealing a physiologically defined ligand-receptor pathway signaling within neuronal cilia. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

The neuropeptide PDF acts directly on evening pacemaker neurons to regulate multiple features of circadian behavior.

PubMed

Lear, Bridget C; Zhang, Luoying; Allada, Ravi

2009-07-01

Discrete clusters of circadian clock neurons temporally organize daily behaviors such as sleep and wake. In Drosophila, a network of just 150 neurons drives two peaks of timed activity in the morning and evening. A subset of these neurons expresses the neuropeptide pigment dispersing factor (PDF), which is important for promoting morning behavior as well as maintaining robust free-running rhythmicity in constant conditions. Yet, how PDF acts on downstream circuits to mediate rhythmic behavior is unknown. Using circuit-directed rescue of PDF receptor mutants, we show that PDF targeting of just approximately 30 non-PDF evening circadian neurons is sufficient to drive morning behavior. This function is not accompanied by large changes in core molecular oscillators in light-dark, indicating that PDF RECEPTOR likely regulates the output of these cells under these conditions. We find that PDF also acts on this focused set of non-PDF neurons to regulate both evening activity phase and period length, consistent with modest resetting effects on core oscillators. PDF likely acts on more distributed pacemaker neuron targets, including the PDF neurons themselves, to regulate rhythmic strength. Here we reveal defining features of the circuit-diagram for PDF peptide function in circadian behavior, revealing the direct neuronal targets of PDF as well as its behavioral functions at those sites. These studies define a key direct output circuit sufficient for multiple PDF dependent behaviors.

Neurotrophic and Neurotoxic Effects of Amyloid |beta Protein: Reversal by Tachykinin Neuropeptides

NASA Astrophysics Data System (ADS)

Yankner, Bruce A.; Duffy, Lawrence K.; Kirschner, Daniel A.

1990-10-01

The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.

Neuropeptides degranulate serous cells of ferret tracheal glands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gashi, A.A.; Borson, D.B.; Finkbeiner, W.E.

1986-08-01

To determine whether serous or mucous cells in tracheal submucosal glands respond to the neuropeptides substance P (SP) and vasoactive intestinal peptide (VIP). The authors studied the peptide-induced changes in gland cell morphology accompanying release of TVSO4-labeled macromolecules from tracheal explants of ferrets. Explants were labeled for 1 h in medium containing TVSO4 and washed for 3.5 additional hours. Base-line secretion in the absence of drugs declined between 1.5 and 3.5 h after the pulse. Between 2.5 and 3.5 h, the average percent change in counts per minute recovered per sample period was not significantly different from zero. Substance Pmore » and VIP added 4 h after labeling each increased greatly the release of TVSO4-labeled macromolecules above base line. Bethanechol, a muscarinic-cholinergic agonist, increased secretion by an average of 142% above base line. Light and electron microscopy of the control tissues showed glands with narrow lumens and numerous secretory granules. Glands treated with SP or VIP had enlarged lumens and the serous cells were markedly degranulated. These phenomena were documented by morphometry and suggest that SP and VIP cause secretion from glands at least partially by stimulating exocytosis from serous cells.« less

The structural characteristics and expression of neuropeptides in the esophagus of patients with congenital esophageal atresia and tracheoesophageal fistula.

PubMed

Li, Kai; Zheng, Shan; Xiao, Xianmin; Wang, Qihong; Zhou, Yiming; Chen, Lian

2007-08-01

The aim of this study was to investigate the structural characteristics and the expression of a group of neuropeptides in the esophagus of patients with congenital esophageal atresia and tracheoesophageal fistula (EA-TEF), as well to elucidate the roles of these neuropeptides in the pathogenesis of postoperative incoordination of esophagus after successful surgical repair of EA-TEF. Twenty-four specimens from distal tracheoesophageal fistulas of patients with EA-TEF (EA-TEF group) and 10 esophageal specimens from neonates who died of nonesophageal diseases (control group) were studied. All of the specimens were subjected to routine pathologic study, ultrastructural observation, and immunohistochemical staining for neuron-specific enolase, substance P, vasoactive intestinal polypeptide, and nitric oxide synthase. In the EA-TEF group, mitochondria were distributed along the membrane of smooth muscle cell, whereas mitochondria in the control group were distributed along the karyotheca of the smooth muscle cells. The ratio of granulated vesicles to clear vesicles in the varicosity of the intramuscular motor nerve ending of the EA-TEF group (0.520 +/- 0.137) was much higher than that in the control group (0.192 +/- 0.020, P < .05). The percentages of specimens shown to have positive expression of neuron-specific enolase and substance P in the EA-TEF group (20.8% and 12.5%, respectively) were significantly lower than those in the control group (90% and 80% respectively, P < .05). The percentages of specimens shown to have positive expression of vasoactive intestinal polypeptide and nitric oxide synthase in the EA-TEF group (83.3% and 75%, respectively) were significantly higher than that in the control group (30% and 10% respectively, P < .05). Imbalance of neurotransmitters excretion in nerve vesicle, abnormal intrinsic dysplasia of nerve plexus and increased expression of certain neuropeptides were the main characteristics of esophagus with abnormal intrinsic

Chronic valproic acid treatment triggers increased neuropeptide y expression and signaling in rat nucleus reticularis thalami.

PubMed

Brill, Julia; Lee, Michelle; Zhao, Sheng; Fernald, Russell D; Huguenard, John R

2006-06-21

Valproate (VPA) can suppress absence and other seizures, but its precise mechanisms of action are not completely understood. We investigated whether VPA influences the expression of neuropeptide Y (NPY), an endogenous anticonvulsant. Chronic VPA administration to young rats (300-600 mg.kg(-1).d(-1) in divided doses over 4 d) resulted in a 30-50% increase in NPY mRNA and protein expression in the nucleus reticularis thalami (nRt) and hippocampus, but not in the neocortex, as shown by real-time PCR, radioimmunoassay, and immunohistochemistry. No increased expression was observed after a single acute dose of VPA. Chronic treatment with the pharmacologically inactive VPA analog octanoic acid did not elicit changes in NPY expression. No significant expression changes could be shown for the mRNAs of the Y1 receptor or of the neuropeptides somatostatin, vasoactive intestinal polypeptide, and choleocystokinin. Fewer synchronous spontaneous epileptiform oscillations were recorded in thalamic slices from VPA-treated animals, and oscillation duration as well as the period of spontaneous and evoked oscillations were decreased. Application of the Y1 receptor inhibitor N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide (BIBP3226) enhanced thalamic oscillations, indicating that NPY is released during those oscillations and acts to downregulate oscillatory strength. Chronic VPA treatment significantly potentiated the effect of BIBP3226 on oscillation duration but not on oscillation period. These results demonstrate a novel mechanism for the antiepileptic actions of chronic VPA therapy.

Autoreceptor Modulation of Peptide/Neurotransmitter Co-release from PDF Neurons Determines Allocation of Circadian Activity in Drosophila

PubMed Central

Choi, Charles; Cao, Guan; Tanenhaus, Anne K.; McCarthy, Ellena v.; Jung, Misun; Schleyer, William; Shang, Yuhua; Rosbash, Michael; Yin, Jerry C.P.; Nitabach, Michael N.

2012-01-01

Drosophila melanogaster flies concentrate behavioral activity around dawn and dusk. This organization of daily activity is controlled by central circadian clock neurons, including the lateral ventral pacemaker neurons (LNvs) that secrete the neuropeptide PDF (Pigment Dispersing Factor). Previous studies have demonstrated the requirement for PDF signaling to PDF receptor (PDFR)-expressing dorsal clock neurons in organizing circadian activity. While LNvs also express functional PDFR, the role of these autoreceptors has remained enigmatic. Here we show that (1) PDFR activation in LNvs shifts the balance of circadian activity from evening to morning, similar to behavioral responses to summer-like environmental conditions and (2) this shift is mediated by stimulation of the Ga,s-cAMP pathway and a consequent change in PDF/neurotransmitter co-release from the LNvs. These results suggest a novel mechanism for environmental control of the allocation of circadian activity and provide new general insight into the role of neuropeptide autoreceptors in behavioral control circuits. PMID:22938867

Neuropeptide Y (NPY) in tumor growth and progression: Lessons learned from pediatric oncology.

PubMed

Tilan, Jason; Kitlinska, Joanna

2016-02-01

Neuropeptide Y (NPY) is a sympathetic neurotransmitter with pleiotropic actions, many of which are highly relevant to tumor biology. Consequently, the peptide has been implicated as a factor regulating the growth of a variety of tumors. Among them, two pediatric malignancies with high endogenous NPY synthesis and release - neuroblastoma and Ewing sarcoma - became excellent models to investigate the role of NPY in tumor growth and progression. The stimulatory effect on tumor cell proliferation, survival, and migration, as well as angiogenesis in these tumors, is mediated by two NPY receptors, Y2R and Y5R, which are expressed in either a constitutive or inducible manner. Of particular importance are interactions of the NPY system with the tumor microenvironment, as hypoxic conditions commonly occurring in solid tumors strongly activate the NPY/Y2R/Y5R axis. This activation is triggered by hypoxia-induced up-regulation of Y2R/Y5R expression and stimulation of dipeptidyl peptidase IV (DPPIV), which converts NPY to a selective Y2R/Y5R agonist, NPY(3-36). While previous studies focused mainly on the effects of NPY on tumor growth and vascularization, they also provided insight into the potential role of the peptide in tumor progression into a metastatic and chemoresistant phenotype. This review summarizes our current knowledge of the role of NPY in neuroblastoma and Ewing sarcoma and its interactions with the tumor microenvironment in the context of findings in other malignancies, as well as discusses future directions and potential clinical implications of these discoveries. Copyright © 2015 Elsevier Ltd. All rights reserved.

Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments.

PubMed

Elhabazi, K; Trigo, J M; Mollereau, C; Moulédous, L; Zajac, J-M; Bihel, F; Schmitt, M; Bourguignon, J J; Meziane, H; Petit-demoulière, B; Bockel, F; Maldonado, R; Simonin, F

2012-01-01

BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments

PubMed Central

Elhabazi, K; Trigo, JM; Mollereau, C; Moulédous, L; Zajac, J-M; Bihel, F; Schmitt, M; Bourguignon, JJ; Meziane, H; Petit-demoulière, B; Bockel, F; Maldonado, R; Simonin, F

2012-01-01

BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence. PMID:21718302

Central proopiomelanocortin but not neuropeptide Y mediates sympathoexcitation and hypertension in fat fed conscious rabbits.

PubMed

Barzel, Benjamin; Lim, Kyungjoon; Davern, Pamela J; Burke, Sandra L; Armitage, James A; Head, Geoffrey A

2016-03-01

High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension. Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter. After 3 weeks HFD (13.5% fat, n = 12) conscious rabbits had higher RSNA (+3.8  nu, P = 0.02), blood pressure (+8.6  mmHg, P < 0.001) and heart rate (+15  b/min, P = 0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n = 11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7  nu) and blood pressure (-8.5  mmHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P < 0.001) in HFD rabbits but had no effect in control rabbits. These findings suggest that obesity-induced hypertension and increased RSNA are dependent on the balance between greater activation of melanocortin signalling through melanocortin receptors and lesser activation of NPY sympathoinhibitory signalling. The amplification of the sympathoexcitatory effects of α-melanocortin stimulating hormone also indicates that the underlying mechanism is related to facilitation of leptin-melanocortin signalling, possibly involving chronic activation of brain-derived neurotrophic factor.

Effect of incubation temperature on neuropeptide Y and neuropeptide Y receptors in turkey and chicken satellite cells.

PubMed

Clark, Daniel L; McCormick, Janet L; Velleman, Sandra G

2018-05-01

Neuropeptide Y (NPY) is an appetite stimulating peptide released from the central nervous system and impacts the function of many different cell types. A recent transcriptome study showed that NPY expression was altered when turkey breast muscle satellite cells were incubated at low or high temperatures, suggesting NPY may mediate temperature effects on satellite cells. However, to date minimal information exists describing the expression and function of NPY in satellite cells. The objective of this study was to determine how temperature impacts NPY and NPY receptor gene expression in satellite cells isolated from turkeys and chickens with differing genetic lineages. Two broiler and two turkey breast muscle satellite cell lines were incubated at 35, 38 or 41 °C during proliferation and differentiation. In both turkey lines, NPY, and receptors NPY2R and NPY5R expression increased at elevated temperatures after 72 h of proliferation. During differentiation NPY and NPY5R expression increased in both turkey lines with higher temperatures, whereas NPY2R was minimally affected by temperature. In contrast, in both chicken cell lines there were few significant differences for NPY and NPY receptor expression across temperature during proliferation. During differentiation, the temperature effect was different in the two chicken cell lines. In the BPM8 chicken line, there were few differences in NPY and NPY receptors across temperature; whereas elevated temperatures increased NPY, NPY2R, and NPY5R expression in the 708 line. The differences between turkey and chicken lines suggest NPY has species specific satellite cell functions in response to heat stress. Copyright © 2018 Elsevier Inc. All rights reserved.

Neuropeptide diversity and the regulation of social behavior in New World primates

PubMed Central

French, Jeffrey A.; Taylor, Jack H.; Mustoe, Aaryn C.; Cavanaugh, Jon

2016-01-01

Oxytocin (OT) and vasopressin (AVP) are important hypothalamic neuropeptides that regulate peripheral physiology, and have emerged as important modulators of brain function, particularly in the social realm. OT structure and the genes that ultimately determine structure are highly conserved among diverse eutherian mammals, but recent discoveries have identified surprising variability in OT and peptide structure in New World monkeys (NWM), with five new OT variants identified to date. This review explores these new findings in light of comparative OT/AVP ligand evolution, documents coevolutionary changes in the oxytocin and vasopressin receptors (OTR and V1aR), and highlights the distribution of neuropeptidergic neurons and receptors in the primate brain. Finally, the behavioral consequences of OT and AVP in regulating NWM sociality are summarized, demonstrating important neuromodulatory effects of these compounds and OT ligand-specific influences in certain social domains. PMID:27020799

Circadian Rhythm Neuropeptides in Drosophila: Signals for Normal Circadian Function and Circadian Neurodegenerative Disease.

PubMed

He, Qiankun; Wu, Binbin; Price, Jeffrey L; Zhao, Zhangwu

2017-04-21

Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on the neuropeptides, neurotransmitters and hormones that mediate its outputs and integration in Drosophila and the links between several of these (pigment dispersing factor (PDF) and insulin-like peptides) and neurodegenerative disease. These signaling molecules convey important network connectivity and signaling information for normal circadian function, but PDF and insulin-like peptides can also convey signals that lead to apoptosis, enhanced neurodegeneration and cognitive decline in flies carrying circadian mutations or in a senescent state.

Circadian Rhythm Neuropeptides in Drosophila: Signals for Normal Circadian Function and Circadian Neurodegenerative Disease

PubMed Central

He, Qiankun; Wu, Binbin; Price, Jeffrey L.; Zhao, Zhangwu

2017-01-01

Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on the neuropeptides, neurotransmitters and hormones that mediate its outputs and integration in Drosophila and the links between several of these (pigment dispersing factor (PDF) and insulin-like peptides) and neurodegenerative disease. These signaling molecules convey important network connectivity and signaling information for normal circadian function, but PDF and insulin-like peptides can also convey signals that lead to apoptosis, enhanced neurodegeneration and cognitive decline in flies carrying circadian mutations or in a senescent state. PMID:28430154

New immunomodulatory role of neuropeptide Y (NPY) in Salmo salar leucocytes.

PubMed

González-Stegmaier, Roxana; Villarroel-Espíndola, Franz; Manríquez, René; López, Mauricio; Monrás, Mónica; Figueroa, Jaime; Enríquez, Ricardo; Romero, Alex

2017-11-01

Neuropeptide Y (NPY) plays different roles in mammals such as: regulate food intake, memory retention, cardiovascular functions, and anxiety. It has also been shown in the modulation of chemotaxis, T lymphocyte differentiation, and leukocyte migration. In fish, NPY expression and functions have been studied but its immunomodulatory role remains undescribed. This study confirmed the expression and synthesis of NPY in S. salar under inflammation, and validated a commercial antibody for NPY detection in teleost. Additionally, immunomodulatory effects of NPY were assayed in vitro and in vivo. Phagocytosis and superoxide anion production in leukocytes and SHK cells were induced under stimulation with a synthetic peptide. IL-8 mRNA was selectively and strongly induced in the spleen, head kidney, and isolated cells, after in vivo challenge with NPY. All together suggest that NPY is expressed in immune tissues and modulates the immune response in teleost fish. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hypothalamic neuropeptides, not leptin sensitivity, contributes to the hyperphagia in lactating Brandt's voles, Lasiopodomys brandtii.

PubMed

Cui, Jian-Guo; Tang, Gang-Bing; Wang, De-Hua

2011-07-01

Both pregnancy and lactation are associated with hyperphagia, and circulating leptin levels are elevated during pregnancy but decreased during lactation in Brandt's voles, Lasiopodomys brandtii. Previous findings suggest that impaired leptin sensitivity contributes to hyperphagia during pregnancy. The present study aimed to examine whether the decreased circulating leptin level and/or hypothalamic leptin sensitivity contributed to the hyperphagia during lactation in Brandt's voles. The serum leptin level and mRNA expression of the long form of the leptin receptor (Ob-Rb), suppressor-of-cytokine-signalling-3 (SOCS-3), neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus were examined on dioestrous, day 5, day 17 of lactation and day 27 (1 week after weaning) in Brandt's voles. Compared with controls, hypothalamic Ob-Rb and SOCS-3 mRNA expression was not significantly changed during lactation. The serum leptin level was significantly lower in lactating females than in the non-reproductive group. Hypothalamic NPY and AgRP mRNA expression significantly increased whereas POMC mRNA expression was significantly decreased during lactation compared with controls. However, there were no significant changes in hypothalamic CART mRNA expression. Food intake was positively correlated with NPY and AgRP mRNA expression but negatively correlated with POMC mRNA expression during lactation. These data suggest that hyperphagia during lactation was associated with low leptin levels, but not impaired leptin sensitivity, and that the hypothalamic neuropeptides NPY, AgRP and POMC are involved in mediating the role of leptin in food intake regulation in lactating Brandt's voles.

Neuropeptide Y rapidly enhances [Ca2+]i transients and Ca2+ sparks in adult rat ventricular myocytes through Y1 receptor and PLC activation.

PubMed

Heredia, María del Puy; Delgado, Carmen; Pereira, Laetitia; Perrier, Romain; Richard, Sylvain; Vassort, Guy; Bénitah, Jean-Pierre; Gómez, Ana María

2005-01-01

Neuropeptide Y (NPY) is the most abundant peptide in the mammalian heart, but its cardiac actions are not fully understood. Here we investigate the effect of NPY in intracellular Ca2+ release, using isolated rat cardiac myocytes and confocal microscopy. Cardiac myocytes were field-stimulated at 1 Hz. The evoked [Ca2+]i transient was of higher amplitude and of faster decay in the presence of 100 nM NPY. Cell contraction was also increased by NPY. We analyzed the occurrence of Ca2+ sparks and their characteristics after NPY application. NPY significantly increased Ca2+ sparks frequency in quiescent cells. The Ca2+ spark amplitude was enhanced by NPY but the other characteristics of Ca2+ sparks were not significantly altered. Because cardiac myocytes express both Y1 and Y2 NPY receptors, we repeated the experiments in the presence of the receptor blockers, BIBP3226 and BIIE0246. We found that Y1 NPY receptor blockade completely inhibited NPY effects on [Ca2+]i transient. PTX-sensitive G-proteins and/or phospholypase C (PLC) have been invoked to mediate NPY effects in other cell types. We tested these two hypotheses. In PTX-treated myocytes NPY was still effective, which suggests that the observed NPY actions are not mediated by PTX-sensitive G-proteins. In contrast, the increase in [Ca2+]i transient by NPY was completely inhibited by the PLC inhibitor U73122. In conclusion, we find that NPY has a positive inotropic effect in isolated rat cardiac myocytes, which involves increase in Ca2+ release after activation of Y1 NPY receptor and subsequent stimulation of PLC.

Prenatal administration of neuropeptide bombesin promotes lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia.

PubMed

Sakai, Kohei; Kimura, Osamu; Furukawa, Taizo; Fumino, Shigehisa; Higuchi, Koji; Wakao, Junko; Kimura, Koseki; Aoi, Shigeyoshi; Masumoto, Kouji; Tajiri, Tatsuro

2014-12-01

Fetal medical treatment to improve lung hypoplasia in congenital diaphragmatic hernia (CDH) has yet to be established. The neuropeptide bombesin (BBS) might play an important role in lung development. The present study aims to determine whether prenatally administered BBS could be useful to promote fetal lung development in a rat model of nitrofen-induced CDH. Pregnant rats were administered with nitrofen (100mg) on gestation day 9.5 (E9.5). BBS (50mg/kg/day) was then daily infused intraperitoneally from E14, and fetal lungs were harvested on E21. The expression of PCNA was assessed by both immunohistochemical staining and RT-PCR to determine the amount of cell proliferation. Lung maturity was assessed as the expression of TTF-1, a marker of alveolar epithelial cell type II. The lung-body-weight ratio was significantly increased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). The number of cells stained positive for PCNA and TTF-1 was significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.01). The TTF-1 mRNA expression levels were significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). Prenatally administered BBS promotes lung development in a rat model of nitrofen-induced CDH. Neuropeptide BBS could help to rescue lung hypoplasia in fetal CDH. Copyright © 2014 Elsevier Inc. All rights reserved.

Autoreceptor control of peptide/neurotransmitter corelease from PDF neurons determines allocation of circadian activity in drosophila.

PubMed

Choi, Charles; Cao, Guan; Tanenhaus, Anne K; McCarthy, Ellena V; Jung, Misun; Schleyer, William; Shang, Yuhua; Rosbash, Michael; Yin, Jerry C P; Nitabach, Michael N

2012-08-30

Drosophila melanogaster flies concentrate behavioral activity around dawn and dusk. This organization of daily activity is controlled by central circadian clock neurons, including the lateral-ventral pacemaker neurons (LN(v)s) that secrete the neuropeptide PDF (pigment dispersing factor). Previous studies have demonstrated the requirement for PDF signaling to PDF receptor (PDFR)-expressing dorsal clock neurons in organizing circadian activity. Although LN(v)s also express functional PDFR, the role of these autoreceptors has remained enigmatic. Here, we show that (1) PDFR activation in LN(v)s shifts the balance of circadian activity from evening to morning, similar to behavioral responses to summer-like environmental conditions, and (2) this shift is mediated by stimulation of the Gα,s-cAMP pathway and a consequent change in PDF/neurotransmitter corelease from the LN(v)s. These results suggest another mechanism for environmental control of the allocation of circadian activity and provide new general insight into the role of neuropeptide autoreceptors in behavioral control circuits. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

[A complex interplay of hormones, neuro-transmitters, neuropeptides and immunity cells is responsible for the control of eating].

PubMed

Rondanelli, M

1997-09-01

Food-seeking behaviour is a complex mechanism which involves an interplay of hormones, neurotransmitters, neuropeptides and immunity cells. In this review the important role of the cooperation between the SNC system, the endocrine system and in particular the immune system in the control of eating is underlined. Like stress and depression, in fact the regulation of eating represents another example of the interplay between these three systems and it is secondary to a bidirectional dialogue between the center and the periphery.

Blockage of neonatal leptin signaling induces changes in the hypothalamus associated with delayed pubertal onset and modifications in neuropeptide expression during adulthood in male rats.

PubMed

Mela, Virginia; Jimenez, Sara; Freire-Regatillo, Alejandra; Barrios, Vicente; Marco, Eva-María; Lopez-Rodriguez, Ana-Belén; Argente, Jesús; Viveros, María-Paz; Chowen, Julie A

2016-12-01

The neonatal leptin surge, occurring from postnatal day (PND) 5 to 13 and peaking at PND9 in rodents, is important for the development of neuroendocrine circuits involved in metabolic control and reproductive function. We previously demonstrated that treatment with a leptin antagonist from PND 5 to 9, coincident with peak leptin levels in the neonatal surge, modified trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus of peri-pubertal rats. The kisspeptin system and metabolic neuropeptide and hormone levels were also modified. Here our aim was to investigate if the timing of pubertal onset is altered by neonatal leptin antagonism and if the previously observed peripubertal modifications in hormones and neuropeptides persist into adulthood and affect male sexual behavior. To this end, male Wistar rats were treated with a pegylated super leptin antagonist (5mg/kg, s.c.) from PND 5 to 9 and killed at PND102-103. The appearance of external signs of pubertal onset was delayed. Hypothalamic kiss1 mRNA levels were decreased in adult animals, but sexual behavior was not significantly modified. Although there was no effect on body weight or food intake, circulating leptin, insulin and triglyceride levels were increased, while hypothalamic leptin receptor, POMC and AgRP mRNA levels were decreased. In conclusion, alteration of the neonatal leptin surge can modify the timing of pubertal onset and have long-term effects on hypothalamic expression of reproductive and metabolic neuropeptides. Copyright © 2016 Elsevier Inc. All rights reserved.

Ejaculation Induced by the Activation of Crz Neurons Is Rewarding to Drosophila Males.

PubMed

Zer-Krispil, Shir; Zak, Hila; Shao, Lisha; Ben-Shaanan, Shir; Tordjman, Lea; Bentzur, Assa; Shmueli, Anat; Shohat-Ophir, Galit

2018-05-07

The reward system is a collection of circuits that reinforce behaviors necessary for survival [1, 2]. Given the importance of reproduction for survival, actions that promote successful mating induce pleasurable feeling and are positively reinforced [3, 4]. This principle is conserved in Drosophila, where successful copulation is naturally rewarding to male flies, induces long-term appetitive memories [5], increases brain levels of neuropeptide F (NPF, the fly homolog of neuropeptide Y), and prevents ethanol, known otherwise as rewarding to flies [6, 7], from being rewarding [5]. It is not clear which of the multiple sensory and motor responses performed during mating induces perception of reward. Sexual interactions with female flies that do not reach copulation are not sufficient to reduce ethanol consumption [5], suggesting that only successful mating encounters are rewarding. Here, we uncoupled the initial steps of mating from its final steps and tested the ability of ejaculation to mimic the rewarding value of full copulation. We induced ejaculation by activating neurons that express the neuropeptide corazonin (CRZ) [8] and subsequently measured different aspects of reward. We show that activating Crz-expressing neurons is rewarding to male flies, as they choose to reside in a zone that triggers optogenetic stimulation of Crz neurons and display conditioned preference for an odor paired with the activation. Reminiscent of successful mating, repeated activation of Crz neurons increases npf levels and reduces ethanol consumption. Our results demonstrate that ejaculation stimulated by Crz/Crz-receptor signaling serves as an essential part of the mating reward mechanism in Drosophila. VIDEO ABSTRACT. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Roles of biologically active peptide in regulation of feeding behavior and energy homeostasis].

PubMed

Sakurai, Takeshi

2003-09-01

The mechanisms for regulating food intake involve a complicated interplay between peripheral systems (including gastrointestinal peptide secretion, leptin, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and/or monoamines. Many hypothalamic neuropeptides are involved in the regulation of energy homeostasis and feeding behavior, including melanocortins, Agouti-related peptide, neuropeptide-Y, cocaine, and amphetamine-regulated transcript, orexin, and melanine concentrating hormone (MCH) as well as monamines (serotonin, dopamine, norepinephrine). Many of these systems are regulated by peripheral metabolic cues including plasma leptin levels. This review summarizes roles of neuropeptides in the regulatory mechanism of feeding and energy homeostasis.

Neuropeptide Y receptor-expressing dorsal horn neurons: role in nocifensive reflex and operant responses to aversive cold after CFA inflammation.

PubMed

Lemons, L L; Wiley, R G

2012-08-02

The spinal Neuropeptide Y (NPY) system is a potential target for development of new pain therapeutics. NPY and two of its receptors (Y1 and Y2) are found in the superficial dorsal horn of the spinal cord, a key area of nociceptive gating and modulation. Lumbar intrathecal injection of (NPY) is antinociceptive, reducing hyper-reflexia to thermal and mechanical stimulation, particularly after nerve injury and inflammation. We have also shown that intrathecal injection of the targeted cytotoxin, Neuropeptide Y-sap (NPY-sap), is also antinociceptive, reducing nocifensive reflex responses to noxious heat and formalin. In the present study, we sought to determine the role of dorsal horn Y1R-expressing neurons in pain by destroying them with NPY-sap and testing the rats on three operant tasks. Lumbar intrathecal NPY-sap (1) reduced Complete Freund's Adjuvant (CFA)-induced hyper-reflexia on the 10°C cold plate, (2) reduced cold aversion on the thermal preference and escape tasks, (3) was analgesic to noxious heat on the escape task, (4) reduced the CFA-induced allodynia to cold temperatures experienced on the thermal preference, feeding interference, and escape tasks, and (5) did not inhibit or interfere with morphine analgesia. Published by Elsevier Ltd.

No association of the neuropeptide Y (Leu7Pro) and ghrelin gene (Arg51Gln, Leu72Met, Gln90Leu) single nucleotide polymorphisms with eating disorders.

PubMed

Kindler, Jochen; Bailer, Ursula; de Zwaan, Martina; Fuchs, Karoline; Leisch, Friedrich; Grün, Bettina; Strnad, Alexandra; Stojanovic, Mirjana; Windisch, Julia; Lennkh-Wolfsberg, Claudia; El-Giamal, Nadja; Sieghart, Werner; Kasper, Siegfried; Aschauer, Harald

2011-06-01

Genetic factors likely contribute to the biological vulnerability of eating disorders. Case-control association study on one neuropeptide Y gene (Leu7Pro) polymorphism and three ghrelin gene (Arg51Gln, Leu72Met and Gln90Leu) polymorphisms. 114 eating disorder patients (46 with anorexia nervosa, 30 with bulimia nervosa, 38 with binge eating disorder) and 164 healthy controls were genotyped. No differences were detected between patients and controls for any of the four polymorphisms in allele frequency and genotype distribution (P > 0.05). Allele frequencies and genotypes had no significant influence on body mass index (P > 0.05) in eating disorder patients. Positive findings of former case-control studies of associations between ghrelin gene polymorphisms and eating disorders could not be replicated. Neuropeptide Y gene polymorphisms have not been investigated in eating disorders before.

Neuropeptide metabolism on intact, regional brain slices: effect of dopaminergic agents on substance P, cholecystokinin and Met-enkephalin degradation.

PubMed

Waters, S M; Konkoy, C S; Davis, T P

1995-08-01

Neuroleptic drugs have been shown to affect the level and messenger ribonucleic acid of specific neuropeptides. The effect of subchronically administered neuroleptics on neuropeptide metabolism, however, has not been systematically characterized. In the present study, the effect of neuroleptics and other dopaminergic compounds on substance P (SP), cholecystokinin and met-enkephalin degradation was determined on intact, regional, rat brain slices. After 7-day administration of haloperidol (1 mg/kg) or chlorpromazine (20 mg/kg), SP degradation was decreased in caudate-putamen and nucleus accumbens. After administration of the dopaminergic agonist apomorphine (5 mg/kg, b.i.d.), SP degradation was increased in the nucleus accumbens. The dopamine D2-receptor antagonist sulpiride (100 mg/kg, b.i.d.) produced no effect on SP degradation. Met-enkephalin degradation was decreased after haloperidol administration in both frontal cortex and caudate-putamen and unaffected by apomorphine administration. The metabolism of cholecystokinin was not affected by neuroleptic treatment. Studies performed with specific peptidase inhibitors suggested that neutral endopeptidase 24.11, metalloendopeptidase 24.15 and aminopeptidases degrade SP on caudate-putamen and nucleus accumbens slices. Therefore, alterations in these peptidases may be responsible for the change noted in SP degradation after dopaminergic compound administration. These metabolic changes noted after neuroleptic administration may therefore contribute to neuroleptic-induced alterations in regional peptide levels.

Metabolism of Cryptic Peptides Derived from Neuropeptide FF Precursors: The Involvement of Insulin-Degrading Enzyme

PubMed Central

Grasso, Giuseppe; Mielczarek, Przemyslaw; Niedziolka, Magdalena; Silberring, Jerzy

2014-01-01

The term “cryptome” refers to the subset of cryptic peptides with bioactivities that are often unpredictable and very different from the parent protein. These cryptic peptides are generated by proteolytic cleavage of proteases, whose identification in vivo can be very challenging. In this work, we show that insulin-degrading enzyme (IDE) is able to degrade specific amino acid sequences present in the neuropeptide pro-NPFFA (NPFF precursor), generating some cryptic peptides that are also observed after incubation with rat brain cortex homogenate. The reported experimental findings support the increasingly accredited hypothesis, according to which, due to its wide substrate selectivity, IDE is involved in a wide variety of physiopathological processes. PMID:25247577

Endogenous neuropeptide S tone influences sleep-wake rhythm in rats.

PubMed

Oishi, Masafumi; Kushikata, Tetsuya; Niwa, Hidetomo; Yakoshi, Chihiro; Ogasawara, Chihiro; Calo, Girolamo; Guerrini, Remo; Hirota, Kazuyoshi

2014-10-03

Neuropeptide S (NPS) is an endogenous peptide that exerts wakefulness promoting, analgesic, and anxiolytic effects when administered exogenously. However, it remains to be determined if endogenous NPS tone is involved in the control of the diurnal sleep-wake cycle, or spontanous behavior. In this study, we examined the effects of the NPS receptor antagonist [D-Cys((t)Bu)(5)]NPS (2 and 20 nmol, icv) on physiological sleep and spontaneous locomotor behavior. The higher dose of [D-Cys((t)Bu)(5)]NPS decreased the amount of time spent in wakefulness [control 782.5 ± 25.5 min, treatment 751.7 ± 28.1 min; p<0.05] and increased the time spent in NREMS [control 572.6 ± 17.2 min, treatment 600.2 ± 26.1 min; p<0.05]. There was no statistically significant difference in time spent in REMS. There were no behavioral changes including abnormal gross motor behavior in response to [D-Cys((t)Bu)(5)]NPS administration. Collectively these data suggest an involvement of the endogenous NPS/NPS receptor system in physiological sleep architecture. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The role of the neuropeptide somatostatin on methamphetamine and glutamate-induced neurotoxicity in the striatum of mice.

PubMed

Afanador, Lauriaselle; Mexhitaj, Ina; Diaz, Carolyn; Ordonez, Dalila; Baker, Lisa; Angulo, Jesus A

2013-05-13

A large body of evidence shows that methamphetamine (METH) causes sustained damage to the brain in animal models and human METH users. In chronic users there are indications of cognitive and motor deficits. Striatal neuropeptides are in a position to modulate the neurochemical effects of METH and consequently striatal neural damage. Somatostatin (SST) is an intrinsic striatal neuropeptide that has been shown to inhibit glutamate transmission; glutamate is integral to METH toxicity and contributes to nitric oxide (NO) synthesis. We hypothesize that SST will protect from METH by inhibition of NO synthesis and thus reducing oxidative stress. To this end, the SST analogue octreotide (OCT) was microinjected into the striatum prior to a systemic injection of METH (30mg/kg). We then assessed 3-nitrotyrosine (3-NT), an indirect index of NO production, tyrosine hydroxylase (TH) protein levels (dopamine terminal marker) and Fluoro-Jade C positive cells (degenerating cells). The SST agonist OCT dose dependently attenuated the METH-induced accumulation of striatal 3-NT. Moreover, pretreatment with OCT effectively mitigated cell death but failed to protect dopamine terminals. Next we co-infused OCT and NMDA and measured 3-NT and Fluoro-Jade C staining. Treatment with OCT had no effect on these parameters. The data demonstrate that SST attenuates the METH-induced production of NO protecting the striatum from the METH-induced cell loss. However, SST failed to prevent the toxicity of the dopamine terminals suggesting that pre- and post-synaptic striatal damage occur via independent mechanisms. Copyright © 2013 Elsevier B.V. All rights reserved.

The Role of the Neuropeptide Somatostatin on Methamphetamine and Glutamate-Induced Neurotoxicity in the Striatum of Mice

PubMed Central

Afanador, Lauriaselle; Mexhitaj, Ina; Diaz, Carolyn; Ordonez, Dalila; Baker, Lisa; Angulo, Jesus A.

2014-01-01

A large body of evidence shows that methamphetamine (METH) causes sustained damage to the brain in animal models and human METH users. In chronic users there are indications of cognitive and motor deficits. Striatal neuropeptides are in a position to modulate the neurochemical effects of METH and consequently striatal neural damage. Somatostatin (SST) is an intrinsic striatal neuropeptide that has been shown to inhibit glutamate transmission; glutamate is integral to METH toxicity and contributes to nitric oxide (NO) synthesis. We hypothesize that SST will protect from METH by inhibition of NO synthesis and thus reducing oxidative stress. To this end, the SST analogue octreotide (OCT) was microinjected into the striatum prior to a systemic injection of METH (30 mg/kg). We then assessed 3-nitrotyrosine (3-NT), an indirect index of NO production, tyrosine hydroxylase (TH) protein levels (dopamine terminal marker) and Fluoro-Jade C positive cells (degenerating cells). The SST agonist OCT dose dependently attenuated the METH-induced accumulation of striatal 3-NT. Moreover, pretreatment with OCT effectively mitigated cell death but failed to protect dopamine terminals. Next we co-infused OCT and NMDA and measured 3-NT and Fluoro-Jade C staining. Treatment with OCT had no effect on these parameters. The data demonstrate that SST attenuates the METH-induced production of NO protecting the striatum from the METH-induced cell loss. However, SST failed to prevent the toxicity of the dopamine terminals suggesting that pre- and post-synaptic striatal damage occur via independent mechanisms. PMID:23524190

Inhibitors of calling behavior of Plodia interpunctella

PubMed Central

Hirashima, Akinori; Shigeta, Yoko; Eiraku, Tomohiko; Kuwano, Eiichi

2003-01-01

ODO 2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazine-5(6H)-one PBAN pheromone biosynthesis activating neuropeptide PEO 2-(1-phenylethylamino)-2-oxazoline PI positive ionizable PIT 1-(2,6-dimethylphenyl)imidazolidine-2-thione RA ring aromatic SBO 2-(substituted benzylamino)-2-oxazoline SBT 2-(substituted benzylamino)-2-thiazoline STO 2-(substituted benzylthio)-2-oxazoline ZETA (Z,E)-9,12-tetradecadienyl acetate PMID:15841221

Elevation of neuropeptide Y (NPY) in substantia innominata in Alzheimer's type dementia.

PubMed

Allen, J M; Ferrier, I N; Roberts, G W; Cross, A J; Adrian, T E; Crow, T J; Bloom, S R

1984-06-01

Concentrations of neuropeptide Y (NPY) have been determined in 12 areas of control brains and compared to those found in brains from patients with Alzheimer's type dementia (ATD). The distribution of NPY in the control brains was compared with those reported previously. Highest concentrations were identified in the subcortical structures, in particular, nucleus accumbens (203 +/- 21.7 pmol/g), amygdala (136.7 +/- 15.8 pmol/g), and substantia innominata (109.0 +/- 12.6 pmol/g). A significant elevation in NPY concentrations was identified in the region of the substantia innominata of Alzheimer brains (controls: 109.0 +/- 12.6 pmol/g, ATD: 206 +/- 28.2 pmol/g, P less than 0.001). This change in NPY concentration was similar to the increase in somatostatin concentration in this region of ATD brain. In contrast, although cortical concentrations of somatostatin were reduced in ATD, no change was found in the concentrations of NPY in the 4 regions of cerebral cortex and the remaining subcortical areas examined.

Enhanced inhibitory control by neuropeptide Y Y5 receptor blockade in rats.

PubMed

Bari, A; Dec, A; Lee, A W; Lee, J; Song, D; Dale, E; Peterson, J; Zorn, S; Huang, X; Campbell, B; Robbins, T W; West, A R

2015-03-01

The neuropeptide Y (NPY) system acts in synergy with the classic neurotransmitters to regulate a large variety of functions including autonomic, affective, and cognitive processes. Research on the effects of NPY in the central nervous system has focused on food intake control and affective processes, but growing evidence of NPY involvement in attention-deficit/hyperactivity disorder (ADHD) and other psychiatric conditions motivated the present study. We tested the effects of the novel and highly selective NPY Y5 receptor antagonist Lu AE00654 on impulsivity and the underlying cortico-striatal circuitry in rats to further explore the possible involvement of the NPY system in pathologies characterized by inattention and impulsive behavior. A low dose of Lu AE00654 (0.03 mg/kg) selectively facilitated response inhibition as measured by the stop-signal task, whereas no effects were found at higher doses (0.3 and 3 mg/kg). Systemic administration of Lu AE00654 also enhanced the inhibitory influence of the dorsal frontal cortex on neurons in the caudate-putamen, this fronto-striatal circuitry being implicated in the executive control of behavior. Finally, by locally injecting a Y5 agonist, we observed reciprocal activation between dorsal frontal cortex and caudate-putamen neurons. Importantly, the effects of the Y5 agonist were attenuated by pretreatment with Lu AE00654, confirming the presence of Y5 binding sites modulating functional interactions within frontal-subcortical circuits. These results suggest that the NPY system modulates inhibitory neurotransmission in brain areas important for impulse control, and may be relevant for the treatment of pathologies such as ADHD and drug abuse.

Role of neuropeptide Y in renal sympathetic vasoconstriction: studies in normal and congestive heart failure rats.

PubMed

DiBona, G F; Sawin, L L

2001-08-01

Sympathetic nerve activity, including that in the kidney, is increased in heart failure with increased plasma concentrations of norepinephrine and the vasoconstrictor cotransmitter neuropeptide Y (NPY). We examined the contribution of NPY to sympathetically mediated alterations in kidney function in normal and heart failure rats. Heart failure rats were created by left coronary ligation and myocardial infarction. In anesthetized normal rats, the NPY Y(1) receptor antagonist, H 409/22, at two doses, had no effect on heart rate, arterial pressure, or renal hemodynamic and excretory function. In conscious severe heart failure rats, high-dose H 409/22 decreased mean arterial pressure by 8 +/- 2 mm Hg but had no effect in normal and mild heart failure rats. During graded frequency renal sympathetic nerve stimulation (0 to 10 Hz), high-dose H 409/22 attenuated the decreases in renal blood flow only at 10 Hz (-36% +/- 5%, P <.05) in normal rats but did so at both 4 (-29% +/- 4%, P <.05) and 10 Hz (-33% +/- 5%, P <.05) in heart failure rats. The glomerular filtration rate, urinary flow rate, and sodium excretion responses to renal sympathetic nerve stimulation were not affected by high-dose H 409/22 in either normal or heart failure rats. NPY does not participate in the regulation of kidney function and arterial pressure in normal conscious or anesthetized rats. When sympathetic nervous system activity is increased, as in heart failure and intense renal sympathetic nerve stimulation, respectively, a small contribution of NPY to maintenance of arterial pressure and to sympathetic renal vasoconstrictor responses may be identified.

Ghrelin receptors mediate ghrelin-induced excitation of agouti-related protein/neuropeptide Y but not pro-opiomelanocortin neurons.

PubMed

Chen, Shao-Rui; Chen, Hong; Zhou, Jing-Jing; Pradhan, Geetali; Sun, Yuxiang; Pan, Hui-Lin; Li, De-Pei

2017-08-01

Ghrelin increases food intake and body weight by stimulating orexigenic agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons and inhibiting anorexic pro-opiomelanocortin (POMC) neurons in the hypothalamus. Growth hormone secretagogue receptor (Ghsr) mediates the effect of ghrelin on feeding behavior and energy homeostasis. However, the role of Ghsr in the ghrelin effect on these two populations of neurons is unclear. We hypothesized that Ghsr mediates the effect of ghrelin on AgRP and POMC neurons. In this study, we determined whether Ghsr similarly mediates the effects of ghrelin on AgRP/NPY and POMC neurons using cell type-specific Ghsr-knockout mice. Perforated whole-cell recordings were performed on green fluorescent protein-tagged AgRP/NPY and POMC neurons in the arcuate nucleus in hypothalamic slices. In Ghsr +/+ mice, ghrelin (100 nM) significantly increased the firing activity of AgRP/NPY neurons but inhibited the firing activity of POMC neurons. In Ghsr -/- mice, the excitatory effect of ghrelin on AgRP/NPY neurons was abolished. Ablation of Ghsr also eliminated ghrelin-induced increases in the frequency of GABAergic inhibitory postsynaptic currents of POMC neurons. Strikingly, ablation of Ghsr converted the ghrelin effect on POMC neurons from inhibition to excitation. Des-acylated ghrelin had no such effect on POMC neurons in Ghsr -/- mice. In both Ghsr +/+ and Ghsr -/- mice, blocking GABA A receptors with gabazine increased the basal firing activity of POMC neurons, and ghrelin further increased the firing activity of POMC neurons in the presence of gabazine. Our findings provide unequivocal evidence that Ghsr is essential for ghrelin-induced excitation of AgRP/NPY neurons. However, ghrelin excites POMC neurons through an unidentified mechanism that is distinct from conventional Ghsr. © 2017 International Society for Neurochemistry.

The decapod red pigment-concentrating hormone (Panbo-RPCH) is the first identified neuropeptide of the order Plecoptera and is interpreted as homoplastic character state.

PubMed

Gäde, Gerd; Marco, Heather G

2015-09-15

This paper presents the first neuropeptide structure, identified by mass spectrometry, in two species of Plectoptera (stoneflies) and in one species of the coleopteran family Lycidae. In all three species, the octapeptide Panbo-RPCH (first identified in Pandalus borealis as a red pigment-concentrating hormone: pGlu-Leu-Asn-Phe-Ser-Pro-Gly-Trp amide) is present. A review of the literature available on invertebrate neuropeptides that are identified or predicted from expressed sequence tags, transcriptome shotgun assemblies, and from fully sequenced genomes, show that Panbo-RPCH is found in Malacostraca (Crustacea) and certain hemipteran Heteroptera (Insecta). To date, Panbo-RPCH has not been shown present in non-Malacostracan crustaceans, nor in basal taxa of the Insecta (Archaeognatha, Zygentoma, Ephemeroptera, Odonata). The present data adds to knowledge on the distribution of Panbo-RPCH, and when taking into account the most accepted, current phylogenetics of the Crustacea-Hexapoda relationship, this distribution of Panbo-RPCH in Malacostraca, Plecoptera, some hemipteran Heteroptera and in Coleoptera (Lycidae) can best be explained by homoplasy, implying parallel evolution. Copyright © 2015 Elsevier Inc. All rights reserved.

Fasting and 17β-estradiol differentially modulate the M-current in neuropeptide Y neurons.

PubMed

Roepke, Troy A; Qiu, Jian; Smith, Arik W; Rønnekleiv, Oline K; Kelly, Martin J

2011-08-17

Multiple K(+) conductances are targets for many peripheral and central signals involved in the control of energy homeostasis. Potential K(+) channel targets are the KCNQ subunits that form the channels underlying the M-current, a subthreshold, non-inactivating K(+) current that is a common target for G-protein-coupled receptors. Whole-cell recordings were made from GFP (Renilla)-tagged neuropeptide Y (NPY) neurons from the arcuate nucleus of the hypothalamus using protocols to isolate and characterize the M-current in these orexigenic neurons. We recorded robust K(+) currents in the voltage range of the M-current, which were inhibited by the selective KCNQ channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) (40 μm), in both intact males and ovariectomized, 17β-estradiol (E2)-treated females. Since NPY neurons are orexigenic and are active during fasting, the M-current was measured in fed and fasted male mice. Fasting attenuated the XE991-sensitive current by threefold, which correlated with decreased expression of the KCNQ2 and KCNQ3 subunits as measured with quantitative real-time PCR. Furthermore, E2 treatment augmented the XE991-sensitive M-current by threefold in ovariectomized (vs oil-treated) female mice. E2 treatment increased the expression of the KCNQ5 subunit in females but not KCNQ2 or KCNQ3 subunits. Fasting in females abrogated the effects of E2 on M-current activity, at least in part, by decreasing KCNQ2 and KCNQ3 expression. In summary, these data suggest that the M-current plays a pivotal role in the modulation of NPY neuronal excitability and may be an important cellular target for neurotransmitter and hormonal signals in the control of energy homeostasis in both males and females.

Opposite roles for neuropeptide S in the nucleus accumbens and bed nucleus of the stria terminalis in learned helplessness rats.

PubMed

Shirayama, Yukihiko; Ishima, Tamaki; Oda, Yasunori; Okamura, Naoe; Iyo, Masaomi; Hashimoto, Kenji

2015-09-15

The role of neuropeptide S (NPS) in depression remains unclear. We examined the antidepressant-like effects of NPS infusions into the shell or core regions of the nucleus accumbens (NAc) and into the bed nucleus of the stria terminalis (BNST) of learned helplessness (LH) rats (an animal model of depression). Infusions of NPS (10 pmol/side) into the NAc shell, but not the NAc core and BNST, exerted antidepressant-like effects in the LH paradigm. Implying that behavioral deficits could be improved in the conditioned avoidance test. Coinfusion of SHA68 (an NPS receptor antagonist, 100 pmol/side) with NPS into the NAc shell blocked these effects. In contrast, NPS receptor antagonism by SHA68 in the BNST induced antidepressant-like effects. Infusions of NPS into the NAc shell or SHA68 into the BNST did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. These results suggest that excitatory and inhibitory actions by the NPS system are integral to the depression in LH animals. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of neuropeptide-Y on renal function and its interaction with sympathetic stimulation in conscious dogs.

PubMed Central

Persson, P B; Ehmke, H; Nafz, B; Lang, R; Hackenthal, E; Nobiling, R; Dietrich, M S; Kirchheim, H R

1991-01-01

1. The effects of neuropeptide-Y (NPY) on renal function were investigated in conscious foxhounds. 2. Dose-response curves (n = 7) were obtained for NPY by measuring renal blood flow (RBF), glomerular filtration rate (GFR), urine excretion (VU), sodium excretion (VNa), potassium excretion (VK) and plasma renin activity (PRA) at different infusion rates. All variables decreased with increasing infusion rates except for PRA, which surprisingly did not change during the different infusion rates. 3. The influence of the non-constrictor dose of NPY at control pressure, and after servo-controlling renal arterial pressure at 80 mmHg, was determined for these parameters (n = 6). 4. This was repeated during a reflex sympathetic activation via carotid sinus hypotension, in order to quantify a possible interaction between the sympathetic transmitter and co-transmitter (n = 6). 5. The subthreshold NPY dose raised plasma NPY-like immunoreactivity (NPY-LI IR) significantly (renal venous plasma: 54 +/- 13 vs. 405 +/- 117 pg ml-1; P less than 0.05) and enhanced the pressure-dependent (80 mmHg) antidiuresis (0.48 +/- 0.06 vs. 0.24 +/- 0.02 ml min-1; P less than 0.05), antinatriuresis (46 +/- 11 vs. 25 +/- 3 mumol min-1; P less than 0.05), antikaliuresis (19 +/- 4 vs. 9 +/- 0.7 mumol min-1; P less than 0.05) and pressure-dependent renin release (0.95 +/- 0.27 vs. 3.0 +/- 1.1 ng angiotensin I ml-1 h-1; P less than 0.05). These effects are consistent with a non-uniform vasoconstrictor action of NPY in the renal vascular bed (see accompanying papers). 6. The effects of NPY plus sympathetic activation were less than the sum of the two individual effects, which may rely on a presynaptic mechanism. PMID:1688030

Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome

PubMed Central

Gillard, Laura; Billiauws, Lore; Stan-Iuga, Bogdan; Ribeiro-Parenti, Lara; Jarry, Anne-Charlotte; Cavin, Jean-Baptiste; Cluzeaud, Françoise; Mayeur, Camille; Thomas, Muriel; Freund, Jean-Noël; Lacorte, Jean-Marc; Le Gall, Maude; Bado, André; Joly, Francisca; Le Beyec, Johanne

2016-01-01

Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations. PMID:27323884

Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome.

PubMed

Gillard, Laura; Billiauws, Lore; Stan-Iuga, Bogdan; Ribeiro-Parenti, Lara; Jarry, Anne-Charlotte; Cavin, Jean-Baptiste; Cluzeaud, Françoise; Mayeur, Camille; Thomas, Muriel; Freund, Jean-Noël; Lacorte, Jean-Marc; Le Gall, Maude; Bado, André; Joly, Francisca; Le Beyec, Johanne

2016-06-21

Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations.

Functions of peptide CNP4, encoded by the HCS2 gene, in the nervous system of Helix lucorum.

PubMed

Korshunova, T A; Malyshev, A Yu; Zakharov, I S; Ierusalimskii, V N; Balaban, P M

2006-03-01

The aims of the present work were to study the role of neuropeptide CNP4, encoded by the HCS2 gene (which is expressed mainly in parietal command interneurons), in controlling the activity of the respiratory system, and also to study the effects of this neuropeptide on isolated defensive behavior neurons in prolonged culture. The influence of the command interneuron on the pneumostoma included a direct effect consisting of closure and a delayed effect consisting of intensification of respiratory movements. Application of neuropeptide CNP4 produced a pattern similar to the delayed effects seen on stimulation of the command interneuron, i.e., significant increases in the frequency and intensity of pneumostoma movements and strengthening of the rhythmic activity of the pneumostoma motoneuron. Studies of the effects of neuropeptide CNP4 on isolated neurons after prolonged culture showed that neuron process growth correlated with the presence of the neuropeptide in the medium. Identification of the location of the HCS2 precursor protein and neuropeptide CNP4 in isolated command interneurons after prolonged culture showed that that only those parts of the cell showing active process growth were immunopositive. Thus, neuropeptide CNP4 appears to be a secreted neuropeptide controlling respiratory system activity, which may also be involved in rearrangements of the network controlling defensive behavior in Helix snails.

Influence of Rotary Instrumentation with Continuous Irrigation on Pain and Neuropeptide Release Levels: A Randomized Clinical Trial.

PubMed

Bıçakcı, Hazal; Çapar, İsmail Davut; Genç, Selin; İhtiyar, Alperen; Sütçü, Recep

2016-11-01

The first objective was to determine correlation among various experimental and clinical pain measurement procedures. The second objective was to evaluate the influence of rotary instrumentation with continuous irrigation on pain and neuropeptide release levels. Forty patients who had preoperative pain at the levels of 3-8 on the visual analogue scale were included. Gingival crevicular fluid (GCF) samples were collected. Patients were randomly assigned to 2 treatment groups, the standard preparation group and the preparation with continuous irrigation group. Apical fluid samples (AFS) were collected after instrumentation. In the second visit, the patients' pain levels were recorded, and GCF and AFS were obtained. Substance P, calcitonin-gene related peptide (CGRP), interleukin (IL)-1β, and IL-10 levels were analyzed from the GCF and AFS samples. For comparison between groups, the Mann-Whitney test was used (P < .05). In terms of clinical data, no significant difference was detected in the first and second sessions between groups. The IL-10 level obtained from AFS significantly decreased in the second session in both groups (P < .001). Visual analogue scale scores of spontaneous pain correlated with percussion pain positively (r = 0.718, P < .001). CGRP (GCF) (second session) and IL-10 (GCF) (second session) positively correlated with percussion pain (r = 0.425, P < .01) (r = 0.379, P < .05). Rotary preparation with continuous irrigation has not been more effective than the standard preparation method for reducing pain. Because of determination of the correlation between CGRP and IL-10 with percussion pain, these neuropeptides can be used in further studies. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Evolution of pigment-dispersing factor neuropeptides in Panarthropoda: Insights from Onychophora (velvet worms) and Tardigrada (water bears).

PubMed

Mayer, Georg; Hering, Lars; Stosch, Juliane M; Stevenson, Paul A; Dircksen, Heinrich

2015-09-01

Pigment-dispersing factor (PDF) denotes a conserved family of homologous neuropeptides present in several invertebrate groups, including mollusks, nematodes, insects, and crustaceans (referred to here as pigment-dispersing hormone [PDH]). With regard to their encoding genes (pdf, pdh), insects possess only one, nematodes two, and decapod crustaceans up to three, but their phylogenetic relationship is unknown. To shed light on the origin and diversification of pdf/pdh homologs in Panarthropoda (Onychophora + Tardigrada + Arthropoda) and other molting animals (Ecdysozoa), we analyzed the transcriptomes of five distantly related onychophorans and a representative tardigrade and searched for putative pdf homologs in publically available genomes of other protostomes. This revealed only one pdf homolog in several mollusk and annelid species; two in Onychophora, Priapulida, and Nematoda; and three in Tardigrada. Phylogenetic analyses suggest that the last common ancestor of Panarthropoda possessed two pdf homologs, one of which was lost in the arthropod or arthropod/tardigrade lineage, followed by subsequent duplications of the remaining homolog in some taxa. Immunolocalization of PDF-like peptides in six onychophoran species, by using a broadly reactive antibody that recognizes PDF/PDH peptides in numerous species, revealed an elaborate system of neurons and fibers in their central and peripheral nervous systems. Large varicose projections in the heart suggest that the PDF neuropeptides functioned as both circulating hormones and locally released transmitters in the last common ancestor of Onychophora and Arthropoda. The lack of PDF-like-immunoreactive somata associated with the onychophoran optic ganglion conforms to the hypothesis that onychophoran eyes are homologous to the arthropod median ocelli. © 2015 Wiley Periodicals, Inc.

Increased in vivo release of neuropeptide S in the amygdala of freely moving rats after local depolarisation and emotional stress.

PubMed

Ebner, Karl; Rjabokon, Alesja; Pape, Hans-Christian; Singewald, Nicolas

2011-10-01

Intracerebral microdialysis in conjunction with a highly sensitive radioimmunoassay was used to study the in vivo release of neuropeptide S (NPS) within the amygdala of freely moving rats. NPS was consistently detected in basolateral amygdala dialysates and the release considerably enhanced in response to local depolarisation as well as exposure to forced swim stress. Thus, our data demonstrate for the first time emotional stress-induced release of NPS in the amygdala supporting a functional role of endogenous NPS in stress/anxiety-related phenomena.

RNAi-mediated disruption of neuropeptide genes, nlp-3 and nlp-12, cause multiple behavioral defects in Meloidogyne incognita.

PubMed

Dash, Manoranjan; Dutta, Tushar K; Phani, Victor; Papolu, Pradeep K; Shivakumara, Tagginahalli N; Rao, Uma

2017-08-26

Owing to the current deficiencies in chemical control options and unavailability of novel management strategies, root-knot nematode (M. incognita) infections remain widespread with significant socio-economic impacts. Helminth nervous systems are peptide-rich and appear to be putative drug targets that could be exploited by antihelmintic chemotherapy. Herein, to characterize the novel peptidergic neurotransmitters, in silico mining of M. incognita genomic and transciptomic datasets revealed the presence of 16 neuropeptide-like protein (nlp) genes with structural hallmarks of neuropeptide preproproteins; among which 13 nlps were PCR-amplified and sequenced. Two key nlp genes (Mi-nlp-3 and Mi-nlp-12) were localized to the basal bulb and tail region of nematode body via in situ hybridization assay. Mi-nlp-3 and Mi-nlp-12 were greatly expressed (in qRT-PCR assay) in the pre-parasitic juveniles and adult females, suggesting the association of these genes in host recognition, development and reproduction of M. incognita. In vitro knockdown of Mi-nlp-3 and Mi-nlp-12 via RNAi demonstrated the significant reduction in attraction and penetration of M. incognita in tomato root in Pluronic gel medium. A pronounced perturbation in development and reproduction of NLP-silenced worms was also documented in adzuki beans in CYG growth pouches. The deleterious phenotypes obtained due to NLP knockdown suggests that transgenic plants engineered to express RNA constructs targeting nlp genes may emerge as an environmentally viable option to manage nematode problems in crop plants. Copyright © 2017 Elsevier Inc. All rights reserved.

Expression of regulatory neuropeptides in the hypothalamus of red deer (Cervus elaphus) reveals anomalous relationships in the seasonal control of appetite and reproduction.

PubMed

Barrell, G K; Ridgway, M J; Wellby, M; Pereira, A; Henry, B A; Clarke, I J

2016-04-01

Red deer are seasonal with respect to reproduction and food intake, so we tested the hypothesis that their brains would show seasonal changes in numbers of cells containing hypothalamic neuropeptides that regulate these functions. We examined the brains of male and female deer in non-breeding and breeding seasons to quantify the production of kisspeptin, gonadotropin inhibitory hormone (GnIH), neuropeptide Y (NPY) and γ-melanocyte stimulating hormone (γ-MSH - an index of pro-opiomelanocortin production), using immunohistochemistry. These neuropeptides are likely to be involved in the regulation of reproductive function and appetite. During the annual breeding season there were more cells producing kisspeptin in the arcuate nucleus of the hypothalamus than during the non-breeding season in males and females whereas there was no seasonal difference in the expression of GnIH. There were more cells producing the appetite stimulating peptide, NPY, in the arcuate/median eminence regions of the hypothalamus of females during the non-breeding season whereas the levels of an appetite suppressing peptide, γ-MSH, were highest in the breeding season. Male deer brains exhibited the converse, with NPY cell numbers highest in the breeding season and γ-MSH levels highest in the non-breeding season. These results support a role for kisspeptin as an important stimulatory regulator of seasonal breeding in deer, as in other species, but suggest a lack of involvement of GnIH in the seasonality of reproduction in deer. In the case of appetite regulation, the pattern exhibited by females for NPY and γ-MSH was as expected for the breeding and non-breeding seasons, based on previous studies of these peptides in sheep and the seasonal cycle of appetite reported for various species of deer. An inverse result in male deer most probably reflects the response of appetite regulating cells to negative energy balance during the mating season. Differences between the sexes in the seasonal

Inappropriate activation of the androgen receptor by nonsteroids: involvement of the Src kinase pathway and its therapeutic implications.

PubMed

Desai, Sonal J; Ma, Ai-Hong; Tepper, Clifford G; Chen, Hong-Wu; Kung, Hsing-Jien

2006-11-01

The inappropriate activation of androgen receptor (AR) by nonsteroids is considered a potential mechanism in the emergence of hormone-refractory prostate tumors, but little is known about the properties of these "pseudoactivated" AR. Here, we present the first comprehensive analysis closely examining the properties of AR activated by the neuropeptide bombesin that distinguish it from androgen-activated AR. We show that bombesin-activated AR (a) is required for bombesin-induced growth of LNCaP cells, (b) has a transcriptional profile overlapping with, but not identical to, androgen-activated AR, (c) activates prostate-specific antigen by preferentially binding to its proximal promoter, and (d) assembles a distinct coactivator complex. Significantly, we found that Src kinase is critical for bombesin-induced AR-mediated activity and is required for translocation and transactivation of AR. Additionally, we identify c-Myc, a Src target gene, to be activated by bombesin and a potential coactivator of AR-mediated activity specific to bombesin-induced signaling. Because Src kinase is often activated by other nonsteroids, such as other neuropeptides, growth factors, chemokines, and cytokines, our findings have general applicability and provide rationale for investigating the efficacy of the Src kinase pathway as a target for the prevention of relapsed prostate cancers.

Study of air pollution: Effects of ozone on neuropeptide-mediated responses in human subjects. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boushey, H.A.

1991-11-01

The study examined the hypothesis that ozone inactivates the enzyme, neutral endopeptidase, responsible for limiting the effects of neuropeptides released from afferent nerve endings. Cough response of capsaicin solution delivered from a nebulizer at 2 min. intervals until two or more coughs were produced. Other endpoints measured included irritative symptoms as rated by the subjects on a nonparametric scale, spirometry, of each concentration of ozone were compared to those of filtered air in a single-blind randomized sequence. The results indicate that a 2 h. exposure to 0.4 ppm of ozone with intermittent light exercise alters the sensitivity of airway nervesmore » that mediate the cough response to inhaled materials. This dose of ozone also caused a change in FEV1. A lower level of ozone, 0.02 ppm, caused a change in neither cough threshold nor FEV1, even when the duration of exposure was extended to three hours. The findings are consistent with the author's hypothesis that ozone may sensitize nerve endings in the airways by inactivating neutral endopeptidase, an enzyme that regulates their activity, but they do not demonstrate that directly examining an effect directly mediated by airway nerves allows detection of effects of ozone at doses below those causing effects detected by standard tests of pulmonary function.« less

Substance P as an immunomodulatory neuropeptide in a mouse model for autoimmune hair loss (alopecia areata).

PubMed

Siebenhaar, Frank; Sharov, Andrey A; Peters, Eva M J; Sharova, Tatyana Y; Syska, Wolfgang; Mardaryev, Andrei N; Freyschmidt-Paul, Pia; Sundberg, John P; Maurer, Marcus; Botchkarev, Vladimir A

2007-06-01

Alopecia areata (AA) is an autoimmune disorder of the hair follicle characterized by inflammatory cell infiltrates around actively growing (anagen) hair follicles. Substance P (SP) plays a critical role in the cutaneous neuroimmune network and influences immune cell functions through the neurokinin-1 receptor (NK-1R). To better understand the role of SP as an immunomodulatory neuropeptide in AA, we studied its expression and effects on immune cells in a C3H/HeJ mouse model for AA. During early stages of AA development, the number of SP-immunoreactive nerve fibers in skin is increased, compared to non-affected mice. However, during advanced stages of AA, the number of SP-immunoreactive nerves and SP protein levels in skin are decreased, whereas the expression of the SP-degrading enzyme neutral endopeptidase (NEP) is increased, compared to control skin. In AA, NK-1R is expressed on CD8+ lymphocytes and macrophages accumulating around affected hair follicles. Additional SP supply to the skin of AA-affected mice leads to a significant increase of mast cell degranulation and to accelerated hair follicle regression (catagen), accompanied by an increase of CD8+ cells-expressing granzyme B. These data suggest that SP, NEP, and NK-1R serve as important regulators in the molecular signaling network modulating inflammatory response in autoimmune hair loss.

Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling.

PubMed

Roosterman, Dirk; Cottrell, Graeme S; Padilla, Benjamin E; Muller, Laurent; Eckman, Christopher B; Bunnett, Nigel W; Steinhoff, Martin

2007-07-10

Neuropeptide signaling requires the presence of G protein-coupled receptors (GPCRs) at the cell surface. Activated GPCRs interact with beta-arrestins, which mediate receptor desensitization, endocytosis, and mitogenic signaling, and the peptide-receptor-arrestin complex is sequestered into endosomes. Although dissociation of beta-arrestins is required for receptor recycling and resensitization, the critical event that initiates this process is unknown. Here we report that the agonist availability in the endosomes, controlled by the membrane metalloendopeptidase endothelin-converting enzyme 1 (ECE-1), determines stability of the peptide-receptor-arrestin complex and regulates receptor recycling and resensitization. Substance P (SP) binding to the tachykinin neurokinin 1 receptor (NK1R) induced membrane translocation of beta-arrestins followed by trafficking of the SP-NK1R-beta-arrestin complex to early endosomes containing ECE-1a-d. ECE-1 degraded SP in acidified endosomes, disrupting the complex; beta-arrestins returned to the cytosol, and the NK1R, freed from beta-arrestins, recycled and resensitized. An ECE-1 inhibitor, by preventing NK1R recycling in endothelial cells, inhibited resensitization of SP-induced inflammation. This mechanism is a general one because ECE-1 similarly regulated NK3R resensitization. Thus, peptide availability in endosomes, here regulated by ECE-1, determines the stability of the peptide-receptor-arrestin complex. This mechanism regulates receptor recycling, which is necessary for sustained signaling, and it may also control beta-arrestin-dependent mitogenic signaling of endocytosed receptors. We propose that other endosomal enzymes and transporters may similarly control the availability of transmitters in endosomes to regulate trafficking and signaling of GPCRs. Antagonism of these endosomal processes represents a strategy for inhibiting sustained signaling of receptors, and defects may explain the tachyphylaxis of drugs that are

Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 (DPP4) in blood circulation.

PubMed

Wagner, Leona; Kaestner, Florian; Wolf, Raik; Stiller, Harald; Heiser, Ulrich; Manhart, Susanne; Hoffmann, Torsten; Rahfeld, Jens-Ulrich; Demuth, Hans-Ulrich; Rothermundt, Matthias; von Hörsten, Stephan

2016-06-01

Dipeptidyl peptidase 4 (DPP4; EC 3.4.14.5; CD26) is a membrane-bound or shedded serine protease that hydrolyzes dipeptides from the N-terminus of peptides with either proline or alanine at the penultimate position. Substrates of DPP4 include several stress-related neuropeptides implicated in anxiety, depression and schizophrenia. A decline of DPP4-like activity has been reported in sera from depressed patient, but not fully characterized regarding DPP4-like enzymes, therapeutic interventions and protein. Sera from 16 melancholic- and 16 non-melancholic-depressed patients were evaluated for DPP4-like activities and the concentration of soluble DPP4 protein before and after treatment by anti-depressive therapies. Post-translational modification of DPP4-isoforms and degradation of NPY, Peptide YY (PYY), Galanin-like peptide (GALP), Orexin B (OrxB), OrxA, pituitary adenylate cyclase-activating polypeptide (PACAP) and substance P (SP) were studied in serum and in ex vivo human blood. N-terminal truncation of biotinylated NPY by endothelial membrane-bound DPP4 versus soluble DPP4 was determined in rat brain perfusates and spiked sera. Lower DPP4 activities in depressed patients were reversed by anti-depressive treatment. In sera, DPP4 contributed to more than 90% of the overall DPP4-like activity and correlated with its protein concentration. NPY displayed equal degradation in serum and blood, and was equally truncated by serum and endothelial DPP4. In addition, GALP and rat OrxB were identified as novel substrates of DPP4. NPY is the best DPP4-substrate in blood, being truncated by soluble and membrane DPP4, respectively. The decline of soluble DPP4 in acute depression could be reversed upon anti-depressive treatment. Peptidases from three functional compartments regulate the bioactivity of NPY in blood. Copyright © 2016 Elsevier Ltd. All rights reserved.

The corticotropin-releasing factor-like diuretic hormone 44 (DH44) and kinin neuropeptides modulate desiccation and starvation tolerance in Drosophila melanogaster.

PubMed

Cannell, Elizabeth; Dornan, Anthony J; Halberg, Kenneth A; Terhzaz, Selim; Dow, Julian A T; Davies, Shireen-A

2016-06-01

Malpighian tubules are critical organs for epithelial fluid transport and stress tolerance in insects, and are under neuroendocrine control by multiple neuropeptides secreted by identified neurons. Here, we demonstrate roles for CRF-like diuretic hormone 44 (DH44) and Drosophila melanogaster kinin (Drome-kinin, DK) in desiccation and starvation tolerance. Gene expression and labelled DH44 ligand binding data, as well as highly selective knockdowns and/or neuronal ablations of DH44 in neurons of the pars intercerebralis and DH44 receptor (DH44-R2) in Malpighian tubule principal cells, indicate that suppression of DH44 signalling improves desiccation tolerance of the intact fly. Drome-kinin receptor, encoded by the leucokinin receptor gene, LKR, is expressed in DH44 neurons as well as in stellate cells of the Malpighian tubules. LKR knockdown in DH44-expressing neurons reduces Malpighian tubule-specific LKR, suggesting interactions between DH44 and LK signalling pathways. Finally, although a role for DK in desiccation tolerance was not defined, we demonstrate a novel role for Malpighian tubule cell-specific LKR in starvation tolerance. Starvation increases gene expression of epithelial LKR. Also, Malpighian tubule stellate cell-specific knockdown of LKR significantly reduced starvation tolerance, demonstrating a role for neuropeptide signalling during starvation stress. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The neuropeptide-12 improves recognition memory and neuronal plasticity of the limbic system in old rats.

PubMed

Hernández-Hernández, Elizabeth Monserrat; Caporal Hernandez, Karen; Vázquez-Roque, Rubén Antonio; Díaz, Alfonso; de la Cruz, Fidel; Florán, Benjamin; Flores, Gonzalo

2018-08-01

Aging is a stage of life where cognitive and motor functions are impaired. This is because oxidative and inflammatory processes exacerbate neurodegeneration, which affects dendritic morphology and neuronal communication of limbic regions with memory loss. Recently, the use of trophic substances has been proposed to prevent neuronal deterioration. The neuropeptide-12 (N-PEP-12) has been evaluated in elderly patients with dementia, showing improvements in cognitive tasks due to acts as a neurotrophic factor. In the present work, we evaluated the effect of N-PEP-12 on motor activity and recognition memory, as well as its effects on dendritic morphology and the immunoreactivity of GFAP, Synaptophysin (SYP), and BDNF in neurons of the prefrontal cortex (PFC), dorsal hippocampus (DH) and nucleus accumbens (NAcc) of aged rats. The results show that N-PEP-12 improved the recognition memory, but the motor activity was not modified compared to the control animals. N-PEP-12 increases the density of dendritic spines and the total dendritic length in neurons of the PFC (layers 3 and 5) and in DH (CA1 and CA3). Interestingly NAcc neurons showed a reduction in the number of dendritic spines. In the N-PEP-12 animals, when evaluating the immunoreactivity for SYP and BDNF, there was an increase in the three brain regions, while the mark for GFAP decreased significantly. Our results suggest that N-PEP-12 promotes neuronal plasticity in the limbic system of aged animals, which contributes to improving recognition memory. In this sense, N-PEP-12 can be considered as a pharmacological alternative to prevent or delay brain aging and control senile dementias. © 2018 Wiley Periodicals, Inc.

Novel tactics for neuroprotection in Parkinson's disease: Role of antibiotics, polyphenols and neuropeptides.

PubMed

Reglodi, Dora; Renaud, Justine; Tamas, Andrea; Tizabi, Yousef; Socías, Sergio B; Del-Bel, Elaine; Raisman-Vozari, Rita

2017-08-01

Parkinson's disease is a progressive neurodegenerative disorder characterized by the degeneration of midbrain nigral dopaminergic neurons. Although its etiology remains unknown, the pathological role of several factors has been highlighted, namely oxidative stress, neuroinflammation, protein misfolding, and mitochondrial dysfunction, in addition to genetic predispositions. The current therapy is mainly symptomatic with l-DOPA aiming to replace dopamine. Novel therapeutic approaches are being investigated with the intention of influencing pathways leading to neuronal death and dysfunction. The present review summarizes three novel approaches, the use of which is promising in pre-clinical studies. Polyphenols have been shown to possess neuroprotective properties on account of their well-established antioxidative and anti-inflammatory actions but also due to their influence on protein misfolding and mitochondrial homeostasis. Within the amazing ancillary effects of antibiotics, their neuroprotective properties against neurodegenerative and neuroinflammatory processes are of great interest for the development of effective therapies against Parkinson's disease. Experimental evidence supports the potential of antibiotics as neuroprotective agents, being useful not only to prevent the formation of toxic α-synuclein oligomers but also to ameliorate mitochondrial dysfunction and neuroinflammation. Neuropeptides offer another approach with their diverse effects in the nervous system. Among them, pituitary adenylate cyclase-activating polypeptide, a member of the secretin/glucagon superfamily, has several advantageous effects in models of neurodegeneration, namely anti-apoptotic, anti-inflammatory and antioxidant actions, the combination of which offers a potent protective effect in dopaminergic neurons. Owing to their pleiotropic modes of action, these novel therapeutic candidates have potential in tackling the multidimensional features of Parkinson's disease. Copyright �

Neuropeptide y gates a stress-induced, long-lasting plasticity in the sympathetic nervous system.

PubMed

Wang, Qian; Wang, Manqi; Whim, Matthew D

2013-07-31

Acute stress evokes the fight-or-flight reflex, which via release of the catecholamine hormones affects the function of every major organ. Although the reflex is transient, it has lasting consequences that produce an exaggerated response when stress is reexperienced. How this change is encoded is not known. We investigated whether the reflex affects the adrenal component of the sympathetic nervous system, a major branch of the stress response. Mice were briefly exposed to the cold-water forced swim test (FST) which evoked an increase in circulating catecholamines. Although this hormonal response was transient, the FST led to a long-lasting increase in the catecholamine secretory capacity measured amperometrically from chromaffin cells and in the expression of tyrosine hydroxylase. A variety of approaches indicate that these changes are regulated postsynaptically by neuropeptide Y (NPY), an adrenal cotransmitter. Using immunohistochemistry, RT-PCR, and NPY(GFP) BAC mice, we find that NPY is synthesized by all chromaffin cells. Stress failed to increase secretory capacity in NPY knock-out mice. Genetic or pharmacological interference with NPY and Y1 (but not Y2 or Y5) receptor signaling attenuated the stress-induced change in tyrosine hydroxylase expression. These results indicate that, under basal conditions, adrenal signaling is tonically inhibited by NPY, but stress overrides this autocrine negative feedback loop. Because acute stress leads to a lasting increase in secretory capacity in vivo but does not alter sympathetic tone, these postsynaptic changes appear to be an adaptive response. We conclude that the sympathetic limb of the stress response exhibits an activity-dependent form of long-lasting plasticity.

Nesfatin-1, a unique regulatory neuropeptide of the brain.

PubMed

Pałasz, Artur; Krzystanek, Marek; Worthington, John; Czajkowska, Beata; Kostro, Karol; Wiaderkiewicz, Ryszard; Bajor, Grzegorz

2012-06-01

Nesfatin-1, a newly discovered NUCB2-derived satiety neuropeptide is expressed in several neurons of forebrain, hindbrain, brainstem and spinal cord. This novel anorexigenic substance seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. Nesfatin-1 immunoreactive cells are detectable in arcuate (ARC), paraventricular (PVN) and supraoptic nuclei (SON), where the peptide is colocalized with POMC/CART, NPY, oxytocin and vasopressin. The nesfatin-1 molecule interacts with a G-protein coupled receptor and its cytophysiological effect depends on inhibitory hyperpolarization of NPY/AgRP neurons in ARC and melanocortin signaling in PVN. Administration of nesfatin-1 significantly inhibits consumatory behavior and decreases weight gain in experimental animals. These recent findings suggest the evidence for nesfatin-1 involvement in other important brain functions such as reproduction, sleep, cognition and anxiety- or stress-related responses. The neuroprotective and antiapoptotic properties of nesfatin-1 were also reported. From the clinical viewpoint it should be noteworthy, that the serum concentration of nesfatin-1 may be a sensitive marker of epileptic seizures. However, the details of nesfatin-1 physiology ought to be clarified, and it may be considered suitable in the future, as a potential drug in the pharmacotherapy of obesity, especially in patients treated with antipsychotics and antidepressants. On the other hand, some putative nesfatin-1 antagonists may improve eating disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Gene expression and pharmacology of nematode NLP-12 neuropeptides.

PubMed

McVeigh, Paul; Leech, Suzie; Marks, Nikki J; Geary, Timothy G; Maule, Aaron G

2006-05-31

This study examines the biology of NLP-12 neuropeptides in Caenorhabditis elegans, and in the parasitic nematodes Ascaris suum and Trichostrongylus colubriformis. DYRPLQFamide (1 nM-10 microM; n > or =6) produced contraction of innervated dorsal and ventral Ascaris body wall muscle preparations (10 microM, 6.8+/-1.9 g; 1 microM, 4.6+/-1.8 g; 0.1 microM, 4.1+/-2.0 g; 10 nM, 3.8+/-2.0 g; n > or =6), and also caused a qualitatively similar, but quantitatively lower contractile response (10 microM, 4.0+/-1.5 g, n=6) on denervated muscle strips. Ovijector muscle displayed no measurable response (10 microM, n=5). nlp-12 cDNAs were characterised from A. suum (As-nlp-12) and T. colubriformis (Tc-nlp-12), both of which show sequence similarity to C. elegans nlp-12, in that they encode multiple copies of -LQFamide peptides. In C. elegans, reverse transcriptase (RT)-PCR analysis showed that nlp-12 was transcribed throughout the life cycle, suggesting that DYRPLQFamide plays a constitutive role in the nervous system of this nematode. Transcription was also identified in both L3 and adult stages of T. colubriformis, in which Tc-nlp-12 is expressed in a single tail neurone. Conversely, As-nlp-12 is expressed in both head and tail tissue of adult female A. suum, suggesting species-specific differences in the transcription pattern of this gene.

Inhibitory effect of D3 dopamine receptors on neuropeptide Y‑induced migration in vascular smooth muscle cells.

PubMed

Xia, Xue-Wei; Zhou, Yong-Qiao; Luo, Hao; Zeng, Chunyu

2017-10-01

Abnormal migration of vascular smooth muscle cells (VSMCs) serves an important role in hypertension, atherosclerosis and restenosis following angioplasty, which is regulated numerous hormonal and humoral factors, including neuropeptide Y (NPY) and dopamine. Dopamine and NPY are both sympathetic neurotransmitters, and a previous study reported that NPY increased VSMC proliferation, while dopamine receptor inhibited it. Therefore, the authors wondered whether or not there is an inhibitory effect of dopamine receptor on NPY‑mediated VSMC migration. The present study demonstrated that stimulation with NPY dose‑dependence (10‑10‑10‑7M, 24 h) increased VSMC migration, the stimulatory effect of NPY was via the Y1 receptor. This is because, in the presence of the Y1 receptor antagonist, BIBP3226 (10‑7 M), the stimulatory effect of NPY on VSMC migration was blocked. Activation of the D3 receptor by PD128907 dose‑dependence (10‑11‑10‑8 M) reduced the stimulatory effect of NPY on VSMC migration. The effect of PD128907 was via the D3 receptor, because the inhibitory effect of PD128907 on NPY‑mediated migration was blocked by the D3 receptor antagonist, U99194. The authors' further study suggested that the inhibitory effect of the D3 receptor was via the PKA signaling pathway, in the presence of the PKA inhibitor, 14‑22 (10‑6 M), the inhibitory effect of PD128907 on VSMC migration was blocked. Moreover, the inhibitory effect of PD128907 was imitated by PKA activator, Sp‑cAMP [S], in the presence of Sp‑cAMP [S], the NPY‑mediated stimulatory effect on VSMC migration was abolished. The present study indicated that activation of the D3 receptor inhibits NPY Y1‑mediated migration on VSMCs, PKA is involved in the signaling pathway.

Methylphenidate-induced motor activity in rats: modulation by melatonin and vasopressin.

PubMed

Appenrodt, Edgar; Schwarzberg, Helmut

2003-04-01

Methylphenidate (MPH), a dopamine (DA) reuptake inhibitor, is well known to enhance motor activity, in part depending on the time of its application during the light-dark cycle. Moreover, after MPH administration, the hypothalamo-neurohypophysial axis including the neuropeptide vasopressin (AVP) was found influenced. Both the latter and behavioural effects of central AVP can also be modulated by the pineal gland with its light-dark-dependent activity. The present study was performed to investigate whether the pineal gland, its hormone melatonin (Mel), and AVP are involved in the MPH-evoked stimulation of activity. After application of 10 mg/kg MPH, the motor activity in pinealectomised (PE) rats was significantly higher than in sham-operated (SO) animals. After application of 250 microg Mel before MPH treatment, the stimulation of motor activity was diminished in PE rats and augmented in SO animals; however, when SO and PE rats were compared after Mel pretreatment, the reaction to MPH was nearly identical. Blocking the endogenous AVP by 25 or 1 microg of the V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP (AAVP) before MPH treatment significantly augmented the motor activity in SO rats only and abolished the differences seen between SO and PE animals after MPH application. The present results indicate that the behavioural stimulation of MPH was modulated by both the pineal gland with its hormone Mel as well as the neuropeptide AVP.

Influence of feeding status on neuronal activity in the hypothalamus during lipopolysaccharide-induced anorexia in rats.

PubMed

Gautron, L; Mingam, R; Moranis, A; Combe, C; Layé, S

2005-01-01

Fasting attenuates disease-associated anorexia, but the mechanisms underlying this effect are not well understood. In the present study, we investigated the extent to which a 48 h fast alters hypothalamic neuronal activity in response to the anorectic effects of lipopolysaccharide in rats. Male rats were fed ad libitum or fasted, and were injected with i.p. saline or lipopolysaccharide (250 microg/kg). Immunohistochemistry for Fos protein was used to visualize neuronal activity in response to lipopolysaccharide within selected hypothalamic feeding regulatory nuclei. Additionally, food intake, body weight, plasma interleukin-1 and leptin levels, and the expression of mRNA for appetite-related neuropeptides (neuropeptide Y, proopiomelanocortin and cocaine-amphetamine-regulated transcript) were measured in a time-related manner. Our data show that the pattern of lipopolysaccharide-induced Fos expression was similar in most hypothalamic nuclei whatever the feeding status. However, we observed that fasting significantly reduced lipopolysaccharide-induced Fos expression in the paraventricular nucleus, in association with an attenuated lipopolysaccharide-induced anorexia and body weight loss. Moreover, lipopolysaccharide reduced fasting-induced Fos expression in the perifornical area of the lateral hypothalamus. Lipopolysaccharide-induced circulating levels of interleukin-1 were similar across feeding status. Finally, fasting, but not lipopolysaccharide, affected circulating level of leptin and appetite-related neuropeptides expression in the arcuate nucleus. Together, our data show that fasting modulates lipopolysaccharide-induced anorexia and body weight loss in association with neural changes in specific hypothalamic nuclei.

Metabolism of neuropeptides. Hydrolysis of the angiotensins, bradykinin, substance P and oxytocin by pig kidney microvillar membranes.

PubMed Central

Stephenson, S L; Kenny, A J

1987-01-01

Microvillar membranes derived from the brush border of the renal proximal tubule are very rich in peptidases. Pig kidney microvilli contain endopeptidase-24.11 associated with a battery of exopeptidases. The manner by which some neuropeptides are degraded by the combined attack of the peptidases of this membrane has been investigated. The contribution of individual peptidases was assessed by including inhibitors (phosphoramidon, captopril, amastatin and di-isopropyl fluorophosphate) with the membrane fraction when incubated with the peptides. Substance P, bradykinin and angiotensins I, II and III and insulin B-chain were rapidly hydrolysed by kidney microvilli. Oxytocin was hydrolysed much more slowly, but no products were detected from [Arg8]vasopressin or insulin under the conditions used for other peptides. The peptide bonds hydrolysed were identified and the contributions of the different peptidases were quantified. For each of the susceptible peptides, the main contribution came from endopeptidase-24.11 (inhibited by phosphoramidon). Peptidyl dipeptidase A (angiotensin-I-converting enzyme) was of less importance, even in respect of angiotensin I and bradykinin. When [2,3-Pro3,4-3H]bradykinin was also investigated at a lower concentration (20 nM), the conclusions in regard to the contributions of the two peptidases were unchanged. The possibility that endopeptidase-24.11 might attack within the six-residue disulphide-bridged rings of oxytocin and vasopressin was examined by dansyl(5-dimethylaminonaphthalene-1-sulphonyl)ation and by reduction and carboxymethylation of the products after incubation. Additional peptides were only observed after prolonged incubation, consistent with hydrolysis at the Tyr2-Ile3 and Tyr2-Phe3 bonds respectively. These results show that a range of neuropeptides are efficiently degraded by microvillar membranes and that endopeptidase-24.11 plays a key role in this process. PMID:2436610