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Sample records for activating neuropeptide pban

  1. Identification of a new member of PBAN family of neuropeptides from the fire ant, Solenopsis invicta

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptide hormones produced by neurosecretory cells in the central or peripheral nervous systems regulate various physiological and behavioral events during insect development and reproduction. Pyrokinin/Pheromone Biosynthesis Activating Neuropeptide (PBAN) is a major neuropeptide family, chara...

  2. The pyrokinin/ pheromone biosynthesis-activating neuropeptide (PBAN) family of peptides and their receptors in Insecta: evolutionary trace indicates potential receptor ligand-binding domains.

    PubMed

    Jurenka, R; Nusawardani, T

    2011-06-01

    The pyrokinin/pheromone biosynthesis-activating neuropeptide (PBAN) family of G-protein-coupled receptors and their ligands have been identified in various insects. Physiological functions of pyrokinin peptides include muscle contraction, whereas PBAN regulates, among other functions, pheromone production in moths which indicates the pleiotropic nature of these peptides. Based on the alignment of annotated genomic sequences, the pyrokinin/PBAN family of receptors have similarity with the corresponding structures of the capa or periviscerokinin receptors of insects and the neuromedin U receptors of vertebrates. In our study, evolutionary trace (ET) analysis on the insect receptor sequences was conducted to predict the putative ligand recognition and binding sites. The ET analysis of four class-specific receptors indicated several amino acid residues that are conserved in the transmembrane domains. The receptor extracellular domains exhibit several class-specific amino acid residues, which could indicate putative domains for activation of these receptors by ligand recognition and binding.

  3. 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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The pyrokinin/pheromone biosynthesis activating neuropeptide (PK/PBAN) family plays a multifunctional role in an array of important physiological processes in a variety of insects. An active core analog containing an (E)-alkene, transPro isosteric component was evaluated in four disparate PK/PBAN b...

  4. The FXPRLamide (pyrokinin/PBAN) family

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The pyrokinin/pheromone biosynthesis-activating neuropeptide (PK/PBAN) family is one of the most studied neuropeptide (Np) families in insects, and is one of the most important in insect physiology regulation. Physiological functions regulated by the PK/PBAN peptides include development, mating, mus...

  5. Potent activity of a PK/PBAN analog with an (E)-alkene, trans-Pro mimic identifies the Pro orientation and core conformation during interaction with HevPBANR-C receptor

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The pyrokinin/pheromone biosynthesis activating neuropeptide (PK/PBAN) family plays a multifunctional role in an array of important physiological processes in insects, including regulation of sex pheromone biosynthesis in moths. A cyclic PK/PBAN analog (cyclo[NTSFTPRL]) retains significant activity...

  6. PBAN/Pyrokinin peptides in Central Nervous System from Fire Ant, Solenopsis invicta

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peptides from the PBAN/Pyrokinin family are expected to be found from all insect groups and some other arthropods. These neuropeptides are characterized by a conserved pentapeptide, FXPRLamide, at the C-terminus. This amino acid sequence is required for physiological activity. The PBAN/Pyrokinin pep...

  7. Identification of functionally important residues in the silkmoth pheromone biosynthesis-activating neuropeptide receptor, an insect ortholog of the vertebrate Neuromedin U Receptor

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The biosynthesis of sex pheromone components in many lepidopteran insects is regulated by interactions between pheromone biosynthesis-activating neuropeptide (PBAN) and the PBAN receptor (PBANR), a class-A G-protein-coupled receptor (GPCR). To identify functionally important amino acid residues in t...

  8. Atlas of Central Nervous System and the first Neuropeptide from Fire Ant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In some insects, especially lepidopteran species, regulation of pheromone biosynthesis and production is under hormonal control. The neuropeptide hormone responsible, PBAN (Pheromone Biosynthesis Activating Neuropeptide), is synthesized in the subesophageal ganglion (SG) and released into the hemoly...

  9. Identification of a new member of PBAN family and immunoreactivity in the central nervous system from Adoxophyes sp. (Lepidoptera: Tortricidae).

    PubMed

    Choi, Man-Yeon; Lee, Jae Min; Han, Kyeung Sik; Boo, Kyung Saeng

    2004-09-01

    Production of sex pheromones, Z9-14:OAc and Z11-14:OAc, of the smaller tea tortrix, Adoxophyes sp. was stimulated by injection of the female or male head extracts as well as synthetic pheromone biosynthesis activating neuropeptide (PBAN) into decapitated females. The amount of pheromone produced reached a maximum level 3 h after injection of synthetic PBAN into females. A cDNA isolated from brain-suboesophageal ganglion complex (Br-SEG) of A. sp. females contained an ORF of 576 nucleotides encoding 192 amino acids. Based on endoproteolytic sites, it can be predicted to be cleaved into five putative peptide domains including PBAN and four other neuropeptides. Ado-PBAN consisting of 31-amino acids is the shortest PBAN so far reported. Four other putative PBAN-encoding gene neuropeptides (PGN) are predicted with PGN-24, PGN-7, PGN-20, and PGN-8 amino acids. All of the peptides are amidated in their C-termini with a FXPR(or I, K)L structure, except for PGN-8 (TVKLTPRLamide). PBAN-like immunoreactive material was observed in Br, SEG and ventral nerve cord (VNC) of the female adult. In the brain, 5-7 pairs of neurons containing PBAN-like immunoreactivity were found in each protocerebral hemisphere. Three groups of cell clusters found in the SEG corresponded to the mandibular, maxillary and labial neurons as in other moths. PBAN-like immunoreactive neurons in the VNC were found in thoracic (three pairs) and abdominal ganglia (two pairs). As compared to other moths, a relatively low similarity of peptide sequences deduced from Ado-PBAN gene and a different expression pattern of PBAN-like immunoreactivity could indicate phylogenetical distance from the other species.

  10. Regulatory Role of PBAN in Sex Pheromone Biosynthesis of Heliothine Moths

    PubMed Central

    Jurenka, Russell; Rafaeli, Ada

    2011-01-01

    Both males and females of heliothine moths utilize sex-pheromones during the mating process. Females produce and release a sex pheromone for the long–range attraction of males for mating. Production of sex pheromone in females is controlled by the peptide hormone (pheromone biosynthesis activating neuropeptide, PBAN). This review will highlight what is known about the role PBAN plays in controlling pheromone production in female moths. Male moths produce compounds associated with a hairpencil structure associated with the aedaegus that are used as short-range aphrodisiacs during the mating process. We will discuss the role that PBAN plays in regulating male production of hairpencil pheromones. PMID:22654810

  11. Molecular Structure and Diversity of PBAN/pyrokinin Family Peptides in Ants.

    PubMed

    Choi, Man-Yeon; Vander Meer, Robert K

    2012-01-01

    Neuropeptides are the largest group of insect hormones. They are produced in the central and peripheral nervous systems and affect insect development, reproduction, feeding, and behavior. A variety of neuropeptide families have been identified in insects. One of these families is the PBAN/pyrokinin family defined by a common FXPRLamide or similar amino acid fragment at the C-terminal end. These peptides, found in all insects studied thus far, have been conserved throughout evolution. The most well studied physiological function is regulation of moth sex pheromone biosynthesis through the pheromone biosynthesis activating neuropeptide (PBAN), although several developmental functions have also been reported. Over the past years we have extended knowledge of the PBAN/pyrokinin family of peptides to ants, focusing mainly on the fire ant, Solenopsis invicta. The fire ant is one of the most studied social insects and over the last 60 years a great deal has been learned about many aspects of this ant, including the behaviors and chemistry of pheromone communication. However, virtually nothing is known about the regulation of these pheromone systems. Recently, we demonstrated the presence of PBAN/pyrokinin immunoreactive neurons in the fire ant, and identified and characterized PBAN and additional neuropeptides. We have mapped the fire ant PBAN gene structure and determined the tissue expression level in the central nervous system of the ant. We review here our research to date on the molecular structure and diversity of ant PBAN/pyrokinin peptides in preparation for determining the function of the neuropeptides in ants and other social insects.

  12. PBAN/Pyrokinin peptides in the central nervous system of the fire ant, Solenopsis invicta

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The pyrokinin/pheromone biosynthesis activating neuropeptide (PBAN) family of peptides found in insects is characterized by a 5-amino-acid C-terminal sequence, FXPRLamide. The pentapeptide is the active core required for diverse physiological functions, including stimulation of pheromone biosynthesi...

  13. 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

  14. PBAN/pyrokinin peptides in the central nervous system of the fire ant, Solenopsis invicta.

    PubMed

    Choi, Man-Yeon; Raina, Ashok; Vander Meer, Robert K

    2009-02-01

    The pyrokinin/pheromone-biosynthesis-activating neuropeptide (PBAN) family of peptides found in insects is characterized by a 5-amino-acid C-terminal sequence, FXPRLamide. The pentapeptide is the active core required for diverse physiological functions, including the stimulation of pheromone biosynthesis in female moths, muscle contraction, induction of embryonic diapause, melanization, acceleration of puparium formation, and termination of pupal diapause. We have used immunocytochemical techniques to demonstrate the presence of pyrokinin/PBAN-like peptides in the central nervous system of the fire ant, Solenopsis invicta. Polyclonal antisera against the C-terminal end of PBAN have revealed the location of the peptide-producing cell bodies and axons in the central nervous system. Immunoreactive material is detectable in at least three groups of neurons in the subesophageal ganglion and corpora cardiaca of all adult sexual forms. The ventral nerve cord of adults consists of two segmented thoracic ganglia and four segmented abdominal ganglia. Two immunoreactive pairs of neurons are present in the thoracic ganglia, and three neuron pairs in each of the first three abdominal ganglia. The terminal abdominal ganglion has no immunoreactive neurons. PBAN immunoreactive material found in abdominal neurons appears to be projected to perisympathetic organs connected to the abdominal ganglia. These results indicate that the fire ant nervous system contains pyrokinin/PBAN-like peptides, and that these peptides are released into the hemolymph. In support of our immunocytochemical results, significant pheromonotropic activity is found in fire ant brain-subesophageal ganglion extracts from all adult fire ant forms (queens, female and male alates, and workers) when extracts are injected into decapitated females of Helicoverpa zea. This is the first demonstration of the presence of pyrokinin/PBAN-like peptides and pheromonotropic activity in an ant species.

  15. Pyrokinin/PBAN-like peptides in the central nervous system of mosquitoes.

    PubMed

    Hellmich, Erica; Nusawardani, Tyasning; Bartholomay, Lyric; Jurenka, Russell

    2014-04-01

    The pyrokinin/pheromone biosynthesis activating neuropeptide (PBAN) family of peptides is characterized by a common C-terminal pentapeptide, FXPRLamide, which is required for diverse physiological functions in various insects. Polyclonal antisera against the C-terminus was utilized to determine the location of cell bodies and axons in the central nervous systems of larval and adult mosquitoes. Immunoreactive material was detected in three groups of neurons in the subesophageal ganglion of larvae and adults. The corpora cardiaca of both larvae and adults contained immunoreactivity indicating potential release into circulation. The adult and larval brains had at least one pair of immunoreactive neurons in the protocerebrum with the adult brain having additional immunoreactive neurons in the dorsal medial part of the protocerebrum. The ventral ganglia of both larvae and adults each contained one pair of neurons that sent their axons to a perisympathetic organ associated with each abdominal ganglion. These results indicate that the mosquito nervous system contains pyrokinin/PBAN-like peptides and that these peptides could be released into the hemolymph. The peptides in insects and mosquitoes are produced by two genes, capa and pk/pban. Utilizing PCR protocols, we demonstrate that products of the capa gene could be produced in the abdominal ventral ganglia and the products of the pk/pban gene could be produced in the subesophageal ganglion. Two receptors for pyrokinin peptides were differentially localized to various tissues.

  16. Molecular structure and diversity of PBAN/Pyrokinin family peptides in ants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptides are the largest group of insect hormones. They are produced in the central and peripheral nervous systems and affect insect development, reproduction, feeding and behavior. A variety of neuropeptide families have been identified in insects. One of these families is the PBAN/Pyrokinin f...

  17. Active conformation of an insect neuropeptide family.

    PubMed Central

    Nachman, R J; Roberts, V A; Dyson, H J; Holman, G M; Tainer, J A

    1991-01-01

    To understand the structural and chemical basis for insect neuropeptide activity, we have designed, synthesized, and determined the conformation of a biologically active cyclic analog of the pyrokinins, an insect neuropeptide family that mediates myotropic (visceral muscle contractile) activity. Members of this insect neuropeptide family share the common C-terminal pentapeptide sequence Phe-Xaa-Pro-Arg-Leu-NH2 (Xaa = Ser, Thr, or Val). Circular dichroic, nuclear magnetic resonance, and molecular dynamics analyses of the conformationally restricted cyclic pyrokinin analog cyclo(-Asn-Thr-Ser-Phe-Thr-Pro-Arg-Leu-) indicated the presence of a beta-turn in the active core region encompassing residues Thr-Pro-Arg-Leu. The rigid cyclic analog retains biological activity, suggesting that its C-terminal beta-turn is the active pyrokinin conformation recognized by the myotropic receptor. As individual pyrokinins and pyrokinin-like neuropeptides demonstrate both oviduct-contractile and pheromone-biosynthesis activities in various insects, the biologically active beta-turn structure reported here holds broad significance for many biological processes. Images PMID:2034692

  18. Role of extracellular domains in PBAN/pyrokinin GPCRs from insects using chimera receptors.

    PubMed

    Choi, Man-Yeon; Fuerst, Emily-Jean; Rafaeli, Ada; Jurenka, Russell

    2007-04-01

    Pheromone biosynthesis-activating neuropeptide (PBAN) is a peptide used by a variety of moths to regulate pheromone production. Pyrokinins are peptides that activate muscle contraction in a variety of insects. These peptides have a common FXPRLamide C-terminal ending that is required for activity. Receptors have been identified from a moth and Drosophila as belonging to the rhodopsin family of G-protein coupled receptors (GPCRs) with sequence similarity to neuromedin U receptors from vertebrates. No insect GPCR has been characterized with regard to role of extracellular domains required for peptide binding and receptor activation. To begin characterizing these GPCRs we created chimera receptors using a PBAN-receptor from a moth and pyrokinin-receptors from Drosophila where extracellular domains were swapped. The N-terminal of the moth GPCR has two N-glycosylation sites that when replaced with glutamines, activity was reduced but not absent, indicating these sites contribute to receptor stability. Activity was greatly reduced by replacing the 2nd extracellular loop that has an N-glycosylation site and a cysteine that can form a disulfide bridge with a cysteine at the beginning of the 3rd transmembrane domain. Exchange of the 3rd extracellular loop between the moth and Drosophila receptor resulted in differential activation by PBAN or a diapause hormone peptide. This result indicates that the 3rd extracellular loop is directly involved in peptide ligand recognition. Results are discussed in context of the structural features of insect GPCRs that are required for receptor activation as compared to vertebrate receptors.

  19. Identification and expression of the PBAN/pyrokinin gene in the sand fly Phlebotomus papatasi

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The PBAN/pyrokinin peptides are a major neuropeptide (NP) family defined by a common FXPRL-NH2 or similar sequence at the C-termini. This family of peptides has been found in all insect groups investigated to date and is implicated in regulating various physiological functions, including pheromone ...

  20. PBAN gene architecture and expression in the fire ant, Solenopsis invicta

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The PBAN/Pyrokinin peptides are a major neuropeptide family characterized by a common FXPRLamide at the C-termini. These peptides are distributed ubiquitously in the Insecta and are involved in many essential endocrine functions, e.g. pheromone production. We report the gene architecture of the fire...

  1. 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

  2. Biosynthesis and PBAN-regulated transport of pheromone polyenes in the winter moth, Operophtera brumata.

    PubMed

    Wang, Hong-Lei; Zhao, Cheng-Hua; Szöcs, Gabor; Chinta, Satya Prabhakar; Schulz, Stefan; Löfstedt, Christer

    2013-06-01

    The trienoic and tetraenoic polyenes, (3Z,6Z,9Z)-3,6,9-nonadecatriene, (3Z,6Z,9Z)-3,6,9-henicosatriene, and (3Z,6Z,9Z)-1,3,6,9-henicosatetraene were found in the abdominal cuticle and pheromone gland of the winter moth Operophtera brumata L. (Lepidoptera: Geometridae), in addition to the previously identified single component sex pheromone (3Z,6Z,9Z)-1,3,6,9-nonadecatetraene. The pheromone biosynthesis activating neuropeptide (PBAN) is involved in the regulation of polyene transport from abdominal cuticle to the pheromone gland. In vivo deuterium labeling experiments showed that (11Z,14Z,17Z)-11,14,17-icosatrienoic acid, the malonate elongation product of linolenic acid, (9Z,12Z,15Z)-9,12,15-octadecatrienoic acid, is used to produce (3Z,6Z,9Z)-3,6,9-nonadecatriene and (3Z,6Z,9Z)-1,3,6,9-nonadecatetraene.

  3. 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.

  4. Control of Neuropeptide Expression by Parallel Activity-dependent Pathways in Caenorhabditis elegans

    PubMed Central

    Rojo Romanos, Teresa; Petersen, Jakob Gramstrup; Pocock, Roger

    2017-01-01

    Monitoring of neuronal activity within circuits facilitates integrated responses and rapid changes in behavior. We have identified a system in Caenorhabditis elegans where neuropeptide expression is dependent on the ability of the BAG neurons to sense carbon dioxide. In C. elegans, CO2 sensing is predominantly coordinated by the BAG-expressed receptor-type guanylate cyclase GCY-9. GCY-9 binding to CO2 causes accumulation of cyclic GMP and opening of the cGMP-gated TAX-2/TAX-4 cation channels; provoking an integrated downstream cascade that enables C. elegans to avoid high CO2. Here we show that cGMP regulation by GCY-9 and the PDE-1 phosphodiesterase controls BAG expression of a FMRFamide-related neuropeptide FLP-19 reporter (flp-19::GFP). This regulation is specific for CO2-sensing function of the BAG neurons, as loss of oxygen sensing function does not affect flp-19::GFP expression. We also found that expression of flp-19::GFP is controlled in parallel to GCY-9 by the activity-dependent transcription factor CREB (CRH-1) and the cAMP-dependent protein kinase (KIN-2) signaling pathway. We therefore show that two parallel pathways regulate neuropeptide gene expression in the BAG sensory neurons: the ability to sense changes in carbon dioxide and CREB transcription factor. Such regulation may be required in particular environmental conditions to enable sophisticated behavioral decisions to be performed. PMID:28139692

  5. NMR Analysis of C. elegans FLP-18 Neuropeptides: Implications for NPR-1 Activation

    PubMed Central

    Dossey, Aaron T.; Reale, Vincenzina; Chatwin, Heather; Zachariah, Cherian; deBono, Mario; Evans, Peter D.; Edison, Arthur S.

    2008-01-01

    FMRFamide-Like-Peptides (FLPs) are the largest neuropeptide family in animals, particularly invertebrates. FLPs are characterized by a C-to-N-terminal gradient of decreasing amino acid conservation. NPR-1 is a GPCR (G Protein Coupled Receptor) which has been shown to be a strong regulator of foraging behavior and aggregation responses in Caenorhabditis elegans. Recently, ligands for NPR-1 were identified as neuropeptides coded by the precursor genes flp-18 and flp-21 in C. elegans. The flp-18 gene encodes eight FLPs including DFDGAMPGVLRF-NH2 and EMPGVLRF-NH2. These peptides exhibit considerably different activities on NPR-1, the longer showing lower potency. We have used NMR and biological activity to investigate structural features that may explain these activity differences. Our data demonstrate that long range electrostatic interactions exist between N-terminal aspartates and the C-terminal penultimate arginine as well as N-terminal H-bonding interactions that form transient loops within DFDGAMPGVLRF-NH2. We hypothesize that these loops, along with peptide charge, diminish this peptide's activity on NPR-1 relative to that of EMPGVLRF-NH2. These results provide some insight into the large amino acid diversity in FLPs. PMID:16768454

  6. Developmental effects of oxytocin on neural activation and neuropeptide release in response to social stimuli.

    PubMed

    Kramer, Kristin M; Choe, Christina; Carter, C Sue; Cushing, Bruce S

    2006-02-01

    Previous studies have revealed that the neuropeptide hormone oxytocin (OT) has developmental effects on subsequent social behavior and on mechanisms underlying social behavior such as OT neurons and estrogen receptor alpha. This suggests that OT might also have developmental effects on neural responses to social stimuli. This was tested in socially monogamous prairie voles (Microtus ochrogaster) by manipulating OT on the first day of life and then assessing the response to a heterosexual pairing in adulthood. The response to cohabitation was assessed by quantifying neural activation in regions of the brain associated with sociosexual behavior and anxiety using c-Fos immunoreactivity. Additionally, immunocytochemistry was used to label OT and vasopressin neurons and plasma was assayed for both neuropeptides. Treatment effects were evident in females, but not in males. Blockade of OT receptors with an OT antagonist on the first day of life resulted in neural activation of the central amygdala in response to a pairing with a novel male in adulthood. The central amygdala does not normally express c-Fos after a heterosexual pairing in reproductively naïve prairie voles. Treatment effects also were observed in vasopressin immunoreactivity in the SON with OT-treated females showing a decrease.

  7. Identification of a Neuropeptide S Responsive Circuitry Shaping Amygdala Activity via the Endopiriform Nucleus

    PubMed Central

    Meis, Susanne; Bergado-Acosta, Jorge Ricardo; Yanagawa, Yuchio; Obata, Kunihiko; Stork, Oliver; Munsch, Thomas

    2008-01-01

    Neuropeptide S (NPS) and its receptor are thought to define a set of specific brain circuits involved in fear and anxiety. Here we provide evidence for a novel, NPS-responsive circuit that shapes neural activity in the mouse basolateral amygdala (BLA) via the endopiriform nucleus (EPN). Using slice preparations, we demonstrate that NPS directly activates an inward current in 20% of EPN neurons and evokes an increase of glutamatergic excitation in this nucleus. Excitation of the EPN is responsible for a modulation of BLA activity through NPS, characterized by a general increase of GABAergic inhibition and enhancement of spike activity in a subset of BLA projection neurons. Finally, local injection of NPS to the EPN interferes with the expression of contextual, but not auditory cued fear memory. Together, these data suggest the existence of a specific NPS-responsive circuitry between EPN and BLA, likely involved in contextual aspects of fear memory. PMID:18628994

  8. 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

  9. Sleep-active neuron specification and sleep induction require FLP-11 neuropeptides to systemically induce sleep.

    PubMed

    Turek, Michal; Besseling, Judith; Spies, Jan-Philipp; König, Sabine; Bringmann, Henrik

    2016-03-07

    Sleep is an essential behavioral state. It is induced by conserved sleep-active neurons that express GABA. However, little is known about how sleep neuron function is determined and how sleep neurons change physiology and behavior systemically. Here, we investigated sleep in Caenorhabditis elegans, which is induced by the single sleep-active neuron RIS. We found that the transcription factor LIM-6, which specifies GABAergic function, in parallel determines sleep neuron function through the expression of APTF-1, which specifies the expression of FLP-11 neuropeptides. Surprisingly FLP-11, and not GABA, is the major component that determines the sleep-promoting function of RIS. FLP-11 is constantly expressed in RIS. At sleep onset RIS depolarizes and releases FLP-11 to induce a systemic sleep state.

  10. Sleep-active neuron specification and sleep induction require FLP-11 neuropeptides to systemically induce sleep

    PubMed Central

    Turek, Michal; Besseling, Judith; Spies, Jan-Philipp; König, Sabine; Bringmann, Henrik

    2016-01-01

    Sleep is an essential behavioral state. It is induced by conserved sleep-active neurons that express GABA. However, little is known about how sleep neuron function is determined and how sleep neurons change physiology and behavior systemically. Here, we investigated sleep in Caenorhabditis elegans, which is induced by the single sleep-active neuron RIS. We found that the transcription factor LIM-6, which specifies GABAergic function, in parallel determines sleep neuron function through the expression of APTF-1, which specifies the expression of FLP-11 neuropeptides. Surprisingly FLP-11, and not GABA, is the major component that determines the sleep-promoting function of RIS. FLP-11 is constantly expressed in RIS. At sleep onset RIS depolarizes and releases FLP-11 to induce a systemic sleep state. DOI: http://dx.doi.org/10.7554/eLife.12499.001 PMID:26949257

  11. 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.

  12. Neuropeptide Y, substance P, and human bone morphogenetic protein 2 stimulate human osteoblast osteogenic activity by enhancing gap junction intercellular communication

    PubMed Central

    Ma, W.H.; Liu, Y.J.; Wang, W.; Zhang, Y.Z.

    2015-01-01

    Bone homeostasis seems to be controlled by delicate and subtle “cross talk” between the nervous system and “osteo-neuromediators” that control bone remodeling. The purpose of this study was to evaluate the effect of interactions between neuropeptides and human bone morphogenetic protein 2 (hBMP2) on human osteoblasts. We also investigated the effects of neuropeptides and hBMP2 on gap junction intercellular communication (GJIC). Osteoblasts were treated with neuropeptide Y (NPY), substance P (SP), or hBMP2 at three concentrations. At various intervals after treatment, cell viability was measured by the MTT assay. In addition, cellular alkaline phosphatase (ALP) activity and osteocalcin were determined by colorimetric assay and radioimmunoassay, respectively. The effects of NPY, SP and hBMP on GJIC were determined by laser scanning confocal microscopy. The viability of cells treated with neuropeptides and hBMP2 increased significantly in a time-dependent manner, but was inversely associated with the concentration of the treatments. ALP activity and osteocalcin were both reduced in osteoblasts exposed to the combination of neuropeptides and hBMP2. The GJIC of osteoblasts was significantly increased by the neuropeptides and hBMP2. These results suggest that osteoblast activity is increased by neuropeptides and hBMP2 through increased GJIC. Identification of the GJIC-mediated signal transduction capable of modulating the cellular activities of bone cells represents a novel approach to studying the biology of skeletal innervation. PMID:25714881

  13. Role of the ecto-nucleotidases in the cooperative effect of adenosine and neuropeptide-S on locomotor activity in mice.

    PubMed

    Pacheco, Robson; Pescador, Bruna Bardini; Mendonça, Bruna Pescador; Ramos, Saulo Fábio; Guerrini, Remo; Calo', Girolamo; de Andrade, Vanessa Moraes; Gavioli, Elaine Cristina; Boeck, Carina Rodrigues

    2011-10-01

    Activation of adenosine receptors modifies the action of classic neurotransmitters (i.e. dopamine, glutamate and acetylcholine) and other neuromodulators, like vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide S (NPS). Similarly to adenosine, NPS is involved in the regulation of stimulus and response to fear and arousal. Thus, the present study investigates the effects of NPS on locomotor activity in mice treated with or without α,β-methylene adenosine 5'-diphosphate (AOPCP), the inhibitor of ecto-5'-nucleotidase. Additionally, we evaluate the activity of ecto-5'-nucleotidase in brain slices of mice treated with or without NPS. Male adult CF-1 mice received i.c.v. NPS as 0.1 nmol injection with or without pre-treatment with 1 nmol α,β-methylene adenosine 5'-diphosphate (AOPCP), the selective inhibitor of ecto-5'-nucleotidase, to evaluate locomotor activity. In another set of experiments, mice received i.c.v. infusion of 0.1 nmol NPS to assay enzymatic activity in brain slices. The results demonstrated that the pre-treatment with AOPCP, which was inactive per se, prevented NPS-induced hyperlocomotion in mice. The dose of 0.1 nmol NPS was efficient to induce hyperlocomotion in animals during the observation period in the activity cage. Regarding enzymatic activity, i.c.v. NPS injection did not induce any significant alterations in ATP and AMP hydrolysis in striatum and hippocampus brain slices of mice. The present study shows that the hyperlocomotor effect of NPS depends on the ecto-5'-nucleotidase activity.

  14. Identification of Neuropeptide S Antagonists: Structure–Activity Relationship Studies, X-ray Crystallography, and in Vivo Evaluation

    PubMed Central

    2014-01-01

    Modulation of the neuropeptide S (NPS) system has been linked to a variety of CNS disorders such as panic disorder, anxiety, sleeping disorders, asthma, obesity, PTSD, and substance abuse. In this study, a series of diphenyltetrahydro-1H-oxazolo[3,4-α]pyrazin-3(5H)-ones were synthesized and evaluated for antagonist activity at the neuropeptide S receptor. The absolute configuration was determined by chiral resolution of the key synthetic intermediate, followed by analysis of one of the individual enantiomers by X-ray crystallography. The R isomer was then converted to a biologically active compound (34) that had a Ke of 36 nM. The most potent compound displayed enhanced aqueous solubility compared with the prototypical antagonist SHA-68 and demonstrated favorable pharmacokinetic properties for behavioral assessment. In vivo analysis in mice indicated a significant blockade of NPS induced locomotor activity at an ip dose of 50 mg/kg. This suggests that analogs having improved drug-like properties will facilitate more detailed studies of the neuropeptide S receptor system. PMID:24964000

  15. Leptin regulated calcium channels of neuropeptide Y and proopiomelanocortin neurons by activation of different signal pathways.

    PubMed

    Wang, J-H; Wang, F; Yang, M-J; Yu, D-F; Wu, W-N; Liu, J; Ma, L-Q; Cai, F; Chen, J-G

    2008-09-22

    The fat-derived hormone leptin regulates food intake and body weight in part by modulating the activity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC). To investigate the electrophysiological activity of these neurons and their responses to leptin, we recorded whole-cell calcium currents on NPY and POMC neurons in the ARC of rats, which we identified by morphologic features and immunocytochemical identification at the end of recording. Leptin decreased the peak amplitude of high voltage-activated calcium currents (I(HVA)) in the isolated neurons from ARC, which were subsequently shown to be immunoreactive for NPY. The inhibition was prevented by pretreatment with inhibitors of Janus kinase 2 (JAK2) and mitogen-activated protein kinases (MAPK). In contrast, leptin increased the amplitude of I(HVA) in POMC-containing neurons. The stimulations of I(HVA) were inhibited by blockers of JAK2 and phosphatidylino 3-kinase (PI3-k). Both of these effects were counteracted by the L-type calcium channel antagonist nifedipine, suggesting that L-type calcium channels were involved in the regulation induced by leptin. These data indicated that leptin exerted opposite effects on these two classes of neurons. Leptin directly inhibited I(HVA) in NPY neurons via leptin receptor (LEPR) -JAK2-MAPK pathways, whereas evoked I(HVA) in POMC neurons by LEPR-JAK2-PI3-k pathways. These neural pathways and intracellular signaling mechanisms may play key roles in regulating NPY and POMC neuron activity, anorectic action of leptin and, thereby, feeding.

  16. Crustacean neuropeptides.

    PubMed

    Christie, Andrew E; Stemmler, Elizabeth A; Dickinson, Patsy S

    2010-12-01

    Crustaceans have long been used for peptide research. For example, the process of neurosecretion was first formally demonstrated in the crustacean X-organ-sinus gland system, and the first fully characterized invertebrate neuropeptide was from a shrimp. Moreover, the crustacean stomatogastric and cardiac nervous systems have long served as models for understanding the general principles governing neural circuit functioning, including modulation by peptides. Here, we review the basic biology of crustacean neuropeptides, discuss methodologies currently driving their discovery, provide an overview of the known families, and summarize recent data on their control of physiology and behavior.

  17. Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide S receptor activity.

    PubMed

    Slattery, David A; Naik, Roshan R; Grund, Thomas; Yen, Yi-Chun; Sartori, Simone B; Füchsl, Andrea; Finger, Beate C; Elfving, Betina; Nordemann, Uwe; Guerrini, Remo; Calo, Girolamo; Wegener, Gregers; Mathé, Aleksander A; Singewald, Nicolas; Czibere, Ludwig; Landgraf, Rainer; Neumann, Inga D

    2015-03-18

    Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity-an effect that was prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice, respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date.

  18. Introduction: Invertebrate Neuropeptides XIII

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  19. Introduction: Invertebrate Neuropeptides XV

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  20. Introduction: Invertebrate Neuropeptides XIV

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  1. Introduction: Invertebrate Neuropeptides XVI

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  2. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  4. Neuropeptide Cycloprolylglycine Exhibits Neuroprotective Activity after Systemic Administration to Rats with Modeled Incomplete Global Ischemia and in In Vitro Modeled Glutamate Neurotoxicity.

    PubMed

    Povarnina, P Yu; Kolyasnikova, K N; Nikolaev, S V; Antipova, T A; Gudasheva, T A

    2016-03-01

    We studied cerebroprotective properties of neuropeptide cycloprolylglycine (1 mg/kg) administered intraperitoneally to rats with modeled incomplete global ischemia rats and neuroprotective properties for HT-22 cells under conditions of glutamate toxicity. It was shown that the neuropeptide administered during the postischemic period restored the neurological status of rats by preventing sensorimotor impairments in the limb-placing test and suppression of locomotor activity in the open field test. In in vitro experiments, cycloprolylglycine in concentrations of 10(-5)-10(-8) M exhibited pronounced dose-dependent neuroprotective activity. The results attest to high cerebro- and neuroprotective potential of endogenous peptide cycloprolylglycine.

  5. 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

  6. The Satiety Signaling Neuropeptide Perisulfakinin Inhibits the Activity of Central Neurons Promoting General Activity

    PubMed Central

    Wicher, Dieter; Derst, Christian; Gautier, Hélène; Lapied, Bruno; Heinemann, Stefan H.; Agricola, Hans-Jürgen

    2007-01-01

    The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK) in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK) in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR), we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM) neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC50=11pM) due to reduction of a pacemaker Ca2+ current through cAMP-inhibited pTRPγ channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca2+ concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH): PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPγ channel that is activated by AKH under conditions of food shortage. PMID:18946521

  7. Neuropeptide Substance-P-Conjugated Chitosan Nanofibers as an Active Modulator of Stem Cell Recruiting

    PubMed Central

    Kim, Min Sup; Park, Sang Jun; Cho, Wheemoon; Gu, Bon Kang; Kim, Chun-Ho

    2016-01-01

    The goal to successful wound healing is essentially to immobilize and recruit appropriate numbers of host stem or progenitor cells to the wound area. In this study, we developed a chitosan nanofiber-immobilized neuropeptide substance-P (SP), which mediates stem cell mobilization and migration, onto the surfaces of nanofibers using a peptide-coupling agent, and evaluated its biological effects on stem cells. The amount of immobilized SP on chitosan nanofibers was modulated over the range of 5.89 ± 3.27 to 75.29 ± 24.31 ng when reacted with 10 to 500 ng SP. In vitro migration assays showed that SP-incorporated nanofibers induced more rapid migration of human mesenchymal stem cells on nanofibers compared to pristine samples. Finally, the conjugated SP evoked a minimal foreign body reaction and recruited a larger number of CD29- and CD44-positive stem cells into nanofibers in a mouse subcutaneous pocket model. PMID:26751441

  8. 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.

  9. Identification, tissue distribution and orexigenic activity of neuropeptide F (NPF) in penaeid shrimp.

    PubMed

    Christie, Andrew E; Chapline, M Christine; Jackson, James M; Dowda, Jenilee K; Hartline, Niko; Malecha, Spencer R; Lenz, Petra H

    2011-04-15

    The neuropeptide Fs (NPFs) are an invertebrate subgroup of the FMRFamide-like peptides, and are proposed by some to be the homologs of vertebrate neuropeptide Y. Although there is some information about the identity, tissue distribution and function of NPFs in insects, essentially nothing is known about them in crustaceans. We have identified and characterized NPF-encoding transcripts from the penaeid shrimp Litopenaeus vannamei and Melicertus marginatus. Two transcripts were identified from each species. For each shrimp species, the two transcripts differed from one another by the presence or absence of an insert in the portion of the open reading frame that encodes the NPF peptide. The two NPF isoforms are identical in L. vannamei and M. marginatus, with their predicted structures being KPDPSQLANMAEALKYLQELDKYYSQVSRPRFamide and KPDPSQLANMAEALKYLQELDKYYSQVSRPSPRSAPGPASQIQALENTLKFLQLQELGKLYSLRARPRFamide. RT-PCR tissue profiling showed both transcripts are broadly distributed within the nervous system of each species. The transcript encoding the shorter NPF was detected in some, but not all, midgut samples. The transcript encoding the longer NPF was absent in the midgut of both species, and neither transcript was detected in their skeletal muscle. Juvenile L. vannamei fed on a diet supplemented with the shorter NPF exhibited a marked increase in food intake relative to control individuals that did not receive the supplement; the NPF-fed shrimp also showed a significant increase in growth relative to the control group. Our data suggest that NPF is present in both the nervous system and midgut of penaeid shrimp, functioning, at least in part, as a powerful orexigenic agent.

  10. Pheromone biosynthesis activating neuropeptide receptors (PBANRs) in moths: New developments regarding alternative splice variants and the potential for targeted disruption of PBANR in pest control

    Technology Transfer Automated Retrieval System (TEKTRAN)

    For most moths, the ability of conspecific males to locate receptive females is governed by the detection of a blend of semiochemicals known as sex pheromones. Sex pheromone components are de novo synthesized in the female pheromone gland in response to pheromone biosynthesis activating neuropeptid...

  11. 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

  12. 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

  13. Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity.

    PubMed

    Kuruba, Ramkumar; Hattiangady, Bharathi; Parihar, Vipan K; Shuai, Bing; Shetty, Ashok K

    2011-01-01

    Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.

  14. Possible role of serotonin and neuropeptide Y on the disruption of the reproductive axis activity by perfluorooctane sulfonate.

    PubMed

    López-Doval, S; Salgado, R; Fernández-Pérez, B; Lafuente, A

    2015-03-04

    Perfluorooctane sulfonate (PFOS) is an endocrine disruptor, whose exposure can induce several alterations on the reproductive axis activity in males during adulthood. This study was undertaken to evaluate the possible role of serotonin and neuropeptide Y (NPY) on the disruption of the hypothalamic-pituitary-testicular (HPT) axis induced by PFOS in adult male rats. For that, adult male rats were orally treated with 0.5; 1.0; 3.0 and 6.0mg of PFOS/kg/day for 28 days. After PFOS exposure, serotonin concentration increased in the anterior and mediobasal hypothalamus as well as in the median eminence. The metabolism of this amine (expressed as the ratio 5-hydroxyindolacetic acid (5-HIAA)/serotonin) was diminished except in the anterior hypothalamus, with the doses of 3.0 and 6.0mg/kg/day, being this dose 0.5mg/kg/day in the median eminence. In general terms, PFOS-treated rats presented a decrease of the hypothalamic concentration of the gonadotropin releasing hormone (GnRH) and NPY. A diminution of the serum levels of the luteinizing hormone (LH), testosterone and estradiol were also shown. These results suggest that both serotonin and NPY could be involved in the inhibition induced by PFOS on the reproductive axis activity in adult male rats.

  15. 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.

  16. Behavioral effects of neuropeptide Y in F344 rat substrains with a reduced dipeptidyl-peptidase IV activity.

    PubMed

    Karl, Tim; Hoffmann, Torsten; Pabst, Reinhard; von Hörsten, Stephan

    2003-07-01

    Dipeptidyl-peptidase IV (DPPIV/CD26) is involved in several physiological functions by cleavage of dipeptides with a Xaa-Pro or Xaa-Ala sequence of regulatory peptides such as neuropeptide Y (NPY). Cleavage of NPY by DPPIV results in NPY(3-36), which lacks affinity for the Y(1) but not for other NPY receptor subtypes. Among other effects, the NPY Y(1) receptor mediates anxiolytic-like effects of NPY. In previous studies with F344 rat substrains lacking endogenous DPPIV-like activity we found a reduced behavioral stress response, which might be due to a differential degradation of NPY. Here we tested this hypothesis and administered intracerebroventricularly two different doses of NPY (0.0, 0.2, 1.0 nmol) in mutant and wildtype-like F344 substrains. NPY dose-dependently stimulated food intake and feeding motivation, decreased motor activity in the plus maze and social interaction test, and exerted anxiolytic-like effects. More important for the present hypothesis, NPY administration was found to be more potent in the DPPIV-negative substrains in exerting anxiolytic-like effects (increased social interaction time in the social interaction test) and sedative-like effects (decreased motor activity in the elevated plus maze). These data demonstrate for the first time a differential potency of NPY in DPPIV-deficient rats and suggest a changed receptor-specificity of NPY, which may result from a differential degradation of NPY in this genetic model of DPPIV deficiency. Overall, these results provide direct evidence that NPY-mediated effects in the central nervous system are modulated by DPPIV-like enzymatic activity.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. Neuropeptide S facilitates mice olfactory function through activation of cognate receptor-expressing neurons in the olfactory cortex.

    PubMed

    Shao, Yu-Feng; Zhao, Peng; Dong, Chao-Yu; Li, Jing; Kong, Xiang-Pan; Wang, Hai-Liang; Dai, Li-Rong; Hou, Yi-Ping

    2013-01-01

    Neuropeptide S (NPS) is a newly identified neuromodulator located in the brainstem and regulates various biological functions by selectively activating the NPS receptors (NPSR). High level expression of NPSR mRNA in the olfactory cortex suggests that NPS-NPSR system might be involved in the regulation of olfactory function. The present study was undertaken to investigate the effects of intracerebroventricular (i.c.v.) injection of NPS or co-injection of NPSR antagonist on the olfactory behaviors, food intake, and c-Fos expression in olfactory cortex in mice. In addition, dual-immunofluorescence was employed to identify NPS-induced Fos immunereactive (-ir) neurons that also bear NPSR. NPS (0.1-1 nmol) i.c.v. injection significantly reduced the latency to find the buried food, and increased olfactory differentiation of different odors and the total sniffing time spent in olfactory habituation/dishabituation tasks. NPS facilitated olfactory ability most at the dose of 0.5 nmol, which could be blocked by co-injection of 40 nmol NPSR antagonist [D-Val(5)]NPS. NPS administration dose-dependently inhibited food intake in fasted mice. Ex-vivo c-Fos and NPSR immunohistochemistry in the olfactory cortex revealed that, as compared with vehicle-treated mice, NPS markedly enhanced c-Fos expression in the anterior olfactory nucleus (AON), piriform cortex (Pir), ventral tenia tecta (VTT), the anterior cortical amygdaloid nucleus (ACo) and lateral entorhinal cortex (LEnt). The percentage of Fos-ir neurons that also express NPSR were 88.5% and 98.1% in the AON and Pir, respectively. The present findings demonstrated that NPS, via selective activation of the neurons bearing NPSR in the olfactory cortex, facilitates olfactory function in mice.

  19. Neuropeptidases and the metabolic inactivation of insect neuropeptides.

    PubMed

    Isaac, R Elwyn; Bland, Nicholas D; Shirras, Alan D

    2009-05-15

    Neuropeptidases play a key role in regulating neuropeptide signalling activity in the central nervous system of animals. They are oligopeptidases that are generally found on the surface of neuronal cells facing the synaptic and peri-synaptic space and therefore are ideally placed for the metabolic inactivation of neuropeptide transmitters/modulators. This review discusses the structure of insect neuropeptides in relation to their susceptibility to hydrolysis by peptidases and the need for specialist enzymes to degrade many neuropeptides. It focuses on five neuropeptidase families (neprilysin, dipeptidyl-peptidase IV, angiotensin-converting enzyme, aminopeptidase and dipeptidyl aminopeptidase III) that have been implicated in the metabolic inactivation of neuropeptides in the central nervous system of insects. Experimental evidence for the involvement of these peptidases in neuropeptide metabolism is reviewed and their properties are compared to similar neuropeptide inactivating peptidases of the mammalian brain. We also discuss how the sequencing of insect genomes has led to the molecular identification of candidate neuropeptidase genes.

  20. Isolation, characterization and biological activity of a diuretic myokinin neuropeptide from the housefly, Musca domestica.

    PubMed

    Holman, G M; Nachman, R J; Coast, G M

    1999-01-01

    A competitive ELISA employing a polyclonal antiserum raised against leucokinin-I was used to isolate and purify a myokinin (muscakinin) from 1.05 kg of adult houseflies (Musca domestica). Following solid-phase purification, seven HPLC column steps were used to purify 4.8 nmol of leucokinin-immunoreactive material. Sequence analysis and mass spectrometry were consistent with the structure Asn-Thr-Val-Val-Leu-Gly Lys-Lys-Gln-Arg-Phe-His-Ser-Trp-Gly NH2. This peptide was synthesized and co-eluted with the natural peptide on three different HPLC columns. The activities of natural and synthetic muscakinin were identical, with both producing a 4-5 fold increase in fluid secretion by housefly Malpighian tubules at nanomolar concentrations. The presence of a pair of basic residues (Lys-Lys) suggested muscakinin might be processed further, with the peptide pGlu-Arg-Phe-His-Ser-Trp-Gly NH2 being produced by conversion of an N-terminal glutamine to pyroglutamic acid. However, this analog was 1000-fold less active than the intact peptide, comparable to the activity of AK-V which shares the same C-terminal pentapeptide sequence. The diuretic activity of muscakinin is more than double that of a previously identified CRF-related diuretic peptide (Musca-DP) from the housefly, and the two peptides act synergistically in stimulating fluid secretion. Muscakinin also increased the frequency and amplitude of contractions by housefly hindgut which might further contribute to the excretory process.

  1. The insect neuropeptide PTTH activates receptor tyrosine kinase torso to initiate metamorphosis.

    PubMed

    Rewitz, Kim F; Yamanaka, Naoki; Gilbert, Lawrence I; O'Connor, Michael B

    2009-12-04

    Holometabolous insects undergo complete metamorphosis to become sexually mature adults. Metamorphosis is initiated by brain-derived prothoracicotropic hormone (PTTH), which stimulates the production of the molting hormone ecdysone via an incompletely defined signaling pathway. Here we demonstrate that Torso, a receptor tyrosine kinase that regulates embryonic terminal cell fate in Drosophila, is the PTTH receptor. Trunk, the embryonic Torso ligand, is related to PTTH, and ectopic expression of PTTH in the embryo partially rescues trunk mutants. In larvae, torso is expressed specifically in the prothoracic gland (PG), and its loss phenocopies the removal of PTTH. The activation of Torso by PTTH stimulates extracellular signal-regulated kinase (ERK) phosphorylation, and the loss of ERK in the PG phenocopies the loss of PTTH and Torso. We conclude that PTTH initiates metamorphosis by activation of the Torso/ERK pathway.

  2. Suckling-induced activation of neuronal input to the dorsomedial nucleus of the hypothalamus: possible candidates for mediating the activation of DMH neuropeptide Y neurons during lactation.

    PubMed

    Chen, Peilin; Smith, M Susan

    2003-09-12

    Activation of the neuropeptide Y (NPY) neuronal system in the dorsomedial nucleus of the hypothalamus (DMH) during lactation in the rat is in part due to neural impulses arising from the suckling stimulus. However, the afferent neuronal input to the DMH that is activated during lactation and is responsible for activation of NPY neurons is currently unknown. Previously, using cFos as a marker for neuronal activation, we identified several brain areas in the lactating animals that were activated by the suckling stimulus. Thus, the objective of the present study was to determine if any of these suckling activated areas project directly to the DMH. The retrograde tracer, fluorogold (FG), was injected into the DMH on day 4 postpartum. FG-injected lactating rats were then deprived of their eight-pup litters on day 9 postpartum, and 48 h later, the pups were returned to the females to reinitiate the suckling stimulus for 90 min and induce cFos expression. The animals were then perfused and the brains were subjected to double-label immunohistochemistry to visualize both FG- and cFos-positive cells. Substantial numbers of FG/cFos double-labeled cells were found in forebrain regions, including the preoptic area, lateral septal nucleus, ventral subiculum, and supramammillary nucleus, and in brainstem regions, including the lateral parabrachial nucleus, periaqeductal gray, and ventrolateral medulla. In conclusion, these areas are potentially important candidates for mediating the activation of the NPY neuronal system in the DMH during lactation.

  3. The D. melanogaster capa-1 neuropeptide activates renal NF-kB signaling.

    PubMed

    Terhzaz, Selim; Overend, Gayle; Sebastian, Sujith; Dow, Julian A T; Davies, Shireen-A

    2014-03-01

    The capa peptide family exists in a very wide range of insects including species of medical, veterinary and agricultural importance. Capa peptides act via a cognate G-protein coupled receptor (capaR) and have a diuretic action on the Malpighian tubules of Dipteran and Lepidopteran species. Capa signaling is critical for fluid homeostasis and has been associated with desiccation tolerance in the fly, Drosophila melanogaster. The mode of capa signaling is highly complex, affecting calcium, nitric oxide and cyclic GMP pathways. Such complex physiological regulation by cell signaling pathways may occur ultimately for optimal organismal stress tolerance to multiple stressors. Here we show that D. melanogaster capa-1 (Drome-capa-1) acts via the Nuclear Factor kappa B (NF-kB) stress signaling network. Human PCR gene arrays of capaR-transfected Human Embryonic Kidney (HEK) 293 cells showed that Drome-capa-1 increases expression of NF-kB, NF-kB regulated genes including IL8, TNF and PTGS2, and NF-kB pathway-associated transcription factors i.e. EGR1, FOS, cJUN. Furthermore, desiccated HEK293 cells show increased EGR1, EGR3 and PTGS2 - but not IL8, expression. CapaR-transfected NF-kB reporter cells showed that Drome-capa-1 increased NF-kB promoter activity via increased calcium. In Malpighian tubules, both Drome-capa-1 stimulation and desiccation result in increased gene expression of the D. melanogaster NF-kB orthologue, Relish; as well as EGR-like stripe and klumpfuss. Drome-capa-1 also induces Relish translocation in tubule principal cells. Targeted knockdown of Relish in only tubule principal cells reduces desiccation stress tolerance of adult flies. Together, these data suggest that Drome-capa-1 acts in desiccation stress tolerance, by activating NF-kB signaling.

  4. Neuropeptide Y and Epilepsy

    PubMed Central

    Colmers, William F.; El Bahh, Bouchaïb

    2003-01-01

    It is a central tenet of the epilepsy field that seizures result from the imbalance of excitation over inhibition 1. The bulk of excitation is mediated by the neurotransmitter glutamate, whereas inhibition results mainly from the actions of γ-aminobutyric acid (GABA). In the neocortex and hippocampus, the intrinsic sources of GABA are the interneurons, which lately have come under intense scrutiny. It has become clear that a large number of distinct types of interneurons can be differentiated in part by the array of neuropeptides they coexpress (cf. 2). Evidence is emerging that the neuropeptide complement of interneurons plays important roles in the way that interneurons regulate excitability. Here we discuss what is known about the relation of one well-characterized neuropeptide, neuropeptide Y (NPY), and epilepsy in experimental animals and humans, and suggest possible roles for the receptors as targets for the control of excessive excitation in epilepsy. PMID:15309085

  5. Neuropeptides as synaptic transmitters.

    PubMed

    Salio, Chiara; Lossi, Laura; Ferrini, Francesco; Merighi, Adalberto

    2006-11-01

    Neuropeptides are small protein molecules (composed of 3-100 amino-acid residues) that have been localized to discrete cell populations of central and peripheral neurons. In most instances, they coexist with low-molecular-weight neurotransmitters within the same neurons. At the subcellular level, neuropeptides are selectively stored, singularly or more frequently in combinations, within large granular vesicles. Release occurs through mechanisms different from classical calcium-dependent exocytosis at the synaptic cleft, and thus they account for slow synaptic and/or non-synaptic communication in neurons. Neuropeptide co-storage and coexistence can be observed throughout the central nervous system and are responsible for a series of functional interactions that occur at both pre- and post-synaptic levels. Thus, the subcellular site(s) of storage and sorting mechanisms into different neuronal compartments are crucial to the mode of release and the function of neuropeptides as neuronal messengers.

  6. Neuropeptide Y Induces Hematopoietic Stem/Progenitor Cell Mobilization by Regulating Matrix Metalloproteinase-9 Activity Through Y1 Receptor in Osteoblasts.

    PubMed

    Park, Min Hee; Lee, Jong Kil; Kim, Namoh; Min, Woo-Kie; Lee, Jeong Eun; Kim, Kyoung-Tae; Akiyama, Haruhiko; Herzog, Herbert; Schuchman, Edward H; Jin, Hee Kyung; Bae, Jae-Sung

    2016-08-01

    Hematopoietic stem/progenitor cell (HSPC) mobilization is an essential homeostatic process regulated by the interaction of cellular and molecular components in bone marrow niches. It has been shown by others that neurotransmitters released from the sympathetic nervous system regulate HSPC egress from bone marrow to peripheral blood. In this study, we investigate the functional role of neuropeptide Y (NPY) on this process. NPY deficient mice had significantly impaired HSPC mobilization due to increased expression of HSPC maintenance factors by reduction of matrix metalloproteinase-9 (MMP-9) activity in bone marrow. Pharmacological or endogenous elevation of NPY led to decrease of HSPC maintenance factors expression by activating MMP-9 in osteoblasts, resulting in HSPC mobilization. Mice in which the Y1 receptor was deleted in osteoblasts did not exhibit HSPC mobilization by NPY. Furthermore, NPY treatment in ovariectomized mice caused reduction of bone loss due to HSPC mobilization. These results suggest a new role of NPY on HSPC mobilization, as well as the potential therapeutic application of this neuropeptide for stem cell-based therapy. Stem Cells 2016;34:2145-2156.

  7. Neuropeptides and obesity.

    PubMed

    Beck, B

    2000-10-01

    This review focuses on the expression, content, and release of neuropeptides and on their role in the development of obesity in animal models with single-gene mutations. The balance between neuropeptides that contribute to the control of feeding behavior is profoundly and variously altered in these models, supporting the concept of the existence of several types of obesity. The hypothalamic neuropeptide Y (NPY) and the pro-opiomelanocortin (POMC) systems are the networks most studied in relation to energy intake. Both receive information about the nutritional status and the level of energy storage through insulin and leptin signaling mediated by specific receptors located on POMC and NPY neurons present predominantly in the arcuate nucleus (ARC). When leptin signaling is defective, through a defect in either the receptor (Zucker fa/fa rat, cp/cp rat, and db/db mouse) or in the peptide itself (ob/ob mouse), the NPY system is upregulated as shown by mRNA overexpression and increased peptide release, whereas the content and/or release of some inhibitory peptides (neurotensin, cholecystokinin) are diminished. For the POMC system, there is a complex interaction between the tonic inhibition of food intake exerted by alpha-melanocyte-stimulating hormone (alpha-MSH) and the Agouti-related protein at the level of the type 4 melanocortin receptor. The latter peptide is coexpressed with NPY in the ARC. Corticotropin-releasing factor (CRF) is the link between food intake and environmental factors. It not only inhibits food intake and prevents weight gain, likely through hypothalamic effects, but also activates the hypothalamo-pituitary axis and therefore contributes to energy storage in adipose tissue. The factors that prod the CRF system toward the hypothalamic or hypothalamo-pituitary axis system remain to be more clearly defined (comodulators, connections between limbic system and ARC, cellular location, and type of receptors, etc. ). The pathways used by all of these

  8. Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake

    PubMed Central

    Wardman, Jonathan H.; Gomes, Ivone; Bobeck, Erin N.; Stockert, Jennifer A.; Kapoor, Abhijeet; Bisignano, Paola; Gupta, Achla; Mezei, Mihaly; Kumar, Sanjai; Filizola, Marta; Devi, Lakshmi A.

    2016-01-01

    Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide–binding protein (G protein)– coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)–mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders. PMID:27245612

  9. Ghrelin, neuropeptide Y, and other feeding-regulatory peptides active in the hippocampus: role in learning and memory.

    PubMed

    Beck, Bernard; Pourié, Grégory

    2013-08-01

    The hippocampus is a brain region of primary importance for neurogenesis, which occurs during early developmental states as well as during adulthood. Increases in neuronal proliferation and in neuronal death with age have been associated with drastic changes in memory and learning. Numerous neurotransmitters are involved in these processes, and some neuropeptides that mediate neurogenesis also modulate feeding behavior. Concomitantly, feeding peptides, which act primarily in the hypothalamus, are also present in the hippocampus. This review aims to ascertain the role of several important feeding peptides in cognitive functions, either through their local synthesis in the hippocampus or through their actions via specific receptors in the hippocampus. A link between neurogenesis and the orexigenic or anorexigenic properties of feeding peptides is discussed.

  10. Primary structure of a novel neuropeptide isolated from the corpora cardiaca of periodical cicadas having adipokinetic and hypertrehalosemic activities.

    PubMed

    Raina, A; Pannell, L; Kochansky, J; Jaffe, H

    1995-09-01

    A new neuropeptide hormone was isolated from the corpora cardiaca of the periodical cicadas, Magicicada species. Primary structure of the peptide as determined by a combination of automated Edman degradation after enzymatic deblocking with pyroglutamate aminopeptidase and mass spectrometry is: pGlu-Val-Asn-Phe-Ser-Pro-Ser-Trp-Gly-Asn-NH2. Synthetic peptide assayed in the green stink bug Nezara viridula caused a 112% increase in hemolymph lipids at a dose of 0.625 pmol, and a 67% increase in hemolymph carbohydrates at a dose of 2.5 pmol. Based on these results we designate this peptide, a first from order Homoptera, as Magicicada species-adipokinetic hormone (Mcsp-AKH).

  11. 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.

  12. Neuropeptides in cardiovascular control.

    PubMed

    Ganong, W F

    1984-12-01

    Neuropeptides can affect cardiovascular function in various ways. They can serve as cotransmitters in the autonomic nervous system; for example, vasoactive intestinal peptide (VIP) is released with acetylcholine and neuropeptide Y with norepinephrine from postganglionic neurons. Substance P and, presumably, other peptides can can affect cardiovascular function when released near blood vessels by antidromically conducted impulses in branches of stimulated sensory neurons. In the central nervous system, many different neuropeptides appear to function as transmitters or contransmittes in the neural pathways that regulate the cardiovascular system. In addition neuropeptides such as vasopressin and angiotensin II also circulate as hormones that are involved in cardiovascular control. Large doses of exogenous vasopressin are required to increase blood pressure in normal animals because the increase in total peripheral resistance produced by the hormones is accompanied by a decrease in cardiac output. However, studies with synthetic peptides that selectively antagonize the vasopressor action of vasopressin indicate that circulating vasopressin is important in maintaining blood pressure when animals are hypovolemic due to dehydration, haemorrhage or adrenocortical insufficiency. VIP dilates blood vessels and stimulates renin secretion by a direct action on the juxtaglomerular cells. Renin secretion is stimulated when the concentration of VIP in plasma exceeds 75 pmol/litre, and higher values are seen in a number of conditions. Neostigmine, a drug which increases the secretion of endogenous VIP, also increases renin secretion, and this increase is not blocked by renal denervation or propranolol. Thus, VIP may be a physiologically significant renin stimulating hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. The anti-inflammatory effect of neuropeptide Y (NPY) in rats is dependent on dipeptidyl peptidase 4 (DP4) activity and age.

    PubMed

    Dimitrijević, Mirjana; Stanojević, Stanislava; Mitić, Katarina; Kustrimović, Natasa; Vujić, Vesna; Miletić, Tatjana; Kovacević-Jovanović, Vesna

    2008-12-01

    Neuropeptide Y (NPY)-induced modulation of the immune and inflammatory responses is regulated by tissue-specific expression of different receptor subtypes (Y1-Y6) and the activity of the enzyme dipeptidyl peptidase 4 (DP4, CD26) which terminates the action of NPY on Y1 receptor subtype. The present study investigated the age-dependent effect of NPY on inflammatory paw edema and macrophage nitric oxide production in Dark Agouti rats exhibiting a high-plasma DP4 activity, as acknowledged earlier. The results showed that NPY suppressed paw edema in adult and aged, but not in young rats. Furthermore, plasma DP4 activity decreased, while macrophage DP4 activity, as well as macrophage CD26 expression increased with aging. The use of NPY-related peptides and Y receptor-specific antagonists revealed that anti-inflammatory effect of NPY is mediated via Y1 and Y5 receptors. NPY-induced suppression of paw edema in young rats following inhibition of DP4 additionally emphasized the role for Y1 receptor in the anti-inflammatory action of NPY. In contrast to the in vivo situation, NPY stimulated macrophage nitric oxide production in vitro only in young rats, and this effect was mediated via Y1 and Y2 receptors. It can be concluded that age-dependant modulation of inflammatory reactions by NPY is determined by plasma, but not macrophage DP4 activity at different ages.

  14. Hypothalamic Paraventricular and Arcuate Nuclei Contribute to Elevated Sympathetic Nerve Activity in Pregnant Rats: Roles of Neuropeptide Y and α-Melanocyte-Stimulating Hormone.

    PubMed

    Shi, Zhigang; Cassaglia, Priscila A; Gotthardt, Laura C; Brooks, Virginia L

    2015-12-01

    Pregnancy increases sympathetic nerve activity (SNA), but the mechanisms are unknown. Here, we investigated the contributions of the hypothalamic paraventricular and arcuate nuclei in α-chloralose-anesthetized pregnant and nonpregnant rats. Baseline arterial pressure (AP) was lower, and heart rate (HR), lumbar sympathetic activity, and splanchnic SNA were higher in pregnant rats compared with nonpregnant rats. Inhibition of the paraventricular nucleus via bilateral muscimol nanoinjections decreased AP and HR more in pregnant rats than in nonpregnant rats and decreased lumbar SNA only in pregnant rats. Similarly, after arcuate muscimol nanoninjections, the decreases in AP, HR, and lumbar, renal, and splanchnic sympathetic nerve activities were greater in pregnant rats than in nonpregnant rats. Major arcuate neuronal groups that project to the paraventricular nucleus express inhibitory neuropeptide Y (NPY) and excitatory α-melanocyte-stimulating hormone. Inhibition of paraventricular melanocortin 3/4 receptors with SHU9119 also decreased AP, HR, and lumbar SNA in pregnant rats but not in nonpregnant rats. Conversely, paraventricular nucleus NPY expression was reduced in pregnant animals, and although blockade of paraventricular NPY Y1 receptors increased AP, HR, and lumbar sympathetic activity in nonpregnant rats, it had no effects in pregnant rats. Yet, the sympathoinhibitory, depressor, and bradycardic effects of paraventricular NPY nanoinjections were similar between groups. In conclusion, the paraventricular and arcuate nuclei contribute to increased basal SNA during pregnancy, likely due in part to decreased tonic NPY inhibition and increased tonic α-melanocyte-stimulating hormone excitation of presympathetic neurons in the paraventricular nucleus.

  15. Role of neuropeptides in cardiomyopathies.

    PubMed

    Dvorakova, Magdalena Chottova; Kruzliak, Peter; Rabkin, Simon W

    2014-11-01

    The role of neuropeptides in cardiomyopathy-associated heart failure has been garnering more attention. Several neuropeptides--Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP) and their receptors have been studied in the various types of cardiomyopathies. The data indicate associations with the strength of the association varying depending on the kind of neuropeptide and the nature of the cardiomyopathy--diabetic, ischemic, inflammatory, stress-induced or restrictive cardiomyopathy. Several neuropeptides appear to alter regulation of genes involved in heart failure. Demonstration of an association is an essential first step in proving causality or establishing a role for a factor in a disease. Understanding the complexity of neuropeptide function should be helpful in establishing new or optimal therapeutic strategies for the treatment of heart failure in cardiomyopathies.

  16. Protein kinase C activity blocks neuropeptide Y-mediated inhibition of glutamate release and contributes to excitability of the hippocampus in status epilepticus.

    PubMed

    Silva, Ana P; Lourenço, Joana; Xapelli, Sara; Ferreira, Raquel; Kristiansen, Heidi; Woldbye, David P D; Oliveira, Catarina R; Malva, João O

    2007-03-01

    The unbalanced excitatory/inhibitory neurotransmitter function in the neuronal network afflicted by seizures is the main biochemical and biophysical hallmark of epilepsy. The aim of this work was to identify changes in the signaling mechanisms associated with neuropeptide Y (NPY)-mediated inhibition of glutamate release that may contribute to hyperexcitability. Using isolated rat hippocampal nerve terminals, we showed that the KCl-evoked glutamate release is inhibited by NPY Y2 receptor activation and is potentiated by the stimulation of protein kinase C (PKC). Moreover, we observed that immediately after status epilepticus (6 h postinjection with kainate, 10 mg/kg), the functional inhibition of glutamate release by NPY Y2 receptors was transiently blocked concomitantly with PKC hyperactivation. The pharmacological blockade of seizure-activated PKC revealed again the Y2 receptor-mediated inhibition of glutamate release. The functional activity of PKC immediately after status epilepticus was assessed by evaluating phosphorylation of the AMPA receptor subunit GluR1 (Ser-831), a substrate for PKC. Moreover, NPY-stimulated [35S]GTPgammaS autoradiographic binding studies indicated that the common target for Y2 receptor and PKC on the inhibition/potentiation of glutamate release was located downstream of the Y2 receptor, or its interacting G-protein, and involves voltage-gated calcium channels.

  17. Signaling by Drosophila capa neuropeptides.

    PubMed

    Davies, Shireen-A; Cabrero, Pablo; Povsic, Manca; Johnston, Natalie R; Terhzaz, Selim; Dow, Julian A T

    2013-07-01

    The capa peptide family, originally identified in the tobacco hawk moth, Manduca sexta, is now known to be present in many insect families, with increasing publications on capa neuropeptides each year. The physiological actions of capa peptides vary depending on the insect species but capa peptides have key myomodulatory and osmoregulatory functions, depending on insect lifestyle, and life stage. Capa peptide signaling is thus critical for fluid homeostasis and survival, making study of this neuropeptide family attractive for novel routes for insect control. In Dipteran species, including the genetically tractable Drosophila melanogaster, capa peptide action is diuretic; via elevation of nitric oxide, cGMP and calcium in the principal cells of the Malpighian tubules. The identification of the capa receptor (capaR) in several insect species has shown this to be a canonical GPCR. In D. melanogaster, ligand-activated capaR activity occurs in a dose-dependent manner between 10(-6) and 10(-12)M. Lower concentrations of capa peptide do not activate capaR, either in adult or larval Malpighian tubules. Use of transgenic flies in which capaR is knocked-down in only Malpighian tubule principal cells demonstrates that capaR modulates tubule fluid secretion rates and in doing so, sets the organismal response to desiccation. Thus, capa regulates a desiccation-responsive pathway in D. melanogaster, linking its role in osmoregulation and fluid homeostasis to environmental response and survival. The conservation of capa action between some Dipteran species suggests that capa's role in desiccation tolerance may not be confined to D. melanogaster.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  19. Neuromodulatory function of neuropeptides in the normal CNS.

    PubMed

    Merighi, Adalberto; Salio, Chiara; Ferrini, Francesco; Lossi, Laura

    2011-12-01

    Neuropeptides are small protein molecules produced and released by discrete cell populations of the central and peripheral nervous systems through the regulated secretory pathway and acting on neural substrates. Inside the nerve cells, neuropeptides are selectively stored within large granular vesicles (LGVs), and commonly coexist in neurons with low-molecular-weight neurotransmitters (acetylcholine, amino acids, and catecholamines). Storage in LGVs is responsible for a relatively slow response to secretion that requires enhanced or repeated stimulation. Coexistence (i.e. the concurrent presence of a neuropeptide with other messenger molecules in individual neurons), and co-storage (i.e. the localization of two or more neuropeptides within individual LGVs in neurons) give rise to a complicated series of pre- and post-synaptic functional interactions with low-molecular-weight neurotransmitters. The typically slow response and action of neuropeptides as compared to fast-neurotransmitters such as excitatory/inhibitory amino acids and catecholamines is also due to the type of receptors that trigger neuropeptide actions onto target cells. Almost all neuropeptides act on G-protein coupled receptors that, upon ligand binding, activate an intracellular cascade of molecular enzymatic events, eventually leading to cellular responses. The latter occur in a time span (seconds or more) considerably longer (milliseconds) than that of low-molecular-weight fast-neurotransmitters, directly operating through ion channel receptors. As reviewed here, combined immunocytochemical visualization of neuropeptides and their receptors at the ultrastructural level and electrophysiological studies, have been fundamental to better unravel the role of neuropeptides in neuron-to-neuron communication.

  20. Changes in vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide and neuropeptide Y-ergic structures of the enteric nervous system in the carcinoma of the human large intestine.

    PubMed

    Godlewski, Janusz; Łakomy, Ireneusz Mirosław

    2010-01-01

    This investigation was aimed at immunohistochemical analysis of potential changes in the enteric nervous system caused by cancer of the large intestine. In this purpose, neurons and nerve fibers of intestinal plexuses containing neuropeptides: vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and neuropeptide Y (NPY), in pathologically changed part of the large intestine were microscpically observed and compared. Samples were taken from patients operated due to cancer of the sigmoid colon and rectum. The number of neurons and density of nerve fibres containing neuropeptides found in sections with cancer tissues were compared to those observed in sections from the uninvolved intestinal wall. Changes relating to reductions in the number of NPY-ergic neurons and density of nerve fibres in submucous and myenteric plexuses in the sections with cancer tissues (pathological sections) were statistically significant. A statistically similar presence of VIP-ergic and PACAP-ergic neurons in the submucosal and myenteric plexuses was observed in both the pathological and control sections. On the other hand, in the pathological sections, VIP-ergic nerve fibres in the myenteric plexuses and PACAP-ergic nerve fibres in the submucosal and myenteric plexuses were found to be less dense. Analysis revealed changes in pathologically affected part of the large intestine may caused disruption of proper intestinal function. Observed changes in the neural elements which are responsible for relaxation of the intestine may suggest dysfunction in the innervation of this part of the colon.

  1. Capsaicin-Sensitive Sensory Nerves Mediate the Cellular and Microvascular Effects of H2S via TRPA1 Receptor Activation and Neuropeptide Release.

    PubMed

    Hajna, Zsófia; Sághy, Éva; Payrits, Maja; Aubdool, Aisah A; Szőke, Éva; Pozsgai, Gábor; Bátai, István Z; Nagy, Lívia; Filotás, Dániel; Helyes, Zsuzsanna; Brain, Susan D; Pintér, Erika

    2016-10-01

    It is supposed that TRPA1 receptor can be activated by hydrogen sulphide (H2S). Here, we have investigated the role of TRPA1 receptor in H2S-induced [Ca(2+)]i increase in trigeminal ganglia (TRG) neurons, and the involvement of capsaicin-sensitive sensory nerves in H2S-evoked cutaneous vasodilatation. [Ca(2+)]i was measured with ratiometric technique on TRG neurons of TRPA1(+/+) and TRPA1(-/-) mice after NaHS, Na2S, allylisothiocyanate (AITC) or KCl treatment. Microcirculatory changes in the ear were detected by laser Doppler imaging in response to topical NaHS, AITC, NaOH, NaSO3 or NaCl. Mice were either treated with resiniferatoxin (RTX), or CGRP antagonist BIBN4096, or NK1 receptor antagonist CP99994, or K(+) ATP channel blocker glibenclamide. Alpha-CGRP(-/-) and NK1 (-/-) mice were also investigated. NaHS and Na2S increased [Ca(2+)]i in TRG neurons derived from TRPA(+/+) but not from TRPA1(-/-) mice. NaHS increased cutaneous blood flow, while NaOH, NaSO3 and NaCl did not cause significant changes. NaHS-induced vasodilatation was reduced in RTX-treated animals, as well as by pre-treatment with BIBN4096 or CP99994 alone or in combination. NaHS-induced vasodilatation was significantly smaller in alpha-CGRP(-/-) or NK1 (-/-) mice compared to wild-types. H2S activates capsaicin-sensitive sensory nerves through TRPA1 receptors and the resultant vasodilatation is mediated by the release of vasoactive sensory neuropeptides CGRP and substance P.

  2. Insect Neuropeptide Bursicon Homodimers Induce Innate Immune and Stress Genes during Molting by Activating the NF-κB Transcription Factor Relish

    PubMed Central

    Li, Sheng; Gilbert, Lawrence I.; Stanley, David; Song, Qisheng

    2012-01-01

    Background Bursicon is a heterodimer neuropeptide composed of two cystine knot proteins, bursicon α (burs α) and bursicon β (burs β), that elicits cuticle tanning (melanization and sclerotization) through the Drosophila leucine-rich repeats-containing G protein-coupled receptor 2 (DLGR2). Recent studies show that both bursicon subunits also form homodimers. However, biological functions of the homodimers have remained unknown until now. Methodology/Principal Findings In this report, we show in Drosophila melanogaster that both bursicon homodimers induced expression of genes encoding antimicrobial peptides (AMPs) in neck-ligated adults following recombinant homodimer injection and in larvae fat body after incubation with recombinant homodimers. These AMP genes were also up-regulated in 24 h old unligated flies (when the endogenous bursicon level is low) after injection of recombinant homodimers. Up-regulation of AMP genes by the homodimers was accompanied by reduced bacterial populations in fly assay preparations. The induction of AMP expression is via activation of the NF-κB transcription factor Relish in the immune deficiency (Imd) pathway. The influence of bursicon homodimers on immune function does not appear to act through the heterodimer receptor DLGR2, i.e. novel receptors exist for the homodimers. Conclusions/Significance Our results reveal a mechanism of CNS-regulated prophylactic innate immunity during molting via induced expression of genes encoding AMPs and genes of the Turandot family. Turandot genes are also up-regulated by a broader range of extreme insults. From these data we infer that CNS-generated bursicon homodimers mediate innate prophylactic immunity to both stress and infection during the vulnerable molting cycle. PMID:22470576

  3. 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.

  4. Neuropeptide GPCRs in C. elegans

    PubMed Central

    Frooninckx, Lotte; Van Rompay, Liesbeth; Temmerman, Liesbet; Van Sinay, Elien; Beets, Isabel; Janssen, Tom; Husson, Steven J.; Schoofs, Liliane

    2012-01-01

    Like most organisms, the nematode Caenorhabditis elegans relies heavily on neuropeptidergic signaling. This tiny animal represents a suitable model system to study neuropeptidergic signaling networks with single cell resolution due to the availability of powerful molecular and genetic tools. The availability of the worm’s complete genome sequence allows researchers to browse through it, uncovering putative neuropeptides and their cognate G protein-coupled receptors (GPCRs). Many predictions have been made about the number of C. elegans neuropeptide GPCRs. In this review, we report the state of the art of both verified as well as predicted C. elegans neuropeptide GPCRs. The predicted neuropeptide GPCRs are incorporated into the receptor classification system based on their resemblance to orthologous GPCRs in insects and vertebrates. Appointing the natural ligand(s) to each predicted neuropeptide GPCR (receptor deorphanization) is a crucial step during characterization. The development of deorphanization strategies resulted in a significant increase in the knowledge of neuropeptidergic signaling in C. elegans. Complementary localization and functional studies demonstrate that neuropeptides and their GPCRs represent a rich potential source of behavioral variability in C. elegans. Here, we review all neuropeptidergic signaling pathways that so far have been functionally characterized in C. elegans. PMID:23267347

  5. Intracellular Na+, K+ and Cl- activities in Acheta domesticus Malpighian tubules and the response to a diuretic kinin neuropeptide.

    PubMed

    Coast, Geoffrey M

    2012-08-15

    The mechanism of primary urine production and the activity of a diuretic kinin, Achdo-KII, were investigated in malpighian tubules of Acheta domesticus by measuring intracellular Na(+), K(+) and Cl(-) activities, basolateral membrane voltage (V(b)), fluid secretion and transepithelial ion transport. Calculated electrochemical gradients for K(+) and Cl(-) across the basolateral membrane show they are actively transported into principal cells, and basolateral Ba(2+)-sensitive K(+) channels do not contribute to net transepithelial K(+) transport and fluid secretion. A basolateral Cl(-) conductance was revealed after the blockade of K(+) channels with Ba(2+), and a current carried by the passive outward movement of Cl(-) accounts for the hyperpolarization of V(b) in response to Ba(2+). Ion uptake via Na(+)/K(+)/2Cl(-) cotransport, driven by the inwardly directed Na(+) electrochemical gradient, is thermodynamically feasible, and is consistent with the actions of bumetanide, which reduces fluid secretion and both Na(+) and K(+) transport. The Na(+) gradient is maintained by its extrusion across the apical membrane and by a basolateral ouabain-sensitive Na(+)/K(+)-ATPase. Achdo-KII has no significant effect on the intracellular ion activities or V(b). Electrochemical gradients across the apical membrane were estimated from previously published values for the levels of Na(+), K(+) and Cl(-) in the secreted fluid. The electrochemical gradient for Cl(-) favours passive movement into the lumen, but falls towards zero after stimulation by Achdo-KII. This coincides with a twofold increase in Cl(-) transport, which is attributed to the opening of an apical Cl(-) conductance, which depolarises the apical membrane voltage.

  6. 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.

  7. Neuropeptide Y: A stressful review

    PubMed Central

    Reichmann, Florian; Holzer, Peter

    2016-01-01

    Stress is defined as an adverse condition that disturbs the homeostasis of the body and activates adaptation responses. Among the many pathways and mediators involved, neuropeptide Y (NPY) stands out due to its unique stress-relieving, anxiolytic and neuroprotective properties. Stress exposure alters the biosynthesis of NPY in distinct brain regions, the magnitude and direction of this effect varying with the duration and type of stress. NPY is expressed in particular neurons of the brainstem, hypothalamus and limbic system, which explains why NPY has an impact on stress-related changes in emotional-affective behaviour and feeding as well as on stress coping. The biological actions of NPY in mammals are mediated by the Y1, Y2, Y4 and Y5 receptor, Y1 receptor stimulation being anxiolytic whereas Y2 receptor activation is anxiogenic. Emerging evidence attributes NPY a role in stress resilience, the ability to cope with stress. Thus there is a negative correlation between stress-induced behavioural disruption and cerebral NPY expression in animal models of post-traumatic stress disorder. Exogenous NPY prevents the negative consequences of stress, and polymorphisms of the NPY gene are predictive of impaired stress processing and increased risk of neuropsychiatric diseases. Stress is also a factor contributing to, and resulting from, neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease, in which NPY appears to play an important neuroprotective role. This review summarizes the evidence for an implication of NPY in stress-related and neurodegenerative pathologies and addresses the cerebral NPY system as a therapeutic target. PMID:26441327

  8. Costorage and coexistence of neuropeptides in the mammalian CNS.

    PubMed

    Merighi, A

    2002-02-01

    The term neuropeptides commonly refers to a relatively large number of biologically active molecules that have been localized to discrete cell populations of central and peripheral neurons. I review here the most important histological and functional findings on neuropeptide distribution in the central nervous system (CNS), in relation to their role in the exchange of information between the nerve cells. Under this perspective, peptide costorage (presence of two or more peptides within the same subcellular compartment) and coexistence (concurrent presence of peptides and other messenger molecules within single nerve cells) are discussed in detail. In particular, the subcellular site(s) of storage and sorting mechanisms within neurons are thoroughly examined in the view of the mode of release and action of neuropeptides as neuronal messengers. Moreover, the relationship of neuropeptides and other molecules implicated in neural transmission is discussed in functional terms, also referring to the interactions with novel unconventional transmitters and trophic factors. Finally, a brief account is given on the presence of neuropeptides in glial cells.

  9. Neuropeptides and the microbiota-gut-brain axis.

    PubMed

    Holzer, Peter; Farzi, Aitak

    2014-01-01

    Neuropeptides are important mediators both within the nervous system and between neurons and other cell types. Neuropeptides such as substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. Current efforts in elucidating the implication of neuropeptides in the microbiota-gut-brain axis address four information carriers from the gut to the brain (vagal and spinal afferent neurons; immune mediators such as cytokines; gut hormones; gut microbiota-derived signalling molecules) and four information carriers from the central nervous system to the gut (sympathetic efferent neurons; parasympathetic efferent neurons; neuroendocrine factors involving the adrenal medulla; neuroendocrine factors involving the adrenal cortex). Apart from operating as neurotransmitters, many biologically active peptides also function as gut hormones. Given that neuropeptides and gut hormones target the same cell membrane receptors (typically G protein-coupled receptors), the two messenger roles often converge in the same or similar biological implications. This is exemplified by NPY and peptide YY (PYY), two members of the PP-fold peptide family. While PYY is almost exclusively expressed by enteroendocrine cells, NPY is found at all levels of the gut-brain and brain-gut axis. The function of PYY-releasing enteroendocrine cells is directly influenced by short chain fatty acids generated by the intestinal microbiota from indigestible fibre, while NPY may control the impact of the gut microbiota on inflammatory processes, pain, brain function and behaviour. Although the impact of neuropeptides on the interaction between the gut microbiota and brain awaits to be analysed, biologically active peptides

  10. Cyclic analogs of galanin and neuropeptide Y by hydrocarbon stapling.

    PubMed

    Green, Brad R; Klein, Brian D; Lee, Hee-Kyoung; Smith, Misty D; Steve White, H; Bulaj, Grzegorz

    2013-01-01

    Hydrocarbon stapling is an effective strategy to stabilize the helical conformation of bioactive peptides. Here we describe application of stapling to anticonvulsant neuropeptides, galanin (GAL) and neuropeptide Y (NPY), that are implicated in modulating seizures in the brain. Dicarba bridges were rationally introduced into minimized analogs of GAL and NPY resulting in increased α-helical content, in vitro metabolic stability and n-octanol/water partitioning coefficient (logD). The stapled analogs retained agonist activities towards their respective receptors and suppressed seizures in a mouse model of epilepsy.

  11. Physiology of invertebrate oxytocin and vasopressin neuropeptides.

    PubMed

    Gruber, Christian W

    2014-01-01

    Neuropeptides and regulatory peptide hormones control many developmental, physiological and behavioural processes in animals, including humans. The nonapeptides oxytocin and arginine vasopressin are produced and released by the pituitary gland and have actions on many organs and tissues. Receptive cells possess particular receptors to which the peptides bind as ligands, leading to activation of G-protein-coupled receptors, hence cellular responses. In humans and other mammalian species, oxytocin and vasopressin mediate a range of peripheral and central physiological functions that are important for osmoregulation, reproduction, complex social behaviours, memory and learning. The origin of the oxytocin/vasopressin signalling system is thought to date back more than 600 million years. All vertebrate oxytocin- and vasopressin-like peptides have presumably evolved from the ancestral nonapeptide vasotocin by gene duplication and today are present in vertebrates, including mammals, birds, reptiles, amphibians and fish. Oxytocin- and vasopressin-like peptides have been identified in several invertebrate species, including molluscs, annelids, nematodes and arthropods. Members of this peptide family share high sequence similarity, and it is possible that they are functionally related across the entire animal kingdom. However, it is evident that not all animals express oxytocin/vasopressin neuropeptides and that there is little information available about the biology and physiology of this signalling system of invertebrates and, in particular, of insects, which represent more than half of all known living organisms. This report describes the discovery of novel oxytocin- and vasopressin-like peptides in arthropods and summarizes the status quo of the functional relevance of this neuropeptide signalling system in invertebrates, which will have beneficial implications for the design of selective and potent ligands to human oxytocin and vasopressin receptors.

  12. Ethological principles predict the neuropeptides co-opted to influence parenting

    PubMed Central

    Cunningham, Christopher B.; Badgett, Majors J.; Meagher, Richard B.; Orlando, Ron; Moore, Allen J.

    2017-01-01

    Ethologists predicted that parental care evolves by modifying behavioural precursors in the asocial ancestor. As a corollary, we predict that the evolved mechanistic changes reside in genetic pathways underlying these traits. Here we test our hypothesis in female burying beetles, Nicrophorus vespilloides, an insect where caring adults regurgitate food to begging, dependent offspring. We quantify neuropeptide abundance in brains collected from three behavioural states: solitary virgins, individuals actively parenting or post-parenting solitary adults and quantify 133 peptides belonging to 18 neuropeptides. Eight neuropeptides differ in abundance in one or more states, with increased abundance during parenting in seven. None of these eight neuropeptides have been associated with parental care previously, but all have roles in predicted behavioural precursors for parenting. Our study supports the hypothesis that predictable traits and pathways are targets of selection during the evolution of parenting and suggests additional candidate neuropeptides to study in the context of parenting. PMID:28145404

  13. Neuropeptide Y protects cerebral cortical neurons by regulating microglial immune function

    PubMed Central

    Li, Qijun; Dong, Changzheng; Li, Wenling; Bu, Wei; Wu, Jiang; Zhao, Wenqing

    2014-01-01

    Neuropeptide Y has been shown to inhibit the immunological activity of reactive microglia in the rat cerebral cortex, to reduce N-methyl-D-aspartate current (INMDA) in cortical neurons, and protect neurons. In this study, after primary cultured microglia from the cerebral cortex of rats were treated with lipopolysaccharide, interleukin-1β and tumor necrosis factor-α levels in the cell culture medium increased, and mRNA expression of these cytokines also increased. After primary cultured cortical neurons were incubated with the lipopolysaccharide-treated microglial conditioned medium, peak INMDA in neurons increased. These effects of lipopolysaccharide were suppressed by neuropeptide Y. After addition of the neuropeptide Y Y1 receptor antagonist BIBP3226, the effects of neuropeptide Y completely disappeared. These results suggest that neuropeptide Y prevents excessive production of interleukin-1β and tumor necrosis factor-α by inhibiting microglial reactivity. This reduces INMDA in rat cortical neurons, preventing excitotoxicity, thereby protecting neurons. PMID:25206918

  14. Neuropeptide Y stimulates autophagy in hypothalamic neurons

    PubMed Central

    Aveleira, Célia A.; Botelho, Mariana; Carmo-Silva, Sara; Ferreira-Marques, Marisa; Nóbrega, Clévio; Cortes, Luísa; Valero, Jorge; Sousa-Ferreira, Lígia; Álvaro, Ana R.; Santana, Magda; Kügler, Sebastian; Pereira de Almeida, Luís

    2015-01-01

    Aging is characterized by autophagy impairment that contributes to age-related disease aggravation. Moreover, it was described that the hypothalamus is a critical brain area for whole-body aging development and has impact on lifespan. Neuropeptide Y (NPY) is one of the major neuropeptides present in the hypothalamus, and it has been shown that, in aged animals, the hypothalamic NPY levels decrease. Because caloric restriction (CR) delays aging, at least in part, by stimulating autophagy, and also increases hypothalamic NPY levels, we hypothesized that NPY could have a relevant role on autophagy modulation in the hypothalamus. Therefore, the aim of this study was to investigate the role of NPY on autophagy in the hypothalamus. Using both hypothalamic neuronal in vitro models and mice overexpressing NPY in the hypothalamus, we observed that NPY stimulates autophagy in the hypothalamus. Mechanistically, in rodent hypothalamic neurons, NPY increases autophagy through the activation of NPY Y1 and Y5 receptors, and this effect is tightly associated with the concerted activation of PI3K, MEK/ERK, and PKA signaling pathways. Modulation of hypothalamic NPY levels may be considered a potential strategy to produce protective effects against hypothalamic impairments associated with age and to delay aging. PMID:25775546

  15. Physiology of invertebrate oxytocin and vasopressin neuropeptides

    PubMed Central

    Gruber, Christian W

    2014-01-01

    New findings • What is the topic of this review? This article describes the discovery and function of invertebrate oxytocin and vasopressin neuropeptides. • What advances does it highlight? The novel discovery of oxytocin-like peptides in arthropods is described. An up-to date overview is gven of the functional role (physiology and behaviour) of oxytocin and vasopressin signalling. The application of natural peptides for drug development is discussed. Neuropeptides and regulatory peptide hormones control many developmental, physiological and behavioural processes in animals, including humans. The nonapeptides oxytocin and arginine vasopressin are produced and released by the pituitary gland and have actions on many organs and tissues. Receptive cells possess particular receptors to which the peptides bind as ligands, leading to activation of G-protein-coupled receptors, hence cellular responses. In humans and other mammalian species, oxytocin and vasopressin mediate a range of peripheral and central physiological functions that are important for osmoregulation, reproduction, complex social behaviours, memory and learning. The origin of the oxytocin/vasopressin signalling system is thought to date back more than 600 million years. All vertebrate oxytocin- and vasopressin-like peptides have presumably evolved from the ancestral nonapeptide vasotocin by gene duplication and today are present in vertebrates, including mammals, birds, reptiles, amphibians and fish. Oxytocin- and vasopressin-like peptides have been identified in several invertebrate species, including molluscs, annelids, nematodes and arthropods. Members of this peptide family share high sequence similarity, and it is possible that they are functionally related across the entire animal kingdom. However, it is evident that not all animals express oxytocin/vasopressin neuropeptides and that there is little information available about the biology and physiology of this signalling system of invertebrates

  16. Nematode neuropeptides as transgenic nematicides.

    PubMed

    Warnock, Neil D; Wilson, Leonie; Patten, Cheryl; Fleming, Colin C; Maule, Aaron G; Dalzell, Johnathan J

    2017-02-01

    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.

  17. 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

  18. Epigenetic control of cancer by neuropeptides

    PubMed Central

    Galoian, Karina; Patel, Parthik

    2017-01-01

    Neuropeptides act as neurohormones, neurotransmitters and/or neuromodulators. Neuropeptides maintain physiological homeostasis and are paramount in molecular mechanisms of disease progression and regulation, including in cancer. Neuropeptides, by their definition, originate and are secreted from the neuronal cells, they are able to signal to neighboring cells or are released into the blood flow, if they act as neurohormones. The majority of neuropeptides exert their functions through G protein-coupled receptors, with certain exceptions. Although previous studies indicate that neuropeptides function in supporting proliferation of malignant cells in many types of solid tumor, the antitumorigenic action of the neuropeptides and their receptors, for example, in gastric cancers and chondrosarcoma, were also reported. It is known that epigenetically modified chromatin regulates molecular mechanisms involved in gene expression and malignant progression. The epigenetic modifications are genetically heritable, although they do not cause changes in DNA sequence. DNA methylation, histone modifications and miRNA expression are subject to those modifications. While there is substantial data on epigenetic regulation of neuropeptides, the epigenetic control of cancer by neuropeptides is considered to be uncharted territory. The aim of the current review is to describe the involvement of neuropeptides in the epigenetic machinery of cancer based on data obtained from our laboratory and from other authors. PMID:28123699

  19. Epigenetic control of cancer by neuropeptides.

    PubMed

    Galoian, Karina; Patel, Parthik

    2017-01-01

    Neuropeptides act as neurohormones, neurotransmitters and/or neuromodulators. Neuropeptides maintain physiological homeostasis and are paramount in molecular mechanisms of disease progression and regulation, including in cancer. Neuropeptides, by their definition, originate and are secreted from the neuronal cells, they are able to signal to neighboring cells or are released into the blood flow, if they act as neurohormones. The majority of neuropeptides exert their functions through G protein-coupled receptors, with certain exceptions. Although previous studies indicate that neuropeptides function in supporting proliferation of malignant cells in many types of solid tumor, the antitumorigenic action of the neuropeptides and their receptors, for example, in gastric cancers and chondrosarcoma, were also reported. It is known that epigenetically modified chromatin regulates molecular mechanisms involved in gene expression and malignant progression. The epigenetic modifications are genetically heritable, although they do not cause changes in DNA sequence. DNA methylation, histone modifications and miRNA expression are subject to those modifications. While there is substantial data on epigenetic regulation of neuropeptides, the epigenetic control of cancer by neuropeptides is considered to be uncharted territory. The aim of the current review is to describe the involvement of neuropeptides in the epigenetic machinery of cancer based on data obtained from our laboratory and from other authors.

  20. 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

  1. Interaction between neuropeptide Y and noradrenaline on central catecholamine neurons.

    PubMed

    Illes, P; Regenold, J T

    1990-03-01

    Despite their widespread occurrence in the central nervous system, interactions between co-localized transmitters and their receptors remain poorly understood. Noradrenergic neurons of the nucleus locus coeruleus contain the peptide co-transmitter neuropeptide Y (refs 1,2). In locus coeruleus cells, stimulation of alpha2-adrenoceptors 3,4 or opioid mu-receptors 5,6 increases a potassium conductance and thereby leads to hyperpolarization and inhibition of spontaneous firing. Coupling between these receptors and the inward rectifying K+ channels involves a pertussis toxin-sensitive GTP-binding protein (Gi or Go)7. Here we investigate whether the neuropeptide Y and alpha2-receptors of locus coeruleus neurons interact with one another. When administered alone, neuropeptide Y reduces the discharge of action potentials, probably by increasing the permeability of the membrane to potassium ions through the activation of a G protein; this effect is reduced in the presence of alpha2-adrenoceptor antagonists. Moreover, the peptide selectively increases the hyperpolarizing effect of alpha2-agonists, but does not enhance responses to opioid mu-agonists. We suggest that noradrenaline and its co-transmitter neuropeptide Y stimulate separate receptors, which influence each other in a specific way.

  2. [Control of bone remodeling by nervous system. Regulation of bone metabolism by appetite regulating neuropeptides].

    PubMed

    Fukuda, Toru; Takeda, Shu

    2010-12-01

    The traditional view of bone metabolism as a primarily endocrine activity has been expanded in recent years following the identification of nervous system controlling bone metabolism by leptin studies. Especially, hypothalamic appetite regulating-peptides, such as NPY, CART and NMU have been demonstrated to be bone-regulating neuropeptides. Recently, other neuropeptides, such as serotonin and oxytocin, are reported to be associated with bone metabolism.

  3. Identification of the Drosophila and Tribolium receptors for the recently discovered insect RYamide neuropeptides.

    PubMed

    Collin, Caitlin; Hauser, Frank; Krogh-Meyer, Peter; Hansen, Karina K; Gonzalez de Valdivia, Ernesto; Williamson, Michael; Grimmelikhuijzen, Cornelis J P

    2011-09-09

    One year ago, we discovered a new family of insect RYamide neuropeptides, which has the C-terminal consensus sequence FFXXXRYamide, and which is widely occurring in most insects, including the fruitfly Drosophila melanogaster and the red flour beetle Tribolium castaneum (F. Hauser et al., J. Proteome Res. 9 (2010) 5296-5310). Here, we identify a Drosophila G-protein-coupled receptor (GPCR) coded for by gene CG5811 and its Tribolium GPCR ortholog as insect RYamide receptors. The Drosophila RYamide receptor is equally well activated (EC(50), 1×10(-9)M) by the two Drosophila RYamide neuropeptides: RYamide-1 (PVFFVASRYamide) and RYamide-2 (NEHFFLGSRYamide), both contained in a preprohormone coded for by gene CG40733. The Tribolium receptor shows a somewhat higher affinity to Tribolium RYamide-2 (ADAFFLGPRYamide; EC(50), 5×10(-9)M) than to Tribolium RYamide-1 (VQNLATFKTMMRYamide; EC(50), 7×10(-8)M), which might be due to the fact that the last peptide does not completely follow the RYamide consensus sequence rule. There are other neuropeptides in insects that have similar C-terminal sequences (RWamide or RFamide), such as the FMRFamides, sulfakinins, myosuppressins, neuropeptides F, and the various short neuropeptides F. Amazingly, these neuropeptides show no cross-reactivity to the Tribolium RYamide receptor, while the Drosophila RYamide receptor is only very slightly activated by high concentrations (>10(-6)M) of neuropeptide F and short neuropeptide F-1, showing that the two RYamide receptors are quite specific for activation by insect RYamides, and that the sequence FFXXXRYamide is needed for effective insect RYamide receptor activation. Phylogenetic tree analyses and other amino acid sequence comparisons show that the insect RYamide receptors are not closely related to any other known insect or invertebrate/vertebrate receptors, including mammalian neuropeptide Y and insect neuropeptide F and short neuropeptide F receptors. Gene expression data published in

  4. Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions

    PubMed Central

    Pintér, Erika; Pozsgai, Gábor; Hajna, Zsófia; Helyes, Zsuzsanna; Szolcsányi, János

    2014-01-01

    Cross-talk between the nervous, endocrine and immune systems exists via regulator molecules, such as neuropeptides, hormones and cytokines. A number of neuropeptides have been implicated in the genesis of inflammation, such as tachykinins and calcitonin gene-related peptide. Development of their receptor antagonists could be a promising approach to anti-inflammatory pharmacotherapy. Anti-inflammatory neuropeptides, such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin, somatostatin, cortistatin, ghrelin, galanin and opioid peptides, are also released and act on their own receptors on the neurons as well as on different inflammatory and immune cells. The aim of the present review is to summarize the most prominent data of preclinical animal studies concerning the main pharmacological effects of ligands acting on the neuropeptide receptors. Promising therapeutic impacts of these compounds as potential candidates for the development of novel types of anti-inflammatory drugs are also discussed. PMID:23432438

  5. Hypothalamic neuropeptides and the regulation of appetite.

    PubMed

    Parker, Jennifer A; Bloom, Stephen R

    2012-07-01

    Neuropeptides released by hypothalamic neurons play a major role in the regulation of feeding, acting both within the hypothalamus, and at other appetite regulating centres throughout the brain. Where classical neurotransmitters signal only within synapses, neuropeptides diffuse over greater distances affecting both nearby and distant neurons expressing the relevant receptors, which are often extrasynaptic. As well as triggering a behavioural output, neuropeptides also act as neuromodulators: altering the response of neurons to both neurotransmitters and circulating signals of nutrient status. The mechanisms of action of hypothalamic neuropeptides with established roles in feeding, including melanin-concentrating hormone (MCH), the orexins, α-melanocyte stimulating hormone (α-MSH), agouti-gene related protein (AgRP), neuropeptide Y, and oxytocin, are reviewed in this article, with emphasis laid on both their effects on appetite regulating centres throughout the brain, and on examining the evidence for their physiological roles. In addition, evidence for the involvement of several putative appetite regulating hypothalamic neuropeptides is assessed including, ghrelin, cocaine and amphetamine-regulated transcript (CART), neuropeptide W and the galanin-like peptides. This article is part of a Special Issue entitled 'Central control of Food Intake'.

  6. Ligands of the Neuropeptide Y Y2 receptor

    PubMed Central

    Mittapalli, Gopi Kumar; Roberts, Edward

    2015-01-01

    Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian brain and exerts a variety of physiological processes in humans via four different receptor subtypes Y1, Y2, Y4 and Y5. Y2 receptor is the most abundant Y subtype receptor in the central nervous system and implicated with food intake, bone formation, affective disorders, alcohol and drugs of abuse, epilepsy, pain, and cancer. The lack of small molecule non-peptidic Y2 receptor modulators suitable as in vivo pharmacological tools hampered the progress to uncover the precise pharmacological role of Y2. Only in recent years, several potent, selective and non-peptidic Y2 antagonists have been discovered providing the tools to validate Y2 receptor as a therapeutic target. This article reviews Y2 receptor modulators mainly non-peptidic antagonists and their structure-activity relationships. PMID:24365162

  7. Localization of Neuropeptide Gene Expression in Larvae of an Echinoderm, the Starfish Asterias rubens.

    PubMed

    Mayorova, Tatiana D; Tian, Shi; Cai, Weigang; Semmens, Dean C; Odekunle, Esther A; Zandawala, Meet; Badi, Yusef; Rowe, Matthew L; Egertová, Michaela; Elphick, Maurice R

    2016-01-01

    Neuropeptides are an ancient class of neuronal signaling molecules that regulate a variety of physiological and behavioral processes in animals. The life cycle of many animals includes a larval stage(s) that precedes metamorphic transition to a reproductively active adult stage but, with the exception of Drosophila melanogaster and other insects, research on neuropeptide signaling has hitherto largely focused on adult animals. However, recent advances in genome/transcriptome sequencing have facilitated investigation of neuropeptide expression/function in the larvae of protostomian (e.g., the annelid Platynereis dumerilii) and deuterostomian (e.g., the urochordate Ciona intestinalis) invertebrates. Accordingly, here we report the first multi-gene investigation of larval neuropeptide precursor expression in a species belonging to the phylum Echinodermata-the starfish Asterias rubens. Whole-mount mRNA in situ hybridization was used to visualize in bipinnaria and brachiolaria stage larvae the expression of eight neuropeptide precursors: L-type SALMFamide (S1), F-type SALMFamide (S2), vasopressin/oxytocin-type, NGFFYamide, thyrotropin-releasing hormone-type, gonadotropin-releasing hormone-type, calcitonin-type and corticotropin-releasing hormone-type. Expression of only three of the precursors (S1, S2, NGFFYamide) was observed in bipinnaria larvae but by the brachiolaria stage expression of all eight precursors was detected. An evolutionarily conserved feature of larval nervous systems is the apical organ and in starfish larvae this comprises the bilaterally symmetrical lateral ganglia, but only the S1 and S2 precursors were found to be expressed in these ganglia. A prominent feature of brachiolaria larvae is the attachment complex, comprising the brachia and adhesive disk, which mediates larval attachment to a substratum prior to metamorphosis. Interestingly, all of the neuropeptide precursors examined here are expressed in the attachment complex, with distinctive

  8. Localization of Neuropeptide Gene Expression in Larvae of an Echinoderm, the Starfish Asterias rubens

    PubMed Central

    Mayorova, Tatiana D.; Tian, Shi; Cai, Weigang; Semmens, Dean C.; Odekunle, Esther A.; Zandawala, Meet; Badi, Yusef; Rowe, Matthew L.; Egertová, Michaela; Elphick, Maurice R.

    2016-01-01

    Neuropeptides are an ancient class of neuronal signaling molecules that regulate a variety of physiological and behavioral processes in animals. The life cycle of many animals includes a larval stage(s) that precedes metamorphic transition to a reproductively active adult stage but, with the exception of Drosophila melanogaster and other insects, research on neuropeptide signaling has hitherto largely focused on adult animals. However, recent advances in genome/transcriptome sequencing have facilitated investigation of neuropeptide expression/function in the larvae of protostomian (e.g., the annelid Platynereis dumerilii) and deuterostomian (e.g., the urochordate Ciona intestinalis) invertebrates. Accordingly, here we report the first multi-gene investigation of larval neuropeptide precursor expression in a species belonging to the phylum Echinodermata—the starfish Asterias rubens. Whole-mount mRNA in situ hybridization was used to visualize in bipinnaria and brachiolaria stage larvae the expression of eight neuropeptide precursors: L-type SALMFamide (S1), F-type SALMFamide (S2), vasopressin/oxytocin-type, NGFFYamide, thyrotropin-releasing hormone-type, gonadotropin-releasing hormone-type, calcitonin-type and corticotropin-releasing hormone-type. Expression of only three of the precursors (S1, S2, NGFFYamide) was observed in bipinnaria larvae but by the brachiolaria stage expression of all eight precursors was detected. An evolutionarily conserved feature of larval nervous systems is the apical organ and in starfish larvae this comprises the bilaterally symmetrical lateral ganglia, but only the S1 and S2 precursors were found to be expressed in these ganglia. A prominent feature of brachiolaria larvae is the attachment complex, comprising the brachia and adhesive disk, which mediates larval attachment to a substratum prior to metamorphosis. Interestingly, all of the neuropeptide precursors examined here are expressed in the attachment complex, with distinctive

  9. Biostable beta-Amino Acid PK/PBAN Analogs: Agonist and Antagonist Properties

    DTIC Science & Technology

    2009-01-01

    development (egg diapause, pupal diapause and pupariation) [15,22,23,25,28,35,36] and defense ( melanin bio- synthesis) [5,18] in a variety of insects. The...converting enzyme trials Drosophila ACE (Mr, 67,000) was purified from a soluble extract of adults as described elsewhere [9,17] and yielded enzyme that...inhibitory activities were obtained with those peptides when Pss-PT was used as an elicitor where PK-bA-1, PK-bA-2, and PK-bA-4 inhibited PT elicited melanin

  10. Environmental Enrichment Reduces Anxiety by Differentially Activating Serotonergic and Neuropeptide Y (NPY)-Ergic System in Indian Field Mouse (Mus booduga): An Animal Model of Post-Traumatic Stress Disorder

    PubMed Central

    Ragu Varman, Durairaj; Rajan, Koilmani Emmanuvel

    2015-01-01

    Exposure to a predator elicits an innate fear response and mimics several behavioral disorders related to post-traumatic stress disorder (PTSD). The protective role of an enriched condition (EC) against psychogenic stressors in various animal models has been well documented. However, this condition has not been tested in field mice in the context of PTSD. In this study, we show that field mice (Mus booduga) housed under EC exhibit predominantly proactive and less reactive behavior compared with mice housed under standard conditions (SC) during exposure to their natural predator (field rat Rattus rattus). Furthermore, we observed that EC mice displayed less anxiety-like behavior in an elevated plus maze (EPM) and light/dark-box after exposure to the predator (7 hrs/7 days). In EC mice, predator exposure elevated the level of serotonin (5-Hydroxytrypamine, [5-HT]) in the amygdala as part of the coping response. Subsequently, the serotonin transporter (SERT) and 5-HT1A receptor were up-regulated significantly, but the same did not occur in the 5-HT2C receptor, which is associated with the activation of calmodulin-dependent protein kinase-II (CaMKII) and a transcription factor cAMP response element binding protein (CREB). Our results show that predator exposure induced the activation of CaMKII/CREB, which is accompanied with increased levels of histone acetylation (H3, H4) and decreased histone deacetylases (HDAC1, 2). Subsequently, in the amygdala, the transcription of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY) and its Y1 receptor were up-regulated, whereas the Y2 receptor was down-regulated. Therefore, EC facilitated a coping response against a fear associated cue in a PTSD animal model and reduced anxiety by differentially activating serotonergic and NPY-ergic systems. PMID:26016844

  11. Mesolimbic neuropeptide W coordinates stress responses under novel environments.

    PubMed

    Motoike, Toshiyuki; Long, Jeffrey M; Tanaka, Hirokazu; Sinton, Christopher M; Skach, Amber; Williams, S Clay; Hammer, Robert E; Sakurai, Takeshi; Yanagisawa, Masashi

    2016-05-24

    Neuropeptide B (NPB) and neuropeptide W (NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stress-induced inhibition was attenuated in the CeAL neurons of NPW(-/-) mice. Moreover, the response of NPW(-/-) mice to either formalin-induced pain stimuli or a live rat (i.e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW(-/-) mice in a habituated environment was indistinguishable from that of wild-type mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments.

  12. 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.

  13. 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

  14. Neuropeptidomics: Mass Spectrometry-Based Identification and Quantitation of Neuropeptides

    PubMed Central

    2016-01-01

    Neuropeptides produced from prohormones by selective action of endopeptidases are vital signaling molecules, playing a critical role in a variety of physiological processes, such as addiction, depression, pain, and circadian rhythms. Neuropeptides bind to post-synaptic receptors and elicit cellular effects like classical neurotransmitters. While each neuropeptide could have its own biological function, mass spectrometry (MS) allows for the identification of the precise molecular forms of each peptide without a priori knowledge of the peptide identity and for the quantitation of neuropeptides in different conditions of the samples. MS-based neuropeptidomics approaches have been applied to various animal models and conditions to characterize and quantify novel neuropeptides, as well as known neuropeptides, advancing our understanding of nervous system function over the past decade. Here, we will present an overview of neuropeptides and MS-based neuropeptidomic strategies for the identification and quantitation of neuropeptides. PMID:27103886

  15. Neuropeptides: developmental signals in placode progenitor formation.

    PubMed

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

    2013-07-29

    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.

  16. RFamide neuropeptide actions on the molluscan heart.

    PubMed

    Moulis, A

    2004-01-01

    FMRFamide and the related tetrapeptide FLRFamide are highly excitatory in molluscan non-cardiac smooth muscle. They are also exceptionally excitatory in the atrium and internally perfused ventricle of Busycon canaliculatum. These two peptides, usually thought of as classic molluscan cardio-acceleratory agents are in fact simply two members of a large and ever growing superfamily, the RFamide family, whose phylogenetic distribution has been so elegantly mapped by Walker. Members of this family, often with extended peptide chains (e.g. penta, hepta and decapeptides), stretch in their known distribution from the cnidaria to the chordates. The effects of some of the members of this superfamily (FMRFamide. FLRFamide, YMRFamide, TNRNFLRFamide, SDPFLRFamide, LMS) were examined. The neuropeptides were found to be very potent at very low concentrations (10(-9) M) in the ventricle of both Buccinium and Busycon. Other neuropeptides (HFMRdFamide, SCPb, NLERFamide and pEGRFamide) were found to be without any effect. The Ca2+ dependency of these neuropeptides was also tested. The peptides appear to induce contraction of the ventricles by release of Ca2+ from internal pools. The neuropeptides appear to stimulate contraction in these cardiac muscles through a completely different pathway to Serotonin (the main excitatory neurotransmitter for the cardiac muscle). When the peptides were applied together with Serotonin an additive effect was observed clearly indicating the release of Ca2+ through different pathways. The nature of the RFamide receptor was also tested. It appears that the RFamide neuropeptides mobilize the 2nd messenger IP3 (Inositol trisphosphate), since the IP3 blocker Neomycin Sulphate inhibited the response of the neuropeptides.

  17. Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats

    PubMed Central

    Li, Jiali; Luo, Yixiao; Zhang, Ruoxi; Shi, Haishui; Zhu, Weili; Shi, Jie

    2015-01-01

    The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression. PMID:26633367

  18. Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats.

    PubMed

    Li, Jiali; Luo, Yixiao; Zhang, Ruoxi; Shi, Haishui; Zhu, Weili; Shi, Jie

    2015-11-30

    The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.

  19. Peroxisome proliferator-activated receptor γ controls ingestive behavior, agouti-related protein, and neuropeptide Y mRNA in the arcuate hypothalamus.

    PubMed

    Garretson, John T; Teubner, Brett J W; Grove, Kevin L; Vazdarjanova, Almira; Ryu, Vitaly; Bartness, Timothy J

    2015-03-18

    Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide; PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP and NPY in ad libitum-fed animals; (4) whether intraperitoneally administered PPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPARγ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPARγ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPARγ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors.

  20. Neuropeptides associated with the regulation of feeding in insects.

    PubMed

    Audsley, N; Weaver, R J

    2009-05-15

    The stomatogastric nervous system plays a pivotal role in feeding behaviour. Central to this system is the frontal ganglion, which is responsible for foregut motor activity, and hence the passage of food through the gut. Many insect peptides, which exhibit myoactivity on the visceral muscles of the gut in vitro, have been detected in the stomatogastric nervous system by immunochemical or mass spectrometric techniques. This localisation of myoactive peptides, particularly in the frontal ganglion, implies roles for these peptides in the neural control and modulation of feeding in insects. Insect sulfakinins, tachykinins, allatotropin and proctolin have all been shown to stimulate the foregut muscles, whereas myosuppressins, myoinhibitory peptides and allatostatins all inhibited spontaneous contractions of the foregut in a variety of insects. Some of these peptides, when injected, inhibited feeding in vivo. Both the A-type and B-type allatostatins suppressed feeding activity when injected into the cockroach, Blattella germanica and the Manduca sexta C-type allatostatin and allatotropin inhibited feeding when injected into the larvae of two noctuid moths, Lacanobia oleracea and Spodoptera frugiperda, respectively. Injection of sulfakinins into the fly Phormia regina, the locust Schistocera gregaria and the cockroach B. germanica also suppressed feeding, whereas silencing the sulfakinin gene through the injection of double stranded RNA resulted in an increase in food consumption in the cricket Gryllus bimaculatus. The regulation of feeding in insects is clearly very complex, and involves the interaction of a number of mechanisms, one of which is the release, either centrally or locally, of neuropeptides. However, the role of neuropeptides, their mechanisms of action, interactions with each other, and their release are still poorly understood. It is also unclear why insects possess such a number of different peptides, some with multiples copies or homologues, which

  1. The neuropeptide bursicon acts in cuticle metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  2. Crustacean neuropeptides: structures, functions and comparative aspects.

    PubMed

    Keller, R

    1992-05-15

    In this article, an attempt is made to review the presently known, completely identified crustacean neuropeptides with regard to structure, function and distribution. Probably the most important progress has been made in the elucidation of a novel family of large peptides from the X-organ-sinus gland system which includes crustacean hyperglycemic hormone (CHH), putative molt-inhibiting hormone (MIH) and vitellogenesis (= gonad)-inhibiting hormone (VIH). These peptides have so far only been found in crustaceans. Renewed interest in the neurohemal pericardial organs has led to the identification of a number of cardioactive/myotropic neuropeptides, some of them unique to crustaceans. Important contributions have been made by immunocytochemical mapping of peptidergic neurons in the nervous system, which has provided evidence for a multiple role of several neuropeptides as neurohormones on the one hand and as local transmitters or modulators on the other. This has been corroborated by physiological studies. The long-known chromatophore-regulating hormones, red pigment concentrating hormone (RPCH) and pigment-dispending hormone (PDH), have been placed in a broader perspective by the demonstration of an additional role as local neuromodulators. The scope of crustacean neuropeptide research has thus been broadened considerably during the last years.

  3. Neuropeptides as possible targets in sleep disorders.

    PubMed

    Nishino, Seiji; Fujiki, Nobuhiro

    2007-01-01

    Insomnia and hypersomnia are frequent sleep disorders, and they are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on GABA-A receptors, and amfetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep and are, therefore, possibly involved in the pathophysiology of some sleep disorders. Due to the recent developments of molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. It was also discovered that the impairment of the hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide system) is the major pathophysiology of narcolepsy, and hypocretin replacement therapy is anticipated to treat the disease in humans. In this article, the authors briefly review the history of neuropeptide research, followed by the sleep modulatory effects of various neuropeptides. Finally, general strategies for the pharmacological therapeutics targeting the peptidergic systems for sleep disorders are discussed.

  4. Neuropeptides: metabolism to bioactive fragments and the pharmacology of their receptors.

    PubMed

    Hallberg, Mathias

    2015-05-01

    The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals

  5. Allatotropin: An Ancestral Myotropic Neuropeptide Involved in Feeding

    PubMed Central

    Alzugaray, María Eugenia; Adami, Mariana Laura; Diambra, Luis Anibal; Hernandez-Martinez, Salvador; Damborenea, Cristina; Noriega, Fernando Gabriel; Ronderos, Jorge Rafael

    2013-01-01

    Background Cell-cell interactions are a basic principle for the organization of tissues and organs allowing them to perform integrated functions and to organize themselves spatially and temporally. Peptidic molecules secreted by neurons and epithelial cells play fundamental roles in cell-cell interactions, acting as local neuromodulators, neurohormones, as well as endocrine and paracrine messengers. Allatotropin (AT) is a neuropeptide originally described as a regulator of Juvenile Hormone synthesis, which plays multiple neural, endocrine and myoactive roles in insects and other organisms. Methods A combination of immunohistochemistry using AT-antibodies and AT-Qdot nanocrystal conjugates was used to identify immunoreactive nerve cells containing the peptide and epithelial-muscular cells targeted by AT in Hydra plagiodesmica. Physiological assays using AT and AT- antibodies revealed that while AT stimulated the extrusion of the hypostome in a dose-response fashion in starved hydroids, the activity of hypostome in hydroids challenged with food was blocked by treatments with different doses of AT-antibodies. Conclusions AT antibodies immunolabeled nerve cells in the stalk, pedal disc, tentacles and hypostome. AT-Qdot conjugates recognized epithelial-muscular cell in the same tissues, suggesting the existence of anatomical and functional relationships between these two cell populations. Physiological assays indicated that the AT-like peptide is facilitating food ingestion. Significance Immunochemical, physiological and bioinformatics evidence advocates that AT is an ancestral neuropeptide involved in myoregulatory activities associated with meal ingestion and digestion. PMID:24143240

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  7. The venom of Conus pennaceus inhibits the binding of [3H]neuropeptide Y by direct interaction with the radioligand.

    PubMed

    Diallo, B; Vanderheyden, P M; De Backer, J P; Vauquelin, G

    1998-01-01

    The venom from the marine snail Conus pennaceus inhibits the binding of [3H]neuropeptide Y to calf brain membranes (Czerwiec et al., 1996a) and, in the present study, also to rat forebrain membranes. These membranes contain about 80% Y1- and 20% Y2-receptors. The inhibition by the venom was concentration-dependent with an IC50 value of 3.4 micrograms ml-1. However, the venom also inhibited the binding of [3H]neuropeptide Y to the glass fibre filters and to the previously discovered ANPY toxin from the venom of Conus anemone (Czerwiec et al., 1996b). This inhibition was related to the ability of one or more of the venom components to bind directly to the radioligand instead of the initially assumed interaction with the neuropeptide Y receptors present in membrane preparations. The complex with Conus pennaceus venom was not retained by the glass fibre filter during the separation of the bound from the unbound [3H]neuropeptide Y. Gel filtration chromatography and denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the active [3H]neuropeptide Y-binding component is likely a approximately 30 kDa polypeptide. Binding of [3H]neuropeptide Y to the venom component(s) was not displaced by 20 microM of the (1-24) N-terminal and the (25-36) C-terminal neuropeptide Y fragments. It is therefore likely that the recognition of the venom component(s) requires both the C- and the N-terminal segments of the neuropeptide Y molecule.

  8. Sexual experience affects ethanol intake in Drosophila through Neuropeptide F

    PubMed Central

    Shohat-Ophir, G.; Kaun, K.R.; Azanchi, R.; Mohammed, H; Heberlein, U.

    2014-01-01

    The brain's reward systems evolved to reinforce behaviors required for species survival, including sex, food consumption, and social interaction. Drugs of abuse co-opt these neural pathways, which can lead to addiction. Here, we use Drosophila melanogaster to investigate the relationship between natural and drug rewards. In males, mating increased Neuropeptide F (NPF) levels, whereas sexual deprivation reduced NPF. Activation or inhibition of the NPF system in turn enhanced or reduced ethanol preference. These results thus link sexual experience, NPF system activity, and ethanol consumption. Artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF/NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly. PMID:22422983

  9. 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...bioassays, including hindgut contractile ( cockroach L. maderae) [23], oviduct contractile ( cockroach L. maderae) [22], Peptides 30 (2009) 1254–1259 A R...acceleration in the larval fly Neobellieria bullata, and hindgut contraction in the cockroach Leucophaea maderae. The conformationally constrained analog

  10. Neuropeptide Y binding sites in rat brain identified with purified neuropeptide Y-I125

    SciTech Connect

    Walker, M.W.; Miller, R.J.

    1986-03-05

    Neuropeptide Y (NPY) is a widely distributed neuronally localized peptide with 36 amino acids, 5 of which are tyrosines. The authors wished to investigate the properties of specific receptors for NPY. They therefore labeled the tyrosines with I125 using chloramine T and then purified the peptide using HPLC. A single mono-iodinated species of NPY which yielded > 85% specific binding in rat forebrain synaptosomes was selected as the ligand for all subsequent experiments. A time course of binding showed that equilibrium conditions were reached in 60 minutes at 21/sup 0/C. Scatchard plots revealed a single class of binding sites with a Kd and a Bmax of 3 x 10-10 M and 28 pmol/mg, respectively. Competition binding with unlabeled NPY showed 50% displacement of bound ligand at 1 x 10-10 M NPY. Competition binding with rat pancreatic polypeptide (RPP), a homologous peptide possessing little NPY-like activity, showed 50% displacement of bound ligand at 2 x 10/sup -7/ M RPP. No binding was observed on F-11 or PC12 neuronal cell lines, or on HSWP fibroblast cells. They conclude that NPY-I125 purified to homogeneity with HPLC is a highly selective ligand for NPY receptor sites. They are currently investigating such sites in brain, gut, and other tissues.

  11. Microglia-Induced Maladaptive Plasticity Can Be Modulated by Neuropeptides In Vivo

    PubMed Central

    Morara, Stefano; Colangelo, Anna Maria; Provini, Luciano

    2015-01-01

    Microglia-induced maladaptive plasticity is being recognized as a major cause of deleterious self-sustaining pathological processes that occur in neurodegenerative and neuroinflammatory diseases. Microglia, the primary homeostatic guardian of the central nervous system, exert critical functions both during development, in neural circuit reshaping, and during adult life, in the brain physiological and pathological surveillance. This delicate critical role can be disrupted by neural, but also peripheral, noxious stimuli that can prime microglia to become overreactive to a second noxious stimulus or worsen underlying pathological processes. Among regulators of microglia, neuropeptides can play a major role. Their receptors are widely expressed in microglial cells and neuropeptide challenge can potently influence microglial activity in vitro. More relevantly, this regulator activity has been assessed also in vivo, in experimental models of brain diseases. Neuropeptide action in the central nervous system has been associated with beneficial effects in neurodegenerative and neuroinflammatory pathological experimental models. This review describes some of the mechanisms of the microglia maladaptive plasticity in vivo and how neuropeptide activity can represent a useful therapeutical target in a variety of human brain pathologies. PMID:26273481

  12. Neuropeptide Y is an angiogenic factor in cardiovascular regeneration.

    PubMed

    Saraf, Rabya; Mahmood, Feroze; Amir, Rabia; Matyal, Robina

    2016-04-05

    In diabetic cardiomyopathy, there is altered angiogenic signaling and increased oxidative stress. As a result, anti-angiogenic and pro-inflammatory pathways are activated. These disrupt cellular metabolism and cause fibrosis and apoptosis, leading to pathological remodeling. The autonomic nervous system and neurotransmitters play an important role in angiogenesis. Therapies that promote angiogenesis may be able to relieve the pathology in these disease states. Neuropeptide Y (NPY) is the most abundantly produced and expressed neuropeptide in the central and peripheral nervous systems in mammals and plays an important role in promoting angiogenesis and cardiomyocyte remodeling. It produces effects through G-protein-coupled Y receptors that are widely distributed and also present on the myocardium. Some of these receptors are also involved in diseased states of the heart. NPY has been implicated as a potent growth factor, causing cell proliferation in multiple systems while the NPY3-36 fragment is selective in stimulating angiogenesis and cardiomyocyte remodeling. Current research is focusing on developing a drug delivery mechanism for NPY to prolong therapy without having significant systemic consequences. This could be a promising innovation in the treatment of diabetic cardiomyopathy and ischemic heart disease.

  13. Cloning and expression of a novel neuropeptide Y receptor.

    PubMed

    Weinberg, D H; Sirinathsinghji, D J; Tan, C P; Shiao, L L; Morin, N; Rigby, M R; Heavens, R H; Rapoport, D R; Bayne, M L; Cascieri, M A; Strader, C D; Linemeyer, D L; MacNeil, D J

    1996-07-12

    The neuropeptide Y family of peptides, which includes neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP), are found in the central and peripheral nervous system and display a wide array of biological activities. These actions are believed to be mediated through pharmacologically distinct G protein-coupled receptors, and, to date, three members of the NPY receptor family have been cloned. In this study we describe the cloning and expression of a novel NPY receptor from mouse genomic DNA. This receptor, designated NPY Y5, shares 60% amino acid identity to the murine NPY Y1 receptor. The pharmacology of this novel receptor resembles that of the NPY Y1 receptor and is distinct from that described for the NPY Y2, Y3, and Y4 receptors. In situ hybridization of mouse brain sections reveals expression of this receptor within discrete regions of the hypothalamus including the suprachiasmatic nucleus, anterior hypothalamus, bed nucleus stria terminalis, and the ventromedial nucleus with no localization apparent elsewhere in the brain.

  14. Salusin-β as a powerful endogenous antidipsogenic neuropeptide

    PubMed Central

    Suzuki-Kemuriyama, Noriko; Nakano-Tateno, Tae; Tani, Yuji; Hirata, Yukio; Shichiri, Masayoshi

    2016-01-01

    Salusin-β is an endogenous parasympathomimetic peptide, predominantly localized to the hypothalamus and posterior pituitary. Subcutaneously administered salusin-β (50 nmol/mouse) significantly increased water intake but did not affect locomotor activity or food intake. The salusin-β-induced increase in water intake was completely abrogated by pretreatment with muscarinic antagonist, atropine sulphate. In contrast, intracerebroventricular injection of salusin-β, at lower doses (10–100 fmol/mouse) caused a long-lasting decrease in water intake and locomotor activity throughout the entire dark phase of the diurnal cycle. Pre-injection of intracerebroventricular anti-salusin-β IgG completely abrogated the central salusin-β mediated suppression of water intake and locomotor activity. These results demonstrate contrasting actions of salusin-β in the control of water intake via the central and peripheral systems and highlight it as a potent endogenous antidipsogenic neuropeptide. PMID:26869388

  15. The Role of Neuropeptides in Suicidal Behavior: A Systematic Review

    PubMed Central

    Pompili, Maurizio; Dwivedi, Yogesh; Girardi, Paolo

    2013-01-01

    There is a growing evidence that neuropeptides may be involved in the pathophysiology of suicidal behavior. A critical review of the literature was conducted to investigate the association between neuropeptides and suicidal behavior. Only articles from peer-reviewed journals were selected for the inclusion in the present review. Twenty-six articles were assessed for eligibility but only 22 studies were included. Most studies have documented an association between suicidality and some neuropeptides such as corticotropin-releasing factor (CRF), VGF, cholecystokinin, substance P, and neuropeptide Y (NPY), which have been demonstrated to act as key neuromodulators of emotional processing. Significant differences in neuropeptides levels have been found in those who have attempted or completed suicide compared with healthy controls or those dying from other causes. Despite cross-sectional associations between neuropeptides levels and suicidal behavior, causality may not be inferred. The implications of the mentioned studies were discussed in this review paper. PMID:23986909

  16. Peripheral site of action of levodropropizine in experimentally-induced cough: role of sensory neuropeptides.

    PubMed

    Lavezzo, A; Melillo, G; Clavenna, G; Omini, C

    1992-06-01

    The mechanism of action of levodropropizine has been investigated in different models of experimentally-induced cough in guinea-pigs. In particular it has been demonstrated that the antitussive drug has a peripheral site of action by injecting the drug intracerebroventricularly (i.c.v.). In these experiments levodropropizine (40 micrograms/50 microliters i.c.v.) did not prevent electrically-induced cough. On the other hand, codeine (5 micrograms/50 microliters i.c.v.) markedly prevented coughing. A difference in the potency ratio of levodropropizine and codeine has been demonstrated in capsaicin-induced cough; after oral administration, codeine was about two to three times more potent than levodropropizine. However, after aerosol administration the two compounds were equipotent. These data might suggest a peripheral site of action for levodropropizine which is related to sensory neuropeptides. Further support for the role of sensory neuropeptides in the mechanism of action of levodropropizine comes from the results obtained in capsaicin-desensitized animals. In this experimental model levodropropizine failed to prevent the vagally elicited cough in neuropeptide-depleted animals, whereas codeine did not differentiate between control and capsaicin-treated animals. In conclusion, our results support the suggestion that levodropropizine has a peripheral site of action. In addition, the interference with the sensory neuropeptide system may explain, at least in part, its activity in experimentally-induced cough.

  17. Neuropeptides Exert Direct Effects on Rat Thymic Epithelial Cells in Culture

    PubMed Central

    Head, Gail M.; Mentlein, R.; Patay, Birte Von; Downing, J. E.G.

    1998-01-01

    To determine if major thymic neuropeptides and neurotransmitters can directly influence the functional activity of cultured rat thymic epithelium, neuropeptides and neurotransmitters were applied, and intercellular communication, proliferation, and thymulin secretion assessed. After injections of a mixture of lucifer yellow dextran (too large to pass gap junctions) and cascade blue (which does) into single cells, some neuropeptides decrease dye coupling: 0.1 mM GABA (P < 0.0001), 100 nM NPY (P < 0.0001), 100 nM VIP (P < 0.001), 100 nM CGRP (P < 0.001), 100 nM SP (P < 0.01), and 0.1 mM histamine (P < 0.01), whereas 0.1 mM 5-HT, mM acetylcholine, and 1 μM isoproterenol (β-adrenergic agonist) had no effect. Proliferation (incorporation of tritiated thymidine) was increased by CGRP (P = 0.004) and histamine (P < 0.02), but decreased by isoproterenol (P = 0.002), 5-HT (P = 0.003), and acetylcholine (P < 0.05). The percentage of multinucleate cells was decreased after isoproterenol (2.5%), and increased after 5-HT (21.3%), GABA (15%), and histamine (15.1%). Compared to controls, thymulin in the supernatant was decreased after challenge with acetylcholine (52%), isoproterenol (71%), 5-HT (73%), and histamine (84%). This study demonstrates direct effects of neuropeptides and neurotransmitters on functional aspects of cultured thymic epithelial cells. PMID:9716910

  18. A neuromedin-pyrokinin-like neuropeptide signaling system in Caenorhabditis elegans.

    PubMed

    Lindemans, Marleen; Janssen, Tom; Husson, Steven J; Meelkop, Ellen; Temmerman, Liesbet; Clynen, Elke; Mertens, Inge; Schoofs, Liliane

    2009-02-13

    Neuromedin U (NMU) in vertebrates is a structurally highly conserved neuropeptide of which highest levels are found in the pituitary and gastrointestinal tract. In Drosophila, two neuropeptide genes encoding pyrokinins (PKs), capability (capa) and hugin, are possible insect homologs of vertebrate NMU. Here, the ligand for an orphan G protein-coupled receptor in the nematode Caenorhabditis elegans (Ce-PK-R) was found using a bioinformatics approach. After cloning and expressing Ce-PK-R in HEK293T cells, we found that it was activated by a neuropeptide from the C. elegans NLP-44 precursor (EC(50)=18nM). This neuropeptide precursor is reminiscent of insect CAPA precursors since it encodes a PK-like peptide and two periviscerokinin-like peptides (PVKs). Analogous to CAPA peptides in insects and NMUs in vertebrates, whole mount immunostaining in C. elegans revealed that the CAPA precursor is expressed in the nervous system. The present data also suggest that the ancestral CAPA precursor was already present in the common ancestor of Protostomians and Deuterostomians and that it might have been duplicated into CAPA and HUGIN in insects. In vertebrates, NMU is the putative homolog of a protostomian CAPA-PK.

  19. Isolation of NPY-25 (neuropeptide Y[12-36]), a potent inhibitor of calmodulin, from porcine brain.

    PubMed

    Kitamura, K; Kangawa, K; Tanaka, K; Matsuo, H

    1990-06-29

    In the present purification of low molecular weight fractions (Mr: 2000-4000) containing basic peptides, twenty nmol of novel calmodulin binding peptide, possessing a potent affinity for calmodulin, was isolated from 18 kg of porcine brain. By analysis with gas phase sequencer, the sequence was determined to be APAEDLARYYSALRHYINLITRQRY. Carboxy terminus of the peptide was determined to be Tyr-NH2. The peptide was a carboxy terminal pentacosanepeptide of neuropeptide Y and was termed NPY-25. NPY-25 competitively inhibited the activation of cAMP-phosphodiesterase through CaM binding in a Ca++ dependent fashion, but did not inhibit the basal activity of cAMP phosphodiesterase. NPY-25 elicited a more potent activity than did neuropeptide Y. IC50 values of NPY-25 and Neuropeptide Y were 0.06 microM and 0.54 microM respectively.

  20. 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.

  1. Neuropeptide Y: An Anti-Aging Player?

    PubMed

    Botelho, Mariana; Cavadas, Cláudia

    2015-11-01

    Accumulating evidence suggests that neuropeptide Y (NPY) has a role in aging and lifespan determination. In this review, we critically discuss age-related changes in NPY levels in the brain, together with recent findings concerning the contribution of NPY to, and impact on, six hallmarks of aging, specifically: loss of proteostasis, stem cell exhaustion, altered intercellular communication, deregulated nutrient sensing, cellular senescence, and mitochondrial dysfunction. Understanding how NPY contributes to, and counteracts, these hallmarks of aging will open new avenues of research on limiting damage related to aging.

  2. 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

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

    PubMed

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

    2016-02-01

    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.

  4. Mimetic analogs of pyrokinin neuropeptides for pest management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Neuropeptides are potent regulators of critical life processes in insects, but are subjected to rapid degradation by peptidases in the hemolymph (blood), tissues and gut. This limitation can be overcome via replacement of peptidase susceptible portions of the insect neuropeptides to create analogs ...

  5. Neuropeptides of human thymus in normal and pathological conditions.

    PubMed

    Mignini, F; Sabbatini, M; D'Andrea, V; Cavallotti, C

    2011-05-01

    Human thymus of healthy subjects and patients affected by thymoma-associated Myastenia Gravis were studied in order to visualize and compare the morphological distributive pattern of four neuropeptides: vasoactive intestinal peptide, substance P, neuropeptide Y, and neurotensin. Based on our observations, we formulated hypotheses on their relations in neuro-immunomodulation under physiological and pathophysiological conditions. Immuno-histochemical staining for neuropeptides was performed and morphological and morphometrical analyses were conducted on healthy and diseased thymus. In normal thymus, a specific distributive pattern was observed for the several neuropeptide-positive nerves in different thymus lobular zones. In particular substance P-positive fibers were observed in subcapsular zone, specifically located into parenchyma, where they represent the almost total amount of fibers; neurotensin-positive fibers were observed primarily located in parenchyma than perivascular site of several thymus lobular zones, and more abundant the cortico-medullary and medullary zones. Instead VIP- and NPY-positive fibers were widely distributed in perivascular and parenchymal sites of several thymus lobular zones. In thymoma, the distribution of neuropeptide-positive fibers was quantitatively reduced, while cells immunopositive to VIP and substance P were quantitatively increased and dispersed. Observation of the perivascular and parenchymal distribution of the analyzed neuropeptides suggests evidence that a regulatory function is performed by nerves and cells that secrete neuropeptide into the thymus. The alteration of neuropeptide patterns in thymoma suggests that these neurotransmitters play a role in autoimmune diseases such as Myastenia Gravis.

  6. [Effects of neuropeptides on interferon production in vitro].

    PubMed

    Kul'chikov, A E; Makarenko, A N

    2008-01-01

    The study of an interferon-inducing action of neuropeptides (a cerebrolysin model) on production of interferons by human blood leukocytes has shown that neuropeptides induce gamma-interferon production in the titer 267 IU/ml that determines one of the mechanisms of a neuroimmunocorrecting effect of cerebrolysin (Ebewe, Austria) in many neurological diseases (acute stroke, brain traumas and different neuroinfectious diseases).

  7. Mini-review: the evolution of neuropeptide signaling.

    PubMed

    Grimmelikhuijzen, Cornelis J P; Hauser, Frank

    2012-08-10

    Neuropeptides and their G protein-coupled receptors (GPCRs) have an early evolutionary origin and are already abundant in basal animals with primitive nervous systems such as cnidarians (Hydra, jellyfishes, corals, and sea anemones). Most animals emerging after the Cnidaria belong to two evolutionary lineages, the Protostomia (to which the majority of invertebrates belong) and Deuterostomia (to which some minor groups of invertebrates, and all vertebrates belong). These two lineages split about 700 million years (Myr) ago. Many mammalian neuropeptide GPCRs have orthologues in the Protostomia and this is also true for some of the mammalian neuropeptides. Examples are oxytocin/vasopressin, GnRH, gastrin/CCK, and neuropeptide Y and their GPCRs. These results implicate that protostomes (for example insects and nematodes) can be used as models to study the biology of neuropeptide signaling.

  8. Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain

    PubMed Central

    Baram, Tallie Z.; Hatalski, Carolyn G.

    2012-01-01

    Most human seizures occur early in life, consistent with established excitability-promoting features of the developing brain. Surprisingly, the majority of developmental seizures are not spontaneous but are provoked by injurious or stressful stimuli. What mechanisms mediate ‘triggering’ of seizures and limit such reactive seizures to early postnatal life? Recent evidence implicates the excitatory neuropeptide, corticotropin-releasing hormone (CRH). Stress activates expression of the CRH gene in several limbic regions, and CRH-expressing neurons are strategically localized in the immature rat hippocampus, in which this neuropeptide increases the excitability of pyramidal cells in vitro. Indeed, in vivo, activation of CRH receptors – maximally expressed in hippocampus and amygdala during the developmental period which is characterized by peak susceptibility to ‘provoked’ convulsions – induces severe, age-dependent seizures. Thus, converging data indicate that activation of expression of CRH constitutes an important mechanism for generating developmentally regulated, triggered seizures, with considerable clinical relevance. PMID:9829688

  9. NG peptides: a novel family of neurophysin-associated neuropeptides.

    PubMed

    Elphick, Maurice R

    2010-06-15

    Neurophysins are prohormone-derived polypeptides that are required for biosynthesis of the neurohypophyseal hormones vasopressin and oxytocin. Accordingly, mutations in the neurophysin domain of the human vasopressin gene can cause diabetes insipidus. The association of neurophysins with vasopressin/oxytocin-type peptides dates back to the common ancestor of bilaterian animals and until recently it was thought to be unique. This textbook perspective on neurophysins changed with the discovery of a gene in the sea urchin Strongylocentrotus purpuratus (phylum Echinodermata) encoding a precursor protein comprising a neurophysin domain in association with NGFFFamide, a myoactive neuropeptide that is structurally unrelated to vasopressin/oxytocin-type neuropeptides (Elphick, M.R., Rowe, M.L., 2009. NGFFFamide and echinotocin: structurally unrelated myoactive neuropeptides derived from neurophysin-containing precursors in sea urchins. J. Exp. Biol. 212, 1067-1077). What is not known, however, is when and how the association of neurophysin with NGFFFamide-like neuropeptides originated. Here I report the discovery of genes encoding proteins comprising a neurophysin domain in association with putative NGFFFamide-like peptides in the hemichordate Saccoglossus kowalevskii (NGFWNamide and NGFYNamide) and in the cephalochordate Branchiostoma floridae (SFRNGVamide). Together with NGFFFamide, these peptides constitute a novel family of neuropeptides in invertebrate deuterostomes that are derived from neurophysin-containing precursors and that have the sequence motif NG - "NG peptides". Genes encoding NG peptides in association with neurophysin were not found in protostomes, urochordates or vertebrates. Interestingly, however, SFRNGVamide is identical to the N-terminal region of neuropeptide S, a peptide that modulates arousal and anxiety in mammals, whilst NGFFFamide shares sequence similarity with SIFamide (AYRKPPFNGSIFamide), a neuropeptide that regulates sexual behaviour in

  10. Age-related changes in the competency of the pheromone gland and the pheromonotropic activity of the brain of both virgin and mated females of two Choristoneura species.

    PubMed

    Delisle, J; Simard, J

    2003-01-01

    Nine-day-old decapitated females injected with different doses of Hez-PBAN produced significantly less pheromone than 1-day-old individuals, suggesting that the age-related decline in the pheromone titre of Choristoneura fumiferana and C. rosaceana virgin females was primarily the result of a reduced ability of the glands to produce pheromone. In C. fumiferana, lower pheromonotropic activity of the Br-SEG may also contribute to the pheromone decline with age but not in C. rosaceana, as the pheromonotropic activity of the Br-SEG remained constant throughout the females' life. In both Choristoneura species, mating also suppressed pheromone production (pheromonostasis) after 24 h. The Br-SEG of mated females contained PBAN but there was no indication that its concentration changed with time post-mating since Br-SEG homogenates obtained from different-aged mated females showed the same level of pheromonotropic activity in both Choristoneura species. However, as observed in virgins, pheromone glands of older mated females were less sensitive to PBAN than those of younger ones. This suggests that the probability of Choristoneura females to attract a second mate may decrease with an increase in the refractory period following the first mating.

  11. GABA excitation in mouse hilar neuropeptide Y neurons

    PubMed Central

    Fu, Li-Ying; van den Pol, Anthony N

    2007-01-01

    Neuropeptide Y-containing interneurons in the dentate hilar area play an important role in inhibiting the activity of hippocampal circuitry. Hilar cells are often among the first lost in hippocampal epilepsy. As many types of neurons are found in the hilus, we used a new transgenic mouse expressing green fluorescent protein (GFP) in a subset of neurons that colocalized neuropeptide Y (NPY), somatostatin (SST), and GABA for whole-cell, perforated, and cell-attached recording in 240 neurons. As these neurons have not previously been identifiable in live slices, they have not been the focus of physiological analysis. Hilar NPY neurons showed modest spike frequency adaptation, a large 15.6 ± 1.0 mV afterhyperpolarization, a mean input resistance of 335 ± 26 mΩ, and were capable of fast-firing. Muscimol-mediated excitatory actions were found in a nominally Ca2+-free/high-Mg2+ bath solution using cell-attached recording. GABAA receptor antagonists inhibited half the recorded neurons and blocked burst firing. Gramicidin perforated-patch recording revealed a GABA reversal potential positive to both the resting membrane potential and spike threshold. Together, these data suggest GABA is excitatory to many NPY cells. NPY and SST consistently hyperpolarized and reduced spike frequency in these neurons. No hyperpolarization of NPY on membrane potential was detected in the presence of tetrodotoxin, AP5, CNQX and bicuculline, supporting an indirect effect. Under similar conditions, SST hyperpolarized the cells, suggesting a direct postsynaptic action. Depolarizing actions of GABA and GABA-dependent burst-firing may synchronize a rapid release of GABA, NPY, and SST, leading to pre- and postsynaptic inhibition of excitatory hippocampal circuits. PMID:17204505

  12. Immunohistochemical mapping of neuropeptide Y in the tree shrew brain.

    PubMed

    Ni, Rong-Jun; Shu, Yu-Mian; Luo, Peng-Hao; Fang, Hui; Wang, Yu; Yao, Lei; Zhou, Jiang-Ning

    2015-02-15

    Day-active tree shrews are promising animals as research models for a variety of human disorders. Neuropeptide Y (NPY) modulates many behaviors in vertebrates. Here we examined the distribution of NPY in the brain of tree shrews (Tupaia belangeri chinensis) using immunohistochemical techniques. The differential distribution of NPY-immunoreactive (-ir) cells and fibers were observed in the rhinencephalon, telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon of tree shrews. Most NPY-ir cells were multipolar or bipolar in shape with triangular, fusiform, and/or globular perikarya. The densest cluster of NPY-ir cells were found in the mitral cell layer of the main olfactory bulb (MOB), arcuate nucleus of the hypothalamus, and pretectal nucleus of the thalamus. The MOB presented a unique pattern of NPY immunoreactivity. Laminar distribution of NPY-ir cells was observed in the MOB, neocortex, and hippocampus. Compared to rats, the tree shrews exhibited a particularly robust and widespread distribution of NPY-ir cells in the MOB, bed nucleus of the stria terminalis, and amygdala as well as the ventral lateral geniculate nucleus and pretectal nucleus of the thalamus. By contrast, a low density of neurons were scattered in the striatum, neocortex, polymorph cell layer of the dentate gyrus, superior colliculus, inferior colliculus, and dorsal tegmental nucleus. These findings provide the first detailed mapping of NPY immunoreactivity in the tree shrew brain and demonstrate species differences in the distribution of this neuropeptide, providing an anatomical basis for the participation of the NPY system in the regulation of numerous physiological and behavioral processes.

  13. 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

  14. Neuropeptide Y and somatostatin inhibit insulin secretion through different mechanisms.

    PubMed

    Schwetz, Tara A; Ustione, Alessandro; Piston, David W

    2013-01-15

    Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through G(i) activation of Y(1) and SSTR(1&5) receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca(2+)](i)) activity upon glucose stimulation, whereas SST alters this response. G(βγ)-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca(2+)](i). mSIRK-induced G(βγ) activation does not modulate glucose metabolism but increases [Ca(2+)](i) activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through G(βγ) inhibition of Ca(2+) activity, while NPY activates a Ca(2+)-independent pathway mediated by G(α). GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies.

  15. Neuropeptide Y and somatostatin inhibit insulin secretion through different mechanisms

    PubMed Central

    Schwetz, Tara A.; Ustione, Alessandro

    2013-01-01

    Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through Gi activation of Y1 and SSTR1&5 receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca2+]i) activity upon glucose stimulation, whereas SST alters this response. Gβγ-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca2+]i. mSIRK-induced Gβγ activation does not modulate glucose metabolism but increases [Ca2+]i activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through Gβγ inhibition of Ca2+ activity, while NPY activates a Ca2+-independent pathway mediated by Gα. GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies. PMID:23211512

  16. Hypotension and reduced catecholamines in neuropeptide Y transgenic rats.

    PubMed

    Michalkiewicz, Mieczyslaw; Knestaut, Kriss M; Bytchkova, Elena Yu; Michalkiewicz, Teresa

    2003-05-01

    The neurons that control blood pressure express neuropeptide Y. Administered centrally, this neuropeptide reduces blood pressure and anxiety, together with lowering sympathetic outflow. The generation of neuropeptide Y transgenic rats overexpressing this peptide, under its natural promoter, has allowed us to examine the role of endogenous neuropeptide Y in the long-term control of blood pressure by the sympathetic nervous system. This study tested a hypothesis that endogenous neuropeptide Y acts to reduce blood pressure and catecholamine release. Blood pressure was measured by radiotelemetry in conscious male transgenic and nontransgenic littermates (control). Novel cage with cold water and forced swimming were used as stressors. Catecholamines were determined in 24-hour urine (baseline) and plasma (cold water stress) by a radioenzymatic assay. Blood pressures in baseline and during the stresses were significantly reduced in the transgenic rats. The lower blood pressure was associated with reduced catecholamines, lower decrease in pressure after autonomic ganglionic blockade, and increased longevity. Data obtained through the use of this transgenic rat model support and extend the evidence for the previously postulated sympatholytic and hypotensive effects of neuropeptide Y and provide novel evidence for an important physiological role of endogenous peptide in blood pressure regulation. As indicated by the increased longevity of these rats, in long-term regulation, these buffering actions of neuropeptide Y may have important cardiovascular protective effects against sympathetic hyperexcitation.

  17. NeuroPep: a comprehensive resource of neuropeptides

    PubMed Central

    Wang, Yan; Wang, Mingxia; Yin, Sanwen; Jang, Richard; Wang, Jian; Xue, Zhidong; Xu, Tao

    2015-01-01

    Neuropeptides play a variety of roles in many physiological processes and serve as potential therapeutic targets for the treatment of some nervous-system disorders. In recent years, there has been a tremendous increase in the number of identified neuropeptides. Therefore, we have developed NeuroPep, a comprehensive resource of neuropeptides, which holds 5949 non-redundant neuropeptide entries originating from 493 organisms belonging to 65 neuropeptide families. In NeuroPep, the number of neuropeptides in invertebrates and vertebrates is 3455 and 2406, respectively. It is currently the most complete neuropeptide database. We extracted entries deposited in UniProt, the database (www.neuropeptides.nl) and NeuroPedia, and used text mining methods to retrieve entries from the MEDLINE abstracts and full text articles. All the entries in NeuroPep have been manually checked. 2069 of the 5949 (35%) neuropeptide sequences were collected from the scientific literature. Moreover, NeuroPep contains detailed annotations for each entry, including source organisms, tissue specificity, families, names, post-translational modifications, 3D structures (if available) and literature references. Information derived from these peptide sequences such as amino acid compositions, isoelectric points, molecular weight and other physicochemical properties of peptides are also provided. A quick search feature allows users to search the database with keywords such as sequence, name, family, etc., and an advanced search page helps users to combine queries with logical operators like AND/OR. In addition, user-friendly web tools like browsing, sequence alignment and mapping are also integrated into the NeuroPep database. Database URL: http://isyslab.info/NeuroPep PMID:25931458

  18. From gonadotropin-inhibitory hormone to SIFamides: are echinoderm SALMFamides the "missing link" in a bilaterian family of neuropeptides that regulate reproductive processes?

    PubMed

    Elphick, Maurice R

    2013-11-01

    Gonadotropin-inhibitory hormone (GnIH) belongs to a family of vertebrate neuropeptides with a C-terminal PxRFamide motif, which exert effects by activating the G-protein coupled receptors NPFF1 and/or NPFF2. Comparative analysis of genome sequence data has revealed that orthologs of NPFF1/NPFF2-type receptors occur throughout the Bilateria and the neuropeptide ligand that activates the Drosophila NPFF1/NPFF2-type receptor has been identified as AYRKPPFNGSIFamide ("SIFamide"). Therefore, SIFamide-type neuropeptides, which occur throughout protostomian invertebrates, probably share a common evolutionary origin with vertebrate PxRFamide-type neuropeptides. Based on structural similarities, here SALMFamide neuropeptides are identified as candidate ligand components of this ancient bilaterian peptide-receptor signaling system in a deuterostomian invertebrate phylum, the echinoderms (e.g., starfish, sea urchins). Furthermore, functional studies provide evidence that PxRFamide/SALMFamide/SIFamide-type neuropeptides have evolutionarily conserved roles in regulation (typically inhibitory) of reproductive processes.

  19. Trafficking and fusion of neuropeptide Y-containing dense-core granules in astrocytes.

    PubMed

    Ramamoorthy, Prabhu; Whim, Matthew D

    2008-12-17

    It is becoming clear that astrocytes are active participants in synaptic functioning and exhibit properties, such as the secretion of classical transmitters, previously thought to be exclusively neuronal. Whether these similarities extend to the release of neuropeptides, the other major class of transmitters, is less clear. Here we show that cortical astrocytes can synthesize both native and foreign neuropeptides and can secrete them in a stimulation-dependent manner. Reverse transcription-PCR and mass spectrometry indicate that cortical astrocytes contain neuropeptide Y (NPY), a widespread neuronal transmitter. Immunocytochemical studies reveal NPY-immunoreactive (IR) puncta that colocalize with markers of the regulated secretory pathway. These NPY-IR puncta are distinct from the synaptic-like vesicles that contain classical transmitters, and the two types of organelles are differentially distributed. After activation of metabotropic glutamate receptors and the release of calcium from intracellular stores, the NPY-IR puncta fuse with the cell membrane, and the peptide-containing dense cores are displayed. To determine whether peptide secretion subsequently occurred, exocytosis was monitored from astrocytes expressing NPY-red fluorescent protein (RFP). In live cells, after activation of glutamate receptors, the intensity of the NPY-RFP-labeled puncta declined in a step-like manner indicating a regulated release of the granular contents. Because NPY is a widespread and potent regulator of synaptic transmission, these results suggest that astrocytes could play a role in the peptidergic modulation of synaptic signaling in the CNS.

  20. Activations of c-fos/c-jun signaling are involved in the modulation of hypothalamic superoxide dismutase (SOD) and neuropeptide Y (NPY) gene expression in amphetamine-mediated appetite suppression

    SciTech Connect

    Hsieh, Y.-S.; Yang, S.-F.; Chiou, H.-L.; Kuo, D.-Y. . E-mail: dykuo@csmu.edu.tw

    2006-04-15

    Amphetamine (AMPH) is known as an anorectic agent. The mechanism underlying the anorectic action of AMPH has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an appetite stimulant in the brain. This study was aimed to examine the molecular mechanisms behind the anorectic effect of AMPH. Results showed that AMPH treatment decreased food intake, which was correlated with changes of NPY mRNA level, but increased c-fos, c-jun and superoxide dismutase (SOD) mRNA levels in hypothalamus. To determine if c-fos or c-jun was involved in the anorectic response of AMPH, infusions of antisense oligonucleotide into the brain were performed at 1 h before daily AMPH treatment in freely moving rats, and the results showed that c-fos or c-jun knockdown could block this anorectic response and restore NPY mRNA level. Moreover, c-fos or c-jun knockdown could partially block SOD mRNA level that might involve in the modulation of NPY gene expression. It was suggested that c-fos/c-jun signaling might involve in the central regulation of AMPH-mediated feeding suppression via the modulation of NPY gene expression.

  1. 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

  2. [Neuropeptides, Cytokines and Thymus Peptides as Effectors of Interactions Between Thymus and Neuroendocrine System].

    PubMed

    Torkhovskaya, T I; Belova, O V; Zimina, I V; Kryuchkova, A V; Moskvina, S N; Bystrova, O V; Arion, V Ya; Sergienko, V I

    2015-01-01

    The review presents data on mutual influence of nervous system and thymus, realized through the neuroendocrine-immune interactions. The pres- ence of adrenergic and peptidergic nerves in thymus creates conditions for implementation of the effect of neuropeptides secreted by them. These neuropeptides induce activation of thymus cells receptors and influence on the main processes in thymus, including T-lymphocyte maturation, cytokine and hormones production. In turn, thymuspeptides and/or cytokines, controlled by them, enter the brain and exert influence on neuro- nalfunction, which creates the basis for changes of behavior and homeostasis maintenance in response to infection. Ageing and some infectious, autoimmune, neurodegenerative and cancer diseases are accompanied by distortion of interactions between thymus and central nervous system. Mechanisms of signaling pathways, which determine these interactions, are not revealed yet, and their understanding will promote the development of effective therapeutic strategies.

  3. 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.

  4. Molecular cloning and functional expression of a Drosophila receptor for the neuropeptides capa-1 and -2.

    PubMed

    Iversen, Annette; Cazzamali, Giuseppe; Williamson, Michael; Hauser, Frank; Grimmelikhuijzen, Cornelis J P

    2002-12-13

    The Drosophila Genome Project website contains an annotated gene (CG14575) for a G protein-coupled receptor. We cloned this receptor and found that the cloned cDNA did not correspond to the annotated gene; it partly contained different exons and additional exons located at the 5(')-end of the annotated gene. We expressed the coding part of the cloned cDNA in Chinese hamster ovary cells and found that the receptor was activated by two neuropeptides, capa-1 and -2, encoded by the Drosophila capability gene. Database searches led to the identification of a similar receptor in the genome from the malaria mosquito Anopheles gambiae (58% amino acid residue identities; 76% conserved residues; and 5 introns at identical positions within the two insect genes). Because capa-1 and -2 and related insect neuropeptides stimulate fluid secretion in insect Malpighian (renal) tubules, the identification of this first insect capa receptor will advance our knowledge on insect renal function.

  5. Shunt related changes in somatostatin, neuropeptide Y, and corticotropin releasing factor concentrations in patients with normal pressure hydrocephalus

    PubMed Central

    Poca, M; Mataro, M; Sahuquillo, J; Catalan, R; Ibanez, J; Galard, R

    2001-01-01

    OBJECTIVES—Recent data indicate that alterations in brain neuropeptides may play a pathogenic role in dementia. Neuropeptide Y (NPY), somastostatin (SOM), and corticotropin releasing factor (CRF) are neuropeptides involved in cognitive performance. Decreased SOM and NPY concentrations have been found in patients with normal pressure hydrocephalus and are probably the result of neuronal dysfunction, which could potentially be restored by shunting. The effects of shunt surgery on preoperative SOM, NPY, and CRF concentrations were studied. Any improvements in neuropeptide concentrations that could lead to clinically significant neuropsychological and functional changes were also investigated.
METHODS—A prospective study was performed in 14 patients with normal pressure hydrocephalus syndrome with a duration of symptoms between 3 months and 12 years. Diagnosis was based on intracranial pressure (ICP) monitoring and CSF dynamics. Concentrations of SOM, NPY, and CRF in lumbar CSF were determined before shunting and again 6-9 months after surgery. A battery of neuropsychological tests and several rating functional scales were also given to patients before and after shunting.
RESULTS—After shunting, SOM and CRF concentrations were significantly increased in all patients. Concentrations of NPY were increased in 12 of the 14 patients studied. The clinical condition of 13of the 14 patients was significantly improved 6 months after surgery. This improvement was more pronounced in gait disturbances and sphincter dysfunction than in cognitive impairment. No significant differences in any of the neuropsychological tests were seen for the group of patients as a whole despite the increased neuropeptide concentrations.
CONCLUSIONS—Shunting can restore SOM, NPY, and CRF concentrations even in patients with longstanding normal pressure hydrocephalus. However, despite the biochemical and clinical improvement in some areas such as ambulation and daily life activities

  6. 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

  7. Urbilaterian origin of paralogous GnRH and corazonin neuropeptide signalling pathways

    PubMed Central

    Tian, Shi; Zandawala, Meet; Beets, Isabel; Baytemur, Esra; Slade, Susan E.; Scrivens, James H.; Elphick, Maurice R.

    2016-01-01

    Gonadotropin-releasing hormone (GnRH) is a key regulator of reproductive maturation in humans and other vertebrates. Homologs of GnRH and its cognate receptor have been identified in invertebrates–for example, the adipokinetic hormone (AKH) and corazonin (CRZ) neuropeptide pathways in arthropods. However, the precise evolutionary relationships and origins of these signalling systems remain unknown. Here we have addressed this issue with the first identification of both GnRH-type and CRZ-type signalling systems in a deuterostome–the echinoderm (starfish) Asterias rubens. We have identified a GnRH-like neuropeptide (pQIHYKNPGWGPG-NH2) that specifically activates an A. rubens GnRH-type receptor and a novel neuropeptide (HNTFTMGGQNRWKAG-NH2) that specifically activates an A. rubens CRZ-type receptor. With the discovery of these ligand-receptor pairs, we demonstrate that the vertebrate/deuterostomian GnRH-type and the protostomian AKH systems are orthologous and the origin of a paralogous CRZ-type signalling system can be traced to the common ancestor of the Bilateria (Urbilateria). PMID:27350121

  8. Advances in Mass Spectrometric Tools for Probing Neuropeptides

    NASA Astrophysics Data System (ADS)

    Buchberger, Amanda; Yu, Qing; Li, Lingjun

    2015-07-01

    Neuropeptides are important mediators in the functionality of the brain and other neurological organs. Because neuropeptides exist in a wide range of concentrations, appropriate characterization methods are needed to provide dynamic, chemical, and spatial information. Mass spectrometry and compatible tools have been a popular choice in analyzing neuropeptides. There have been several advances and challenges, both of which are the focus of this review. Discussions range from sample collection to bioinformatic tools, although avenues such as quantitation and imaging are included. Further development of the presented methods for neuropeptidomic mass spectrometric analysis is inevitable, which will lead to a further understanding of the complex interplay of neuropeptides and other signaling molecules in the nervous system.

  9. The Role of Hypothalamic Neuropeptides in Neurogenesis and Neuritogenesis

    PubMed Central

    Bakos, Jan; Zatkova, Martina; Bacova, Zuzana; Ostatnikova, Daniela

    2016-01-01

    The hypothalamus is a source of neural progenitor cells which give rise to different populations of specialized and differentiated cells during brain development. Newly formed neurons in the hypothalamus can synthesize and release various neuropeptides. Although term neuropeptide recently undergoes redefinition, small-size hypothalamic neuropeptides remain major signaling molecules mediating short- and long-term effects on brain development. They represent important factors in neurite growth and formation of neural circuits. There is evidence suggesting that the newly generated hypothalamic neurons may be involved in regulation of metabolism, energy balance, body weight, and social behavior as well. Here we review recent data on the role of hypothalamic neuropeptides in adult neurogenesis and neuritogenesis with special emphasis on the development of food intake and social behavior related brain circuits. PMID:26881105

  10. Control of sleep-to-wake transitions via fast aminoacid and slow neuropeptide transmission

    PubMed Central

    Mosqueiro, Thiago; de Lecea, Luis; Huerta, Ramon

    2014-01-01

    The Locus Coeruleus (LC) modulates cortical, subcortical, cerebellar, brainstem and spinal cord circuits and it expresses receptors for neuromodulators that operate in a time scale of several seconds. Evidences from anatomical, electrophysiological and optogenetic experiments have shown that LC neurons receive input from a group of neurons called Hypocretins (HCRTs) that release a neuropeptide called hypocretin. It is less known how these two groups of neurons can be coregulated using GABAergic neurons. Since the time scales of GABAA inhibition is several orders of magnitude faster than the hypocretin neuropeptide effect, we investigate the limits of circuit activity regulation using a realistic model of neurons. Our investigation shows that GABAA inhibition is insufficient to control the activity levels of the LCs. Despite slower forms of GABAA can in principle work, there is not much plausibility due to the low probability of the presence of slow GABAA and lack of robust stability at the maximum firing frequencies. The best possible control mechanism predicted by our modeling analysis is the presence of inhibitory neuropeptides that exert effects in a similar time scale as the hypocretin/orexin. Although the nature of these inhibitory neuropeptides has not been identified yet, it provides the most efficient mechanism in the modeling analysis. Finally, we present a reduced mean-field model that perfectly captures the dynamics and the phenomena generated by this circuit. This investigation shows that brain communication involving multiple time scales can be better controlled by employing orthogonal mechanisms of neural transmission to decrease interference between cognitive processes and hypothalamic functions. PMID:25598695

  11. Studies of the secretion of corticotropin-releasing factor and arginine vasopressin into the hypophysial-portal circulation of the conscious sheep. II. The central noradrenergic and neuropeptide Y pathways cause immediate and prolonged hypothalamic-pituitary-adrenal activation. Potential involvement in the pseudo-Cushing's syndrome of endogenous depression and anorexia nervosa.

    PubMed Central

    Liu, J P; Clarke, I J; Funder, J W; Engler, D

    1994-01-01

    Studies were performed to determine the effects of intracerebroventricular norepinephrine (NE) or neuropeptide Y (NPY) on the ovine hypothalamic-pituitary-adrenal (HPA) axis. NE (50 micrograms) increased mean hypophysial-portal corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) levels (1 h, 1.3- and 2.9-fold; 4 h, 2.2- and 5.7-fold) and caused acute and sustained increases in mean plasma ACTH and cortisol. NPY (50 microgram) also increased mean CRF and AVP levels (1 h, 1.4- and 4.2-fold; 4 h, 1.1- and 1.9-fold), increased pituitary-adrenal activity at 1 h, and caused ACTH hypersecretion at 4 h. When added to cultured ovine anterior pituitary cells, NPY neither increased basal ACTH release nor augmented CRF- or AVP-induced ACTH release. We conclude that: (a) activation of either the central noradrenergic or NPY pathways causes an acute and sustained stimulation of the ovine HPA axis; (b) such activation increases the AVP/CRF ratio, suggesting a dominant role for AVP in the ovine stress response; and (c) the central noradrenergic or NPY systems may cause sustained HPA activation by attenuating or disrupting the glucocorticoid negative feedback on those brain areas concerned with regulation of the HPA axis. The possible roles of the central noradrenergic and NPY systems in the etiology of the hypercortisolemia of endogenous depression and anorexia nervosa are discussed. PMID:8163648

  12. Neuropeptide Y inhibits interleukin-1 beta-induced microglia motility.

    PubMed

    Ferreira, Raquel; Santos, Tiago; Cortes, Luísa; Cochaud, Stéphanie; Agasse, Fabienne; Silva, Ana Paula; Xapelli, Sara; Malva, João O

    2012-01-01

    Increasing evidences suggest that neuropeptide Y (NPY) may act as a key modulator of the cross-talk between the brain and the immune system in health and disease. In the present study, we dissected the possible inhibitory role of NPY upon inflammation-associated microglial cell motility. NPY, through activation of Y(1) receptors, was found to inhibit lipopolysaccharide (LPS)-induced microglia (N9 cell line) motility. Moreover, stimulation of microglia with LPS was inhibited by IL-1 receptor antagonist (IL-1ra), suggesting the involvement of endogenous interleukin-1 beta (IL-1β) in this process. Direct stimulation with IL-1β promoted downstream p38 mitogen-activated protein kinase mobilization and increased microglia motility. Moreover, consistently, p38 mitogen-activated protein kinase inhibition decreased the extent of actin filament reorganization occurring during plasma membrane ruffling and p38 phosphorylation was inhibited by NPY, involving Y(1) receptors. Significantly, the key inhibitory role of NPY on LPS-induced motility of CD11b-positive cells was further confirmed in mouse brain cortex explants. In summary, we revealed a novel functional role for NPY in the regulation of microglial function that may have important implications in the modulation of CNS injuries/diseases where microglia migration/motility might play a role.

  13. Neuropeptide signaling in the integration of metabolism and reproduction.

    PubMed

    Crown, Angelena; Clifton, Donald K; Steiner, Robert A

    2007-01-01

    Fertility is gated by nutrition and the availability of stored energy reserves, but the cellular and molecular mechanisms that link energy stores and reproduction are not well understood. Neuropeptides including galanin-like peptide (GALP), neuropeptide Y (NPY), products of the proopiomelanocortin (POMC; e.g., alpha-MSH and beta-endorphin), and kisspeptin are thought to be involved in this process for several reasons. First, the neurons that express these neuropeptides all reside in the hypothalamic arcuate nucleus, a critical site for the regulation of both metabolism and reproduction. Second, these neuropeptides are all targets for regulation by metabolic hormones, such as leptin and insulin. And third, these neuropeptides have either direct or indirect effects on feeding and metabolism, as well as on the secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). As the target for the action of metabolic hormones and sex steroids, these neuropeptides serve as molecular motifs integrating the control of metabolism and reproduction.

  14. Discovery of multiple neuropeptide families in the phylum Platyhelminthes.

    PubMed

    McVeigh, Paul; Mair, Gunnar R; Atkinson, Louise; Ladurner, Peter; Zamanian, Mostafa; Novozhilova, Ekaterina; Marks, Nikki J; Day, Tim A; Maule, Aaron G

    2009-09-01

    Available evidence shows that short amidated neuropeptides are widespread and have important functions within the nervous systems of all flatworms (phylum Platyhelminthes) examined, and could therefore represent a starting point for new lead drug compounds with which to combat parasitic helminth infections. However, only a handful of these peptides have been characterised, the rigorous exploration of the flatworm peptide signalling repertoire having been hindered by the dearth of flatworm genomic data. Through searches of both expressed sequence tags and genomic resources using the basic local alignment search tool (BLAST), we describe 96 neuropeptides on 60 precursors from 10 flatworm species. Most of these (51 predicted peptides on 14 precursors) are novel and are apparently restricted to flatworms; the remainder comprise nine recognised peptide families including FMRFamide-like (FLPs), neuropeptide F (NPF)-like, myomodulin-like, buccalin-like and neuropeptide FF (NPFF)-like peptides; notably, the latter have only previously been reported in vertebrates. Selected peptides were localised immunocytochemically to the Schistosoma mansoni nervous system. We also describe several novel flatworm NPFs with structural features characteristic of the vertebrate neuropeptide Y (NPY) superfamily, previously unreported characteristics which support the common ancestry of flatworm NPFs with the NPY-superfamily. Our dataset provides a springboard for investigation of the functional biology and therapeutic potential of neuropeptides in flatworms, simultaneously launching flatworm neurobiology into the post-genomic era.

  15. NPY/neuropeptide Y enhances autophagy in the hypothalamus: a mechanism to delay aging?

    PubMed

    Aveleira, Célia A; Botelho, Mariana; Cavadas, Cláudia

    2015-01-01

    Aging was recently described as a life event programmed by the hypothalamus, a key brain region that is crucial for the neuroendocrine interaction between the central nervous system and the periphery. Autophagy impairment is a hallmark of aging, contributing to the aging phenotype and to the aggravation of age-related diseases. Since hypothalamic autophagy decreases with age, strategies to promote autophagy in the hypothalamus may be relevant for control of the aging process. NPY (neuropeptide Y) is an endogenous neuropeptide mainly produced by the hypothalamus. We recently reported, for the first time, that NPY stimulates autophagy in rodent hypothalamus and mediates caloric restriction-induced autophagy in hypothalamic neurons. Moreover, we observed that NPY acts through NPY1R (neuropeptide Y receptor Y1) or NPY5R activation involving a concerted action of different signaling pathways. Since both hypothalamic autophagy and NPY levels decrease with age, modulation of NPY levels could provide new putative therapeutic tools to ameliorate age-related deteriorations and extend longevity.

  16. Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons.

    PubMed

    Bucelli, Robert C; Gonsiorek, Eugene A; Kim, Woo-Yang; Bruun, Donald; Rabin, Richard A; Higgins, Dennis; Lein, Pamela J

    2008-03-01

    Clinical and experimental observations suggest that statins may be useful for treating diseases presenting with predominant neurogenic inflammation, but the mechanism(s) mediating this potential therapeutic effect are poorly understood. In this study, we tested the hypothesis that statins act directly on sensory neurons to decrease expression of proinflammatory neuropeptides that trigger neurogenic inflammation, specifically calcitonin gene-related peptide (CGRP) and substance P. Reverse transcriptase-polymerase chain reaction, radioimmunoassay, and immunocytochemistry were used to quantify CGRP and substance P expression in dorsal root ganglia (DRG) harvested from adult male rats and in primary cultures of sensory neurons derived from embryonic rat DRG. Systemic administration of statins at pharmacologically relevant doses significantly reduced CGRP and substance P levels in DRG in vivo. In cultured sensory neurons, statins blocked bone morphogenetic protein (BMP)-induced CGRP and substance P expression and decreased expression of these neuropeptides in sensory neurons pretreated with BMPs. These effects were concentration-dependent and occurred independent of effects on cell survival or axon growth. Statin inhibition of neuropeptide expression was reversed by supplementation with mevalonate and cholesterol, but not isoprenoid precursors. BMPs signal via Smad activation, and cholesterol depletion by statins inhibited Smad1 phosphorylation and nuclear translocation. These findings identify a novel action of statins involving down-regulation of proinflammatory neuropeptide expression in sensory ganglia via cholesterol depletion and decreased Smad1 activation and suggest that statins may be effective in attenuating neurogenic inflammation.

  17. [Neuropeptide Y and autonomic nervous system].

    PubMed

    Nozdrachev, A D; Masliukov, P M

    2011-01-01

    Neuropeptide Y (NPY) containing 36 amino acid residues belongs to peptides widely spread in the central and peripheral nervous system. NPY and its receptors play an extremely diverse role in the nervous system, including regulation of satiety, of emotional state, of vascular tone, and of gastrointestinal secretion. In mammals, NPY has been revealed in the majority of sympathetic ganglion neurons, in a high number of neurons of parasympathetic cranial ganglia as well as of intramural ganglia of the metasympathetic nervous system. At present, six types of receptors to NPY (Y1-Y6) have been identified. All receptors to NPY belong to the family of G-bound proteins. Action of NPY on peripheral organs-targets is predominantly realized through postsynaptic receptors Y1, Y3-Y5, and presynaptic receptors of the Y2 type. NPY is present in large electron-dense vesicles and is released at high-frequency stimulation. NPY affects not only vascular tone, frequency and strength of heart contractions, motorics and secretion of the gastrointestinal tract, but also has trophic effect and produces proliferation of cells of organs-targets, specifically of vessels, myocardium, and adipose tissue. In early postnatal ontogenesis the percent of the NPY-containing neurons in ganglia of the autonomic nervous system increases. In adult organisms, this parameter decreases. This seems to be connected with the trophic NPY effect on cells-targets as well as with regulation of their functional state.

  18. Gut Lymphocyte Phenotype Changes after Parenteral Nutrition and Neuropeptide Administration

    PubMed Central

    Jonker, Mark A; Heneghan, Aaron F; Fechner, John H; Pierre, Joseph F; Sano, Yoshifumi; Lan, Jinggang; Kudsk, Kenneth A

    2016-01-01

    STRUCTURED ABSTRACT Objective Define gut associated lymphocyte phenotype (GALT) changes with parenteral nutrition (PN) and PN with bombesin (BBS). Summary Background Data PN reduces respiratory tract (RT) & GALT Peyer’s patch and lamina propria (LP) lymphocytes, lowers gut and RT IgA levels and destroys established RT antiviral & antibacterial immunity. BBS, an enteric nervous system (ENS) neuropeptide, reverses PN-induced IgA and RT immune defects. Methods Exp 1: IV-cannulated ICR mice received Chow, PN or PN + BBS injections for 5 days. LSR-II flow cytometer analyzed PP and LP isolated lymphocytes for homing phenotypes (L-selectin+ & LPAM-1+) and state of activation (CD25+, CD44+) in T (CD3+) cell subsets (CD4+ & CD8+) along with homing phenotype (L-selectin+ & LPAM-1+) in naive B (IgD+) and antigen-activated (IgD− or IgM+) B (CD45R/B220+) cells. Exp 2: Following initial experiment 1 protocol, LP T regulatory (Treg) cell phenotype was evaluated by Foxp3 expression. Results Exp 1: PN significantly reduced LP 1) CD4+CD25+ (activated) and 2) CD4+CD25+LPAM-1+ (activated cells homed to LP) T cells while PN-BBS assimilated Chow levels. PN significantly reduced LP 1) IgD+ (naïve), 2) IgD-LPAM+ (antigen-activated homed to LP) and CD44+ memory B cells while PN-BBS assimilated Chow levels. Exp 2: PN significantly reduced LP CD4+CD25+Foxp3+ Treg cells compared to Chow mice while PN+BBS assimilated Chow levels. Conclusions PN reduces LP activated and regulatory T cells as well as naïve and memory B cells. BBS addition to PN maintains these cell phenotypes, demonstrating the intimate involvement of the ENS in mucosal immunity. PMID:25563877

  19. 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

  20. BDNF and NT-4 differentiate two pathways in the modulation of neuropeptide protein levels in postnatal hippocampal interneurons.

    PubMed

    Marty, S; Onténiente, B

    1999-05-01

    Neuropeptide protein levels in hippocampal interneurons exhibit a considerable maturation in postnatal animals. This study characterizes the role of neuronal activity in determining neuropeptide protein levels in postnatal hippocampal interneurons, and the involvement of neurotrophins. In hippocampal slices from 7-day-old rats cultured for 2 weeks, treatment with the gamma-aminobutyric acidA (GABAA) receptor antagonist bicuculline increased the staining intensity and the number of neurons immunoreactive for neuropeptide Y (NPY). An opposite effect was observed when non-N-methyl-d-aspartate (non-NMDA) excitatory transmission was blocked. The effects of either treatment were reversed after return to control medium. These findings were similar to those previously obtained on the effects of activity on somatostatin immunostaining. Blockade of endogenous tyrosine kinase neurotrophin receptors using K252a prevented the effects of bicuculline on NPY- and somatostatin-immunoreactive neurons. Application of exogenous neurotrophin-3 (NT-3) increased NPY and somatostatin protein levels in long-term but not short-term cultures, while nerve growth factor (NGF) had no effect. In contrast, brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4) did not affect equally NPY and somatostatin immunoreactivity: they mimicked the effects of bicuculline treatment on NPY-immunoreactive neurons, but exerted no conspicuous effect on somatostatin immunostaining. These results indicate that although neuronal activity plays a major role in determining neuropeptide protein levels in postnatal hippocampal interneurons, its effects on different neuropeptides might be exerted through different mechanisms, with or without the mediation of BDNF or NT-4.

  1. Neuropeptide Y promotes neurogenesis in murine subventricular zone.

    PubMed

    Agasse, Fabienne; Bernardino, Liliana; Kristiansen, Heidi; Christiansen, Søren H; Ferreira, Raquel; Silva, Bruno; Grade, Sofia; Woldbye, David P D; Malva, João O

    2008-06-01

    Stem cells of the subventricular zone (SVZ) represent a reliable source of neurons for cell replacement. Neuropeptide Y (NPY) promotes neurogenesis in the hippocampal subgranular layer and the olfactory epithelium and may be useful for the stimulation of SVZ dynamic in brain repair purposes. We describe that NPY promotes SVZ neurogenesis. NPY (1 microM) treatments increased proliferation at 48 hours and neuronal differentiation at 7 days in SVZ cell cultures. NPY proneurogenic properties are mediated via the Y1 receptor. Accordingly, Y1 receptor is a major active NPY receptor in the mouse SVZ, as shown by functional autoradiography. Moreover, short exposure to NPY increased immunoreactivity for the phosphorylated form of extracellular signal-regulated kinase 1/2 in the nucleus, compatible with a trigger for proliferation, whereas 6 hours of treatment amplified the phosphorylated form of c-Jun-NH(2)-terminal kinase signal in growing axons, consistent with axonogenesis. NPY, as a promoter of SVZ neurogenesis, is a crucial factor for future development of cell-based brain therapy. Disclosure of potential conflicts of interest is found at the end of this article.

  2. Neuropeptide Y system in the retina: From localization to function.

    PubMed

    Santos-Carvalho, Ana; Ambrósio, António Francisco; Cavadas, Cláudia

    2015-07-01

    The retina is a highly complex structure where several types of cells communicate through countless different molecules to codify visual information. Each type of cells plays unique roles in the retina, presenting a singular expression of neurotransmitters. Some neurotransmitter systems in the retina are well understood, while others need to be better explored to unravel the intricate signaling system involved. Neuropeptide Y (NPY), a 36 amino acid peptide, is one of the most common peptide neurotransmitter in the CNS and a highly conserved peptide among species. We review the localization of NPY and NPY receptors (mainly NPY Y1, Y2, Y4 and Y5) in retinal cells. Common features of the expression of NPY and NPY receptors in mammalian and non-mammalian species indicate universal roles of this system in the retina. In the present review, we highlight the putative roles of NPY receptor activation in the retina, discussing, in particular, their involvement in retinal development, neurotransmitter release modulation, neuroprotection, microglia and Muller cells function, retinal pigmented epithelium changes, retinal endothelial physiology and proliferation of retinal progenitor cells. Further studies are needed to confirm that targeting the NPY system might be a potential therapeutic strategy for retinal degenerative diseases.

  3. FRPR-4 Is a G-Protein Coupled Neuropeptide Receptor That Regulates Behavioral Quiescence and Posture in Caenorhabditis elegans

    PubMed Central

    York, Neil; Lee, Kun He; Schoofs, Liliane; Raizen, David M.

    2015-01-01

    Neuropeptides signal through G-protein coupled receptors (GPCRs) to regulate a broad array of animal behaviors and physiological processes. The Caenorhabditis elegans genome encodes approximately 100 predicted neuropeptide receptor GPCRs, but in vivo roles for only a few have been identified. We describe here a role for the GPCR FRPR-4 in the regulation of behavioral quiescence and locomotive posture. FRPR-4 is activated in cell culture by several neuropeptides with an amidated isoleucine-arginine-phenylalanine (IRF) motif or an amidated valine-arginine-phenylalanine (VRF) motif at their carboxy termini, including those encoded by the gene flp-13. Loss of frpr-4 function results in a minor feeding quiescence defect after heat-induced cellular stress. Overexpression of frpr-4 induces quiescence of locomotion and feeding as well as an exaggerated body bend posture. The exaggerated body bend posture requires the gene flp-13. While frpr-4 is expressed broadly, selective overexpression of frpr-4 in the proprioceptive DVA neurons results in exaggerated body bends that require flp-13 in the ALA neuron. Our results suggest that FLP-13 and other neuropeptides signal through FRPR-4 and other receptors to regulate locomotion posture and behavioral quiescence. PMID:26571132

  4. 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.

  5. Neuropeptide Control of Feeding Behavior in Birds and Its Difference with Mammals.

    PubMed

    Tachibana, Tetsuya; Tsutsui, Kazuyoshi

    2016-01-01

    Feeding is an essential behavior for animals to sustain their lives. Over the past several decades, many neuropeptides that regulate feeding behavior have been identified in vertebrates. These neuropeptides are called "feeding regulatory neuropeptides." There have been numerous studies on the role of feeding regulatory neuropeptides in vertebrates including birds. Some feeding regulatory neuropeptides show different effects on feeding behavior between birds and other vertebrates, particularly mammals. The difference is marked with orexigenic neuropeptides. For example, melanin-concentrating hormone, orexin, and motilin, which are regarded as orexigenic neuropeptides in mammals, have no effect on feeding behavior in birds. Furthermore, ghrelin and growth hormone-releasing hormone, which are also known as orexigenic neuropeptides in mammals, suppress feeding behavior in birds. Thus, it is likely that the feeding regulatory mechanism has changed during the evolution of vertebrates. This review summarizes the recent knowledge of peptidergic feeding regulatory factors in birds and discusses the difference in their action between birds and other vertebrates.

  6. Brain neuropeptides in central ventilatory and cardiovascular regulation in trout

    PubMed Central

    Le Mével, Jean-Claude; Lancien, Frédéric; Mimassi, Nagi; Conlon, J. Michael

    2012-01-01

    Many neuropeptides and their G-protein coupled receptors (GPCRs) are present within the brain area involved in ventilatory and cardiovascular regulation but only a few mammalian studies have focused on the integrative physiological actions of neuropeptides on these vital cardio-respiratory regulations. Because both the central neuroanatomical substrates that govern motor ventilatory and cardiovascular output and the primary sequence of regulatory peptides and their receptors have been mostly conserved through evolution, we have developed a trout model to study the central action of native neuropeptides on cardio-ventilatory regulation. In the present review, we summarize the most recent results obtained using this non-mammalian model with a focus on PACAP, VIP, tachykinins, CRF, urotensin-1, CGRP, angiotensin-related peptides, urotensin-II, NPY, and PYY. We propose hypotheses regarding the physiological relevance of the results obtained. PMID:23115556

  7. Job Stress and Neuropeptide Response Contributing to Food Intake Regulation.

    PubMed

    Kim, Ki-Woong; Won, Yong Lim; Ko, Kyung Sun; Kang, Seong-Kyu

    2015-12-01

    The purpose of the present study is to investigate the correlations between food intake behavior and job stress level and neuropeptide hormone concentrations. Job strain and food intake behavior were first identified using a self-reported questionnaire, concentrations of neuropeptide hormones (adiponectin, brain derived neurotrophic factor [BDNF], leptin, and ghrelin) were determined, and the correlations were analyzed. In the results, job strain showed significant correlations with adiponectin (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.001~1.498; p < 0.05) and BDNF (OR, 0.793; 95% CI, 0.646~0.974; p < 0.05), and ghrelin exhibited a significant correlation with food intake score (OR, 0.911; 95% CI, 0.842~0.985, p < 0.05). These results suggest that job stress affects food intake regulation by altering the physiological concentrations of neuropeptide hormones as well as emotional status.

  8. Job Stress and Neuropeptide Response Contributing to Food Intake Regulation

    PubMed Central

    Kim, Ki-Woong; Won, Yong Lim; Ko, Kyung Sun

    2015-01-01

    The purpose of the present study is to investigate the correlations between food intake behavior and job stress level and neuropeptide hormone concentrations. Job strain and food intake behavior were first identified using a self-reported questionnaire, concentrations of neuropeptide hormones (adiponectin, brain derived neurotrophic factor [BDNF], leptin, and ghrelin) were determined, and the correlations were analyzed. In the results, job strain showed significant correlations with adiponectin (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.001~1.498; p < 0.05) and BDNF (OR, 0.793; 95% CI, 0.646~0.974; p < 0.05), and ghrelin exhibited a significant correlation with food intake score (OR, 0.911; 95% CI, 0.842~0.985, p < 0.05). These results suggest that job stress affects food intake regulation by altering the physiological concentrations of neuropeptide hormones as well as emotional status. PMID:26877843

  9. Peptidomics for the discovery and characterization of neuropeptides and hormones

    PubMed Central

    Romanova, Elena V.; Sweedler, Jonathan V.

    2015-01-01

    The discovery of neuropeptides as signaling molecules with paracrine or hormonal regulatory functions has led to trailblazing advances in physiology and fostered the characterization of numerous neuropeptide-binding G-protein coupled receptors (GPCRs) as potential drug targets. The impact on human health has been tremendous: approximately 30% of commercial drugs act via the GPCR pathway. However, about 25% of the GPCRs encoded by the mammalian genome still lack their pharmacological identity. Searching for the orphan GPCR endogenous ligands that likely are neuropeptides has proved to be a formidable task. Here we describe the mass spectrometry-based technologies and experimental strategies that have been successful in achieving high throughput characterization of endogenous peptides in nervous and endocrine systems. PMID:26143240

  10. Changes in cyclic nucleotides, locomotory behavior, and body length produced by novel endogenous neuropeptides in the parasitic nematode Ascaris suum.

    PubMed

    Reinitz, Catharine A; Pleva, Anthony E; Stretton, Antony O W

    2011-11-01

    Recent technical advances have rapidly advanced the discovery of novel peptides, as well as the transcripts that encode them, in the parasitic nematode Ascaris suum. Here we report that many of these novel peptides produce profound and varied effects on locomotory behavior and levels of cyclic nucleotides in A. suum. We investigated the effects of 31 endogenous neuropeptides encoded by transcripts afp-1, afp-2, afp-4, afp-6, afp-7, and afp-9-14 (afp: Ascaris FMRFamide-like Precursor protein) on cyclic nucleotide levels, body length and locomotory behavior. Worms were induced to generate anteriorly propagating waveforms, peptides were injected into the pseudocoelomic cavity, and changes in the specific activity (nmol/mg protein) of second messengers cAMP (3'5' cyclic adenosine monophosphate) and cGMP (3'5' cyclic guanosine monophosphate) were determined. Many of these neuropeptides changed the levels of cAMP (both increases and decreases were found), whereas few neuropeptides changed the level of cGMP. A subset of the peptides that lowered cAMP was investigated for effects on the locomotory waveform and on body length. Injection of AF19, or AF34 (afp-13), AF9 (afp-14), AF26 or AF41 (afp-11) caused immediate paralysis and cessation of propagating body waveforms. These neuropeptides also significantly increased body length. In contrast, injection of AF15 (afp-9) reduced the body length, and decreased the amplitude of waves in the body waveform. AF30 (afp-10) produced worms with tight ventral coils. Although injection of neuropeptides encoded by afp-1 (AF3, AF4, AF10 or AF13) produced an increased number of exaggerated body waves, there were no effects on either cAMP or cGMP. By injecting peptides into behaving A. suum, we have provided an initial screen of the effects of novel peptides on several behavioral and biochemical parameters.

  11. SALMFamide salmagundi: the biology of a neuropeptide family in echinoderms.

    PubMed

    Elphick, Maurice R

    2014-09-01

    The SALMFamides are a family of neuropeptides that occur in species belonging to the phylum Echinodermata. The prototypes for this neuropeptide family (S1 and S2) were discovered in starfish but subsequently SALMFamides were identified in other echinoderms. There are two types of SALMFamides: L-type, which have the C-terminal motif SxLxFamide, and F-type, which have the C-terminal motif SxFxFamide. They are derived from two types of precursor proteins: an L-type SALMFamide precursor, which comprises only L-type or L-type-like SALMFamides and an F-type SALMFamide precursor, which contains several F-type or F-type-like SALMFamides and, typically, one or more L-type SALMFamides. Thus, SALMFamides occur as heterogeneous mixtures of neuropeptides - a SALMFamide salmagundi. SALMFamides are produced by distinct populations of neurons in echinoderm larval and adult nervous systems and are present in the innervation of neuromuscular organs. Both L-type and F-type SALMFamides cause muscle relaxation in echinoderms and, for example, in starfish this effect of SALMFamides may mediate neural control of cardiac stomach eversion in species that feed extra-orally (e.g., Asterias rubens). The SALMFamide S1 also causes inhibition of neural release of a relaxin-like gonadotropin in the starfish Asterina pectinifera. An important issue that remains to be resolved are the relationships of SALMFamides with neuropeptides that have been identified in other phyla. However, it has been noted that the C-terminal SxLxFamide motif of L-type SALMFamides is a feature of some members of a bilaterian neuropeptide family that includes gonadotropin-inhibitory hormone (GnIH) in vertebrates and SIFamide-type neuropeptides in protostomes. Similarly, the C-terminal FxFamide motif of F-type SALMFamides is a feature of vertebrate QRFP (26RFa)-type neuropeptides. These sequence similarities may provide a basis for molecular identification of receptors that mediate effects of SALMFamides. Furthermore

  12. Intracerebral baclofen administration decreases amphetamine-induced behavior and neuropeptide gene expression in the striatum.

    PubMed

    Zhou, Wenxia; Mailloux, Adam W; McGinty, Jacqueline F

    2005-05-01

    In a previous study, systemic administration of the GABA(B) receptor agonist, R-(+)-baclofen (2.5 mg/kg, i.p.) blocked acute amphetamine (2.5 mg/kg, i.p.)-induced rearing and neuropeptide (preprodynorphin (PPD), preprotachykinin (PPT), preproenkephalin (PPE), and secretogranin II (SGII)) mRNA expression in the striatum (Zhou et al, 2004). The purpose of the present study was to investigate the site(s) of action of these baclofen effects in the dorsal and ventral striatal circuitries. Infusion of baclofen (75 ng/side) into the ventral tegmental area (VTA), substantia nigra (SN), nucleus accumbens (NA), caudate-putamen (Cpu), or medial prefrontal cortex (mPFC) had no effect on behavioral activity in saline-treated rats habituated to a photocell apparatus. However, intra-VTA infusion of baclofen (75 ng/side) completely blocked, whereas intra-NA and intra-SN infusion of baclofen attenuated, amphetamine-induced vertical activity without affecting amphetamine-induced total distance traveled. In contrast, intramedial PFC and intra-CPu infusion of baclofen had no effect on behavioral activity in amphetamine-treated rats. Infusion of baclofen into the VTA, NA, or SN decreased amphetamine-induced neuropeptide gene expression in the striatum. These results indicate that GABA(B) receptor stimulation within the ventral striatal circuitry is involved in mediating acute amphetamine-induced behaviors and neuropeptide gene expression in the dorsal and ventral striatum. The present study provides information on the potential targets in the brain for baclofen in the initial behavioral and genomic response to amphetamine.

  13. GABAB receptor stimulation decreases amphetamine-induced behavior and neuropeptide gene expression in the striatum.

    PubMed

    Zhou, Wenxia; Mailloux, Adam W; Jung, Bruce J; Edmunds, Hayward S; McGinty, Jacqueline F

    2004-04-09

    The purpose of this study was to investigate whether GABA(B) receptor activation blocks acute amphetamine-induced behavioral activity, dopamine release, and neuropeptide mRNA expression in the striatum. Systemic administration of R-(+)-baclofen (1.25 mg/kg, i.p.) did not alter total distance traveled or vertical rearing induced by amphetamine (2.5 mg/kg, i.p.). At 2.5 mg/kg, baclofen did not alter spontaneous motor activity or total distance traveled, but completely blocked vertical rearing induced by amphetamine. At 5.0 mg/kg, baclofen completely blocked both total distance traveled and vertical rearing induced by amphetamine. Quantitative in situ hybridization histochemistry revealed that baclofen (2.5 mg/kg, i.p.) decreased the ability of amphetamine to increase preprodynorphin (PPD), preprotachykinin (PPT), preproenkephalin (PPE), and secretogranin II (SGII) mRNA levels in the striatum without altering the basal levels of these signals. Baclofen also blocked the amphetamine-induced rise in SGII mRNA in the core and shell of the nucleus accumbens and cingulate cortex. In a separate experiment, systemic baclofen (2.5 mg/kg) decreased the amphetamine-induced increase in dialysate dopamine levels in the striatum. These results suggest that reduced striatal dopamine release contributes to the ability of GABA(B) receptor activation to decrease acute amphetamine-induced behavioral activity and striatal neuropeptide gene expression.

  14. Breakthrough in neuroendocrinology by discovering novel neuropeptides and neurosteroids: 1. Discovery of gonadotropin-inhibitory hormone (GnIH) across vertebrates.

    PubMed

    Tsutsui, Kazuyoshi; Ubuka, Takayoshi

    2014-09-01

    Bargmann-Scharrer's discovery of "neurosecretion" in the first half of the 20th century has since matured into the scientific discipline of neuroendocrinology. Identification of novel neurohormones, such as neuropeptides and neurosteroids, is essential for the progress of neuroendocrinology. Our studies over the past two decades have significantly broadened the horizons of this field of research by identifying novel neuropeptides and neurosteroids in vertebrates that have opened new lines of scientific investigation in neuroendocrinology. Since the discovery of gonadotropin-releasing hormone (GnRH) in mammals at the beginning of 1970s, it was generally believed that GnRH is the only hypothalamic neuropeptide regulating gonadotropin release in vertebrates. In 2000, however, we discovered a novel hypothalamic neuropeptide that actively inhibits gonadotropin release in quail and termed it gonadotropin-inhibitory hormone (GnIH). It now appears that GnIH is highly conserved across vertebrates, including humans, and serves a number of behavioral and physiological functions other than regulation of reproduction, providing enormous opportunity for investigators from a wide array of disciplines to study this neuropeptide. This review summarizes the discovery of GnIH and its contribution to the progress of neuroendocrinology.

  15. Role of voltage-gated cation channels and axon reflexes in the release of sensory neuropeptides by capsaicin from isolated rat trachea.

    PubMed

    Németh, József; Helyes, Zsuzsanna; Oroszi, Gábor; Jakab, Balázs; Pintér, Erika; Szilvássy, Zoltán; Szolcsányi, János

    2003-01-05

    In order to reveal the role of axon reflexes and sensory receptors in sensory neuropeptide release in response to capsaicin, liberation of substance P, calcitonin gene-related peptide and somatostatin from isolated rat tracheae was investigated in the presence of voltage-sensitive Na(+) and Ca(2+) channel blocking agents. Neuropeptide release induced by capsaicin (10 nM) remained unchanged in the presence of 25 mM lidocaine, 1 microM tetrodotoxin or the N-type Ca(2+) channel inhibitor, omega-conotoxin GVIA (100-300 nM). Peptide release by 100 pulses of 2 Hz field stimulation was prevented by lidocaine or tetrodotoxin. Omega-agatoxin TK (250 nM) significantly inhibited and Cd(2+) (200 microM) prevented capsaicin-induced neuropeptide release. These results suggest that chemical stimulation-induced neuropeptide release does not involve activation of fast Na(+) channels or N- and P-type voltage-dependent Ca(2+) channels, but contribution of Q-type Ca(2+) channels is possible. Sensory neuropeptides are released by capsaicin from sensory receptors without axon reflexes.

  16. Neuropeptide-Driven Cross-Modal Plasticity following Sensory Loss in Caenorhabditis elegans

    PubMed Central

    Rabinowitch, Ithai; Laurent, Patrick; Zhao, Buyun; Walker, Denise; Beets, Isabel; Schoofs, Liliane; Bai, Jihong; Schafer, William R.; Treinin, Millet

    2016-01-01

    Sensory loss induces cross-modal plasticity, often resulting in altered performance in remaining sensory modalities. Whereas much is known about the macroscopic mechanisms underlying cross-modal plasticity, only scant information exists about its cellular and molecular underpinnings. We found that Caenorhabditis elegans nematodes deprived of a sense of body touch exhibit various changes in behavior, associated with other unimpaired senses. We focused on one such behavioral alteration, enhanced odor sensation, and sought to reveal the neuronal and molecular mechanisms that translate mechanosensory loss into improved olfactory acuity. To this end, we analyzed in mechanosensory mutants food-dependent locomotion patterns that are associated with olfactory responses and found changes that are consistent with enhanced olfaction. The altered locomotion could be reversed in adults by optogenetic stimulation of the touch receptor (mechanosensory) neurons. Furthermore, we revealed that the enhanced odor response is related to a strengthening of inhibitory AWC→AIY synaptic transmission in the olfactory circuit. Consistently, inserting in this circuit an engineered electrical synapse that diminishes AWC inhibition of AIY counteracted the locomotion changes in touch-deficient mutants. We found that this cross-modal signaling between the mechanosensory and olfactory circuits is mediated by neuropeptides, one of which we identified as FLP-20. Our results indicate that under normal function, ongoing touch receptor neuron activation evokes FLP-20 release, suppressing synaptic communication and thus dampening odor sensation. In contrast, in the absence of mechanosensory input, FLP-20 signaling is reduced, synaptic suppression is released, and this enables enhanced olfactory acuity; these changes are long lasting and do not represent ongoing modulation, as revealed by optogenetic experiments. Our work adds to a growing literature on the roles of neuropeptides in cross

  17. Neuropeptide-Driven Cross-Modal Plasticity following Sensory Loss in Caenorhabditis elegans.

    PubMed

    Rabinowitch, Ithai; Laurent, Patrick; Zhao, Buyun; Walker, Denise; Beets, Isabel; Schoofs, Liliane; Bai, Jihong; Schafer, William R; Treinin, Millet

    2016-01-01

    Sensory loss induces cross-modal plasticity, often resulting in altered performance in remaining sensory modalities. Whereas much is known about the macroscopic mechanisms underlying cross-modal plasticity, only scant information exists about its cellular and molecular underpinnings. We found that Caenorhabditis elegans nematodes deprived of a sense of body touch exhibit various changes in behavior, associated with other unimpaired senses. We focused on one such behavioral alteration, enhanced odor sensation, and sought to reveal the neuronal and molecular mechanisms that translate mechanosensory loss into improved olfactory acuity. To this end, we analyzed in mechanosensory mutants food-dependent locomotion patterns that are associated with olfactory responses and found changes that are consistent with enhanced olfaction. The altered locomotion could be reversed in adults by optogenetic stimulation of the touch receptor (mechanosensory) neurons. Furthermore, we revealed that the enhanced odor response is related to a strengthening of inhibitory AWC→AIY synaptic transmission in the olfactory circuit. Consistently, inserting in this circuit an engineered electrical synapse that diminishes AWC inhibition of AIY counteracted the locomotion changes in touch-deficient mutants. We found that this cross-modal signaling between the mechanosensory and olfactory circuits is mediated by neuropeptides, one of which we identified as FLP-20. Our results indicate that under normal function, ongoing touch receptor neuron activation evokes FLP-20 release, suppressing synaptic communication and thus dampening odor sensation. In contrast, in the absence of mechanosensory input, FLP-20 signaling is reduced, synaptic suppression is released, and this enables enhanced olfactory acuity; these changes are long lasting and do not represent ongoing modulation, as revealed by optogenetic experiments. Our work adds to a growing literature on the roles of neuropeptides in cross

  18. Functional roles of neuropeptides in the insect central nervous system

    NASA Astrophysics Data System (ADS)

    Nässel, D. R.

    With the completion of the Drosophila genome sequencing project we can begin to appreciate the extent of the complexity in the components involved in signal transfer and modulation in the nervous system of an animal with reasonably complex behavior. Of all the different classes of signaling substances utilized by the nervous system, the neuropeptides are the most diverse structurally and functionally. Thus peptidergic mechanisms of action in the central nervous system need to be analyzed in the context of the neuronal circuits in which they act and generalized traits cannot be established. By taking advantage of Drosophila molecular genetics and the presence of identifiable neurons, it has been possible to interfere with peptidergic signaling in small populations of central neurons and monitor the consequences on behavior. These studies and experiments on other insects with large identifiable neurons, permitting cellular analysis of signaling mechanisms, have outlined important principles for temporal and spatial action of neuropeptides in outputs of the circadian clock and in orchestrating molting behavior. Considering the large number of neuropeptides available in each insect species and their diverse distribution patterns, it is to be expected that different neuropeptides play roles in most aspects of insect physiology and behavior.

  19. 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.

  20. The insect capa neuropeptides impact desiccation and cold stress responses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  1. Oxytocin: the neuropeptide of love reveals some of its secrets.

    PubMed

    Neumann, Inga D

    2007-04-01

    The neuropeptide oxytocin is synthesized in the brain and released from neurohypophyseal terminals into the blood and within defined brain regions that regulate emotional, cognitive, and social behaviors. A recent study of CD38-/- mice (Jin et al., 2007) has demonstrated an essential role for the transmembrane receptor CD38 in secretion of oxytocin into the blood.

  2. Mass Spectrometric Analysis of Spatio-Temporal Dynamics of Crustacean Neuropeptides

    PubMed Central

    OuYang, Chuanzi; Liang, Zhidan; Li, Lingjun

    2014-01-01

    Neuropeptides represent one of the largest classes of signaling molecules used by nervous systems to regulate a wide range of physiological processes. Over the past several years, mass spectrometry (MS)-based strategies have revolutionized the discovery of neuropeptides in numerous model organisms, especially in decapod crustaceans. Here, we focus our discussion on recent advances in the use of MS-based techniques to map neuropeptides in spatial domain and monitoring their dynamic changes in temporal domain. These MS-enabled investigations provide valuable information about the distribution, secretion and potential function of neuropeptides with high molecular specificity and sensitivity. In situ MS imaging and in vivo microdialysis are highlighted as key technologies for probing spatio-temporal dynamics of neuropeptides in the crustacean nervous system. This review summarizes the latest advancement in MS-based methodologies for neuropeptide analysis including typical workflow and sample preparation strategies as well as major neuropeptide families discovered in decapod crustaceans. PMID:25448012

  3. Feeding behavior and gene expression of appetite-related neuropeptides in mice lacking for neuropeptide Y Y5 receptor subclass.

    PubMed

    Higuchi, Hiroshi; Niki, Takeshi; Shiiya, Tomohiro

    2008-11-07

    Neuropeptide Y (NPY) is a potent neurotransmitter for feeding. Besides NPY, orexigenic neuropeptides such as agouti-related protein (AgRP), and anorexigenic neuropeptides such as alpha-melatonin stimulating hormone (MSH) and cocaine-amphetamine-regulated transcript (CART) are also involved in central feeding regulation. During fasting, NPY and AgRP gene expressions are up-regulated and POMC and CART gene expressions are down-regulated in hypothalamus. Based on the network of peptidergic neurons, the former are involved in positive feeding regulation, and the latter are involved in negative feeding, which exert these feeding-regulated peptides especially in paraventricular nucleus (PVN). To clarify the compensatory mechanism of knock-out of NPY system on feeding, change in gene expressions of appetite-related neuropeptides and the feeding behavior was studied in NPY Y5-KO mice. Food intake was increased in Y5-KO mice. Fasting increased the amounts of food and water intake in the KO mice more profoundly. These data indicated the compensatory phenomenon of feeding behavior in Y5-KO mice. RT-PCR and ISH suggested that the compensation of feeding is due to change in gene expressions of AgRP, CART and POMC in hypothalamus. Thus, these findings indicated that the compensatory mechanism involves change in POMC/CART gene expression in arcuate nucleus (ARC). The POMC/CART gene expression is important for central compensatory regulation in feeding behavior.

  4. Identification and characterization of a novel neuropeptide (neuropeptide Y-HS) from leech salivary gland of Haemadipsa sylvestris.

    PubMed

    Liu, Wei-Hui; Chen, Yan; Bai, Xue-Wei; Yao, Hui-Min; Zhang, Xu-Guang; Yan, Xiu-Wen; Lai, Ren

    2016-09-01

    The present study was designed to identify immunomodulatory components from the leech salivary gland of Haemadipsa sylvestris. The Sephadex G-50, Resource(TM) S column chromatography and reverse-phase high performance liquid chromatography (RP-HPLC) were used to isolate and purify the salivary gland extracts (SGE). Structural analysis of isolated compounds was based on Edman degradation and matrix assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS). The cDNA encoding the precursor of the compound was cloned from the cDNA library of the salivary gland of H. sylvestris. The levels of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interferon γ (IFN-γ), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1) were assayed using an enzyme-linked immunosorbent assay (ELISA). The effects on cell proliferation and cell viability were observed using MTT assay. A novel neuropeptide Y (Neuropeptide Y-HS) from the leech salivary gland of H. sylvestris was purified and characterized. It was composed of 36 amino acid residues and the amino acid sequence was determined to be FLEPPERPAVFTSVEQMKSYIKALNDYYLLLGRPRF-NH2, containing an amidated C-terminus. It showed significant inhibitory effects on the production of inflammatory cytokines including TNF-α, IFN-γ, IL-6, and MCP-1. Neuropeptide Y was identified from leeches for the first time. The presence of neuropeptide Y-HS in leech salivary gland may help get blood meal from hosts and inhibit inflammation.

  5. Identification and Functional Characterization of the Phosphorylation Sites of the Neuropeptide FF2 Receptor*

    PubMed Central

    Bray, Lauriane; Froment, Carine; Pardo, Pierre; Candotto, Cédric; Burlet-Schiltz, Odile; Zajac, Jean-Marie; Mollereau, Catherine; Moulédous, Lionel

    2014-01-01

    The neuropeptide FF2 (NPFF2) receptor belongs to the rhodopsin family of G protein-coupled receptors and mediates the effects of several related RFamide neuropeptides. One of the main pharmacological interests of this system resides in its ability to regulate endogenous opioid systems, making it a potential target to reduce the negative effects of chronic opioid use. Phosphorylation of intracellular residues is the most extensively studied post-translational modification regulating G protein-coupled receptor activity. However, until now, no information concerning NPFF2 receptor phosphorylation is available. In this study, we combined mass spectrometric analysis and site-directed mutagenesis to analyze for the first time the phosphorylation pattern of the NPFF2 receptor and the role of the various phosphorylation sites in receptor signaling, desensitization, and trafficking in a SH-SY5Y model cell line. We identified the major, likely GRK-dependent, phosphorylation cluster responsible for acute desensitization, 412TNST415 at the end of the C terminus of the receptor, and additional sites involved in desensitization (372TS373) and internalization (Ser395). We thus demonstrate the key role played by phosphorylation in the regulation of NPFF2 receptor activity and trafficking. Our data also provide additional evidence supporting the concept that desensitization and internalization are partially independent processes relying on distinct phosphorylation patterns. PMID:25326382

  6. Discovery of sea urchin NGFFFamide receptor unites a bilaterian neuropeptide family

    PubMed Central

    Semmens, Dean C.; Beets, Isabel; Rowe, Matthew L.; Blowes, Liisa M.; Oliveri, Paola; Elphick, Maurice R.

    2015-01-01

    Neuropeptides are ancient regulators of physiology and behaviour, but reconstruction of neuropeptide evolution is often difficult owing to lack of sequence conservation. Here, we report that the receptor for the neuropeptide NGFFFamide in the sea urchin Strongylocentrotus purpuratus (phylum Echinodermata) is an orthologue of vertebrate neuropeptide-S (NPS) receptors and crustacean cardioactive peptide (CCAP) receptors. Importantly, this has facilitated reconstruction of the evolution of two bilaterian neuropeptide signalling systems. Genes encoding the precursor of a vasopressin/oxytocin-type neuropeptide and its receptor duplicated in a common ancestor of the Bilateria. One copy of the precursor retained ancestral features, as seen in highly conserved vasopressin/oxytocin–neurophysin-type precursors. The other copy diverged, but this took different courses in protostomes and deuterostomes. In protostomes, the occurrence of a disulfide bridge in neuropeptide product(s) of the precursor was retained, as in CCAP, but with loss of the neurophysin domain. In deuterostomes, we see the opposite scenario—the neuropeptides lost the disulfide bridge, and neurophysin was retained (as in the NGFFFamide precursor) but was subsequently lost in vertebrate NPS precursors. Thus, the sea urchin NGFFFamide precursor and receptor are ‘missing links’ in the evolutionary history of neuropeptides that control ecdysis in arthropods (CCAP) and regulate anxiety in humans (NPS). PMID:25904544

  7. The Evolution and Variety of RFamide-Type Neuropeptides: Insights from Deuterostomian Invertebrates.

    PubMed

    Elphick, Maurice R; Mirabeau, Olivier

    2014-01-01

    Five families of neuropeptides that have a C-terminal RFamide motif have been identified in vertebrates: (1) gonadotropin-inhibitory hormone (GnIH), (2) neuropeptide FF (NPFF), (3) pyroglutamylated RFamide peptide (QRFP), (4) prolactin-releasing peptide (PrRP), and (5) Kisspeptin. Experimental demonstration of neuropeptide-receptor pairings combined with comprehensive analysis of genomic and/or transcriptomic sequence data indicate that, with the exception of the deuterostomian PrRP system, the evolutionary origins of these neuropeptides can be traced back to the common ancestor of bilaterians. Here, we review the occurrence of homologs of vertebrate RFamide-type neuropeptides and their receptors in deuterostomian invertebrates - urochordates, cephalochordates, hemichordates, and echinoderms. Extending analysis of the occurrence of the RFamide motif in other bilaterian neuropeptide families reveals RFamide-type peptides that have acquired modified C-terminal characteristics in the vertebrate lineage (e.g., NPY/NPF), neuropeptide families where the RFamide motif is unique to protostomian members (e.g., CCK/sulfakinins), and RFamide-type peptides that have been lost in the vertebrate lineage (e.g., luqins). Furthermore, the RFamide motif is also a feature of neuropeptide families with a more restricted phylogenetic distribution (e.g., the prototypical FMRFamide-related neuropeptides in protostomes). Thus, the RFamide motif is both an ancient and a convergent feature of neuropeptides, with conservation, acquisition, or loss of this motif occurring in different branches of the animal kingdom.

  8. Discovery of a novel insect neuropeptide signaling system closely related to the insect adipokinetic hormone and corazonin hormonal systems.

    PubMed

    Hansen, Karina K; Stafflinger, Elisabeth; Schneider, Martina; Hauser, Frank; Cazzamali, Giuseppe; Williamson, Michael; Kollmann, Martin; Schachtner, Joachim; Grimmelikhuijzen, Cornelis J P

    2010-04-02

    Neuropeptides and their G protein-coupled receptors (GPCRs) play a central role in the physiology of insects. One large family of insect neuropeptides are the adipokinetic hormones (AKHs), which mobilize lipids and carbohydrates from the insect fat body. Other peptides are the corazonins that are structurally related to the AKHs but represent a different neuropeptide signaling system. We have previously cloned an orphan GPCR from the malaria mosquito Anopheles gambiae that was structurally intermediate between the A. gambiae AKH and corazonin GPCRs. Using functional expression of the receptor in cells in cell culture, we have now identified the ligand for this orphan receptor as being pQVTFSRDWNAamide, a neuropeptide that is structurally intermediate between AKH and corazonin and that we therefore named ACP (AKH/corazonin-related peptide). ACP does not activate the A. gambiae AKH and corazonin receptors and, vice versa, AKH and corazonin do not activate the ACP receptor, showing that the ACP/receptor couple is an independent and so far unknown peptidergic signaling system. Because ACP is structurally intermediate between AKH and corazonin and the ACP receptor between the AKH and corazonin receptors, this is a prominent example of receptor/ligand co-evolution, probably originating from receptor and ligand gene duplications followed by mutations and evolutionary selection, thereby yielding three independent hormonal systems. The ACP signaling system occurs in the mosquitoes A. gambiae, Aedes aegypti, and Culex pipiens (Diptera), the silkworm Bombyx mori (Lepidoptera), the red flour beetle Tribolium castaneum (Coleoptera), the parasitic wasp Nasonia vitripennis (Hymenoptera), and the bug Rhodnius prolixus (Hemiptera). However, the ACP system is not present in 12 Drosophila species (Diptera), the honeybee Apis mellifera (Hymenoptera), the pea aphid Acyrthosiphon pisum (Hemiptera), the body louse Pediculus humanus (Phthiraptera), and the crustacean Daphnia pulex

  9. Genome-wide Census and Expression Profiling of Chicken Neuropeptide and Prohormone Convertase Genes

    PubMed Central

    Delfino, K. R.; Southey, B. R.; Sweedler, J. V.; Rodriguez-Zas, S. L.

    2009-01-01

    Neuropeptides regulate cell-cell signaling and influence many biological processes in vertebrates, including development, growth, and reproduction. The complex processing of neuropeptides from prohormone proteins by prohormone convertases, combined with the evolutionary distance between the chicken and mammalian species that have experienced extensive neuropeptide research, has led to the empirical confirmation of only 18 chicken prohormone proteins. To expand our knowledge of the neuropeptide and prohormone convertase gene complement, we performed an exhaustive survey of the chicken genomic, EST, and proteomic databases using a list of 95 neuropeptide and 7 prohormone convertase genes known in other species. Analysis of the EST resources and 22 microarray studies offered a comprehensive portrait of gene expression across multiple conditions. Five neuropeptide genes (apelin, cocaine-and amphetamine-regulated transcript protein, insulin-like 5, neuropeptide S, and neuropeptide B) previously unknown in chicken were identified and 62 genes were confirmed. Although most neuropeptide gene families known in human are present in chicken, there are several gene not present in the chicken. Conversely, several chicken neuropeptide genes are absent from mammalian species, including C-RF amide, c-type natriuretic peptide 1 precursor, and renal natriuretic peptide. The prohormone convertases, with one exception, were found in the chicken genome. Bioinformatic models used to predict prohormone cleavages confirm that the processing of prohormone proteins into neuropeptides is similar between species. Neuropeptide genes are most frequently expressed in the brain and head, followed by the ovary and small intestine. Microarray analyses revealed that the expression of adrenomedullin, chromogranin-A, augurin, neuromedin-U, platelet-derived growth factor A and D, proenkephalin, relaxin-3, prepronociceptin, and insulin-like growth factor I was most susceptible (P-value < 0.001) to

  10. Neural regulation of sex pheromone biosynthesis in Heliothis moths

    PubMed Central

    Teal, P. E. A.; Tumlinson, J. H.; Oberlander, H.

    1989-01-01

    Pheromone biosynthesis in females of Heliothis zea is regulated endogenously by a neuropeptide produced in the subesophageal ganglion. We have found that the ventral nerve cord must be intact for normal induction of pheromone biosynthesis and that pheromonotropic activity is associated with extracts of the abdominal nerve cord, but only during the period when pheromone is produced. We did not find evidence of pheromonotropic activity in hemolymph obtained from females that were producing pheromone. Extracts of the brain—subesophageal ganglion complex, which contain pheromone biosynthesis activating neuropeptide (PBAN), induced pheromone biosynthesis when applied to the terminal abdominal ganglion only if nerves from this ganglion to the pheromone gland were intact. Brain—subesophageal ganglion extracts did not induce biosynthesis when applied directly to the pheromone glands in vitro. From our results, we conclude that the target site of PBAN is not the pheromone gland but the terminal abdominal ganglion, and we hypothesize that the abdominal nerve cord transports PBAN to the terminal abdominal ganglion. PMID:16594023

  11. 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.

  12. Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response

    PubMed Central

    Shao, Li-Wa; Niu, Rong; Liu, Ying

    2016-01-01

    Neurons have a central role in the systemic coordination of mitochondrial unfolded protein response (UPRmt) and the cell non-autonomous modulation of longevity. However, the mechanism by which the nervous system senses mitochondrial stress and communicates to the distal tissues to induce UPRmt remains unclear. Here we employ the tissue-specific CRISPR-Cas9 approach to disrupt mitochondrial function only in the nervous system of Caenorhabditis elegans, and reveal a cell non-autonomous induction of UPRmt in peripheral cells. We further show that a neural sub-circuit composed of three types of sensory neurons, and one interneuron is required for sensing and transducing neuronal mitochondrial stress. In addition, neuropeptide FLP-2 functions in this neural sub-circuit to signal the non-autonomous UPRmt. Taken together, our results suggest a neuropeptide coordination of mitochondrial stress response in the nervous system. PMID:27767096

  13. 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.

  14. Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans

    PubMed Central

    Leinwand, Sarah G.; Chalasani, Sreekanth H.

    2013-01-01

    Neural circuits detect environmental changes and drive behavior. The routes of information flow through dense neural networks are dynamic; however, the mechanisms underlying this circuit flexibility are poorly understood. Here, we define a novel, sensory context-dependent and neuropeptide-regulated switch in the composition of a C. elegans salt sensory circuit. The primary salt detectors, ASE sensory neurons, use BLI-4 endoprotease-dependent cleavage to release the insulin-like peptide INS-6 in response to large but not small changes in external salt stimuli. Insulins, signaling through the insulin receptor DAF-2, functionally switch the AWC olfactory sensory neuron into an interneuron in the salt circuit. Animals with disrupted insulin signaling have deficits in salt attraction, suggesting that peptidergic signaling potentiates responses to high salt stimuli, which may promote ion homeostasis. Our results show that sensory context and neuropeptide signaling modify neural networks and suggest general mechanisms for generating flexible behavioral outputs by modulating neural circuit composition. PMID:24013594

  15. Expression of diverse neuropeptide cotransmitters by identified motor neurons in Aplysia

    SciTech Connect

    Church, P.J.; Lloyd, P.E. )

    1991-03-01

    Neuropeptide synthesis was determined for individual identified ventral-cluster neurons in the buccal ganglia of Aplysia. Each of these cells was shown to be a motor neuron that innervates buccal muscles that generate biting and swallowing movements during feeding. Individual neurons were identified by a battery of physiological criteria and stained with intracellular injection of a vital dye, and the ganglia were incubated in 35S-methionine. Peptide synthesis was determined by measuring labeled peptides in extracts from individually dissected neuronal cell bodies analyzed by HPLC. Previously characterized peptides found to be synthesized included buccalin, FMRFamide, myomodulin, and the 2 small cardioactive peptides (SCPs). Each of these neuropeptides has been shown to modulate buccal muscle responses to motor neuron stimulation. Two other peptides were found to be synthesized in individual motor neurons. One peptide, which was consistently observed in neurons that also synthesized myomodulin, is likely to be the recently sequenced myomodulin B. The other peptide was observed in a subset of the neurons that synthesize FMRFamide. While identified motor neurons consistently synthesized the same peptide(s), neurons that innervate the same muscle often express different peptides. Neurons that synthesized the SCPs also contained SCP-like activity, as determined by snail heart bioassay. Our results indicate that every identified motor neuron synthesizes a subset of these methionine-containing peptides, and that several neurons consistently synthesize peptides that are likely to be processed from multiple precursors.

  16. Sensory Neuropeptides and Endogenous Opioids Expression in Human Dental Pulp with Asymptomatic Inflammation: In Vivo Study

    PubMed Central

    Chavarria-Bolaños, Daniel; Flores-Reyes, Hector; Lombana-Sanchez, Nelson; Cerda-Cristerna, Bernardino; Pozos-Guillen, Amaury

    2015-01-01

    Purpose. This study quantified the expression of substance P (SP), calcitonin gene-related peptide (CGRP), β-endorphins (β-End), and methionine-enkephalin (Met-Enk) in human dental pulp following orthodontic intrusion. Methods. Eight patients were selected according to preestablished inclusion criteria. From each patient, two premolars (indicated for extraction due to orthodontic reasons) were randomly assigned to two different groups: the asymptomatic inflammation group (EXPg), which would undergo controlled intrusive force for seven days, and the control group (CTRg), which was used to determine the basal levels of each substance. Once extracted, dental pulp tissue was prepared to determine the expression levels of both neuropeptides and endogenous opioids by radioimmunoassay (RIA). Results. All samples from the CTRg exhibited basal levels of both neuropeptides and endogenous opioids. By day seven, all patients were asymptomatic, even when all orthodontic-intrusive devices were still active. In the EXPg, the SP and CGRP exhibited statistically significant different levels. Although none of the endogenous opioids showed statistically significant differences, they all expressed increasing trends in the EXPg. Conclusions. SP and CGRP were identified in dental pulp after seven days of controlled orthodontic intrusion movement, even in the absence of pain. PMID:26538838

  17. The propeptide precursor proSAAS is involved in fetal neuropeptide processing and body weight regulation.

    PubMed

    Morgan, Daniel J; Wei, Suwen; Gomes, Ivone; Czyzyk, Traci; Mzhavia, Nino; Pan, Hui; Devi, Lakshmi A; Fricker, Lloyd D; Pintar, John E

    2010-06-01

    Mice with a targeted mutation in proSAAS have been generated to investigate whether peptides derived from this precursor could function as an inhibitor of prohormone convertase 1/3 (PC1/3) in vivo as well as to determine any alternate roles for proSAAS in nervous and endocrine tissues. Fetal mice lacking proSAAS exhibit complete, adult-like processing of prodynorphin in the prenatal brain instead of the incomplete processing seen in the brains of wild-type fetal mice where inhibitory proSAAS intermediates are transiently accumulated. This study provides evidence that proSAAS is directly involved in the prenatal regulation of neuropeptide processing in vivo. However, adult mice lacking proSAAS have normal levels of all peptides detected using a peptidomics approach, suggesting that PC1/3 activity is not affected by the absence of proSAAS in adult mice. ProSAAS knockout mice exhibit decreased locomotion and a male-specific 10-15% decrease in body weight, but maintain normal fasting blood glucose levels and are able to efficiently clear glucose from the blood in response to a glucose challenge. This work suggests that proSAAS-derived peptides can inhibit PC1/3 in embryonic brain, but in the adult brain proSAAS peptides may function as neuropeptides that regulate body weight and potentially other behaviors.

  18. 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.

  19. 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

  20. Parasite neuropeptide biology: Seeding rational drug target selection?

    PubMed Central

    McVeigh, Paul; Atkinson, Louise; Marks, Nikki J.; Mousley, Angela; Dalzell, Johnathan J.; Sluder, Ann; Hammerland, Lance; Maule, Aaron G.

    2011-01-01

    The rationale for identifying drug targets within helminth neuromuscular signalling systems is based on the premise that adequate nerve and muscle function is essential for many of the key behavioural determinants of helminth parasitism, including sensory perception/host location, invasion, locomotion/orientation, attachment, feeding and reproduction. This premise is validated by the tendency of current anthelmintics to act on classical neurotransmitter-gated ion channels present on helminth nerve and/or muscle, yielding therapeutic endpoints associated with paralysis and/or death. Supplementary to classical neurotransmitters, helminth nervous systems are peptide-rich and encompass associated biosynthetic and signal transduction components – putative drug targets that remain to be exploited by anthelmintic chemotherapy. At this time, no neuropeptide system-targeting lead compounds have been reported, and given that our basic knowledge of neuropeptide biology in parasitic helminths remains inadequate, the short-term prospects for such drugs remain poor. Here, we review current knowledge of neuropeptide signalling in Nematoda and Platyhelminthes, and highlight a suite of 19 protein families that yield deleterious phenotypes in helminth reverse genetics screens. We suggest that orthologues of some of these peptidergic signalling components represent appealing therapeutic targets in parasitic helminths. PMID:24533265

  1. Suprachiasmatic Nucleus Neuropeptide Expression in Patients with Huntington's Disease

    PubMed Central

    van Wamelen, Daniel J.; Aziz, N. Ahmad; Anink, Jasper J.; van Steenhoven, Robin; Angeloni, Debora; Fraschini, Franco; Jockers, Ralf; Roos, Raymund A. C.; Swaab, Dick F.

    2013-01-01

    Study Objective: To study whether sleep and circadian rhythm disturbances in patients with Huntington's disease (HD) arise from dysfunction of the body's master clock, the hypothalamic suprachiasmatic nucleus. Design: Postmortem cohort study. Patients: Eight patients with HD and eight control subjects matched for sex, age, clock time and month of death, postmortem delay, and fixation time of paraffin-embedded hypothalamic tissue. Measurements and Results: Using postmortem paraffin-embedded tissue, we assessed the functional integrity of the suprachiasmatic nucleus in patients with HD and control subjects by determining the expression of two major regulatory neuropeptides, vasoactive intestinal polypeptide and arginine vasopressin. Additionally, we studied melatonin 1 and 2 receptor expression. Compared with control subjects, the suprachiasmatic nucleus contained 85% fewer neurons immunoreactive for vasoactive intestinal polypeptide and 33% fewer neurons for arginine vasopressin in patients with HD (P = 0.002 and P = 0.027). The total amount of vasoactive intestinal polypeptide and arginine vasopressin messenger RNA was unchanged. No change was observed in the number of melatonin 1 or 2 receptor immunoreactive neurons. Conclusions: These findings indicate posttranscriptional neuropeptide changes in the suprachiasmatic nucleus of patients with HD, and suggest that sleep and circadian rhythm disorders in these patients may at least partly arise from suprachiasmatic nucleus dysfunction. Citation: van Wamelen DJ; Aziz NA; Anink JJ; van Steenhoven R; Angeloni D; Fraschini F; Jockers R; Roos RAC; Swaab DF. Suprachiasmatic nucleus neuropeptide expression in patients with Huntington's disease. SLEEP 2013;36(1):117–125. PMID:23288978

  2. Insect capa neuropeptides impact desiccation and cold tolerance.

    PubMed

    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

    2015-03-03

    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.

  3. Hypothalamic plasticity of neuropeptide Y is lacking in brain-type creatine kinase double knockout mice with defective thermoregulation.

    PubMed

    Van der Zee, Catharina E E M

    2013-11-05

    The neural substrate of adaptive thermoregulation in mice lacking both brain-type creatine kinase isoforms is further investigated. The cytosolic brain-type creatine kinase (CK-B) and mitochondrial ubiquitous creatine kinase (UbCKmit) are expressed in neural cells throughout the central and peripheral nervous system, where they have an important role in cellular energy homeostasis. Several integral functions appear altered when creatine kinases are absent in the brain (Jost et al., 2002; Streijger et al., 2004, 2005), which has been explained by inefficient neuronal transmission. The CK--/-- double knockout mice demonstrate every morning a body temperature drop of ~1.0 °C, and they have impaired thermogenesis, as revealed by severe hypothermia upon cold exposure. This defective thermoregulation is not associated with abnormal food intake, decreased locomotive activity, or increased torpor sensitivity. Although white and brown adipose tissue fat pads are diminished in CK--/-- mice, intravenous norepinephrine infusion results in a normal brown adipose tissue response with increasing core body temperatures, indicating that the sympathetic innervation functions correctly (Streijger et al., 2009). This study revealed c-fos changes following a cold challenge, and that neuropeptide Y levels were decreased in the paraventricular nucleus of wildtype, but not CK--/--, mice. A reduction in hypothalamic neuropeptide Y is coupled to increased uncoupling protein 1 expression in brown adipose tissue, resulting in thermogenesis. In CK--/-- mice the neuropeptide Y levels did not change. This lack of hypothalamic plasticity of neuropeptide Y might be the result of inefficient neuronal transmission or can be explained by the previous observation of reduced circulating levels of leptin in CK--/-- mice.

  4. [Changes in neuropeptide Y and substance P immunoreactive nerve fibres and immunocompetent cells in hepatitis].

    PubMed

    Fehér, Erzsébet

    2015-11-22

    Neuropeptide Y and substance P were thought to play a role in the function of immune cells and in amplification or elimination of the inflammatory processes. In hepatitis the number of both neuropeptide Y and substance P immunoreactive nerve fibres are increased, where the increase of neoropeptide Y is significant. A large number of lymphocytes and mast cells are also stained for neuropeptide Y and substance P. Very close associations (less than 1 µm) were observed between neuropeptide Y immunoreactive nerve fibres and immune cells stained also with neuropeptide Y. Some immune cells were also found to be immunoreactive for tumor necrosis factor-α and NF-κB. Some of the SP IR immunocells were also stained for TNF-α and nuclear factor kappaB. Based on these data it is hypothesized that neuropeptid Y and substance P released from nerve fibres and immune cells play a role in inflammation and elimination of inflammation in hepatitis.

  5. Enkephalin levels and the number of neuropeptide Y-containing interneurons in the hippocampus are decreased in female cannabinoid-receptor 1 knock-out mice.

    PubMed

    Rogers, Sophie A; Kempen, Tracey A Van; Pickel, Virginia M; Milner, Teresa A

    2016-05-04

    Drug addiction requires learning and memory processes that are facilitated by activation of cannabinoid-1 (CB1) and opioid receptors in the hippocampus. This involves activity-dependent synaptic plasticity that is partially regulated by endogenous opioid (enkephalin and dynorphin) and non-opioid peptides, specifically cholecystokinin, parvalbumin and neuropeptide Y, the neuropeptides present in inhibitory interneurons that co-express CB1 or selective opioid receptors. We tested the hypothesis that CB1 receptor expression is a determinant of the availability of one or more of these peptide modulators in the hippocampus. This was achieved by quantitatively analyzing the immunoperoxidase labeling for each of these neuropeptide in the dorsal hippocampus of female wild-type (CB1+/+) and cannabinoid receptor 1 knockout (CB1-/-) C57/BL6 mice. The levels of Leu(5)-enkephalin-immunoreactivity were significantly reduced in the hilus of the dentate gyrus and in stratum lucidum of CA3 in CB1-/- mice. Moreover, the numbers of neuropeptide Y-immunoreactive interneurons in the dentate hilus were significantly lower in the CB1-/- compared to wild-type mice. However, CB1+/+ and CB1-/- mice did not significantly differ in expression levels of either dynorphin or cholecystokinin, and showed no differences in numbers of parvalbumin-containing interneurons. These findings suggest that the cannabinoid and opioid systems have a nuanced, regulatory relationship that could affect the balance of excitation and inhibition in the hippocampus and thus processes such as learning that rely on this balance.

  6. Region-specific bioconversion of dynorphin neuropeptide detected by in situ histochemistry and MALDI imaging mass spectrometry.

    PubMed

    Bivehed, Erik; Strömvall, Robert; Bergquist, Jonas; Bakalkin, Georgy; Andersson, Malin

    2017-01-01

    Brain region-specific expression of proteolytic enzymes can control the biological activity of endogenous neuropeptides and has recently been targeted for the development of novel drugs, for neuropathic pain, cancer, and Parkinson's disease. Rapid and sensitive analytical methods to profile modulators of enzymatic activity are important for finding effective inhibitors with high therapeutic value. Combination of in situ enzyme histochemistry with MALDI imaging mass spectrometry allowed developing a highly sensitive method for analysis of brain-area specific neuropeptide conversion of synthetic and endogenous neuropeptides, and for selection of peptidase inhibitors that differentially target conversion enzymes at specific anatomical sites. Conversion and degradation products of Dynorphin B as model neuropeptide and effects of peptidase inhibitors applied to native brain tissue sections were analyzed at different brain locations. Synthetic dynorphin B (2pmol) was found to be converted to the N-terminal fragments on brain sections whereas fewer C-terminal fragments were detected. N-ethylmaleimide (NEM), a non-selective inhibitor of cysteine peptidases, almost completely blocked the conversion of dynorphin B to dynorphin B(1-6; Leu-Enk-Arg), (1-9), (2-13), and (7-13). Proteinase inhibitor cocktail, and also incubation with acetic acid displayed similar results. Bioconversion of synthetic dynorphin B was region-specific producing dynorphin B(1-7) in the cortex and dynorphin B (2-13) in the striatum. Enzyme inhibitors showed region- and enzyme-specific inhibition of dynorphin bioconversion. Both phosphoramidon (inhibitor of the known dynorphin converting enzyme neprilysin) and opiorphin (inhibitor of neprilysin and aminopeptidase N) blocked cortical bioconversion to dynorphin B(1-7), wheras only opiorphin blocked striatal bioconversion to dynorphin B(2-13). This method may impact the development of novel therapies with aim to strengthen the effects of endogenous

  7. The Evolution and Variety of RFamide-Type Neuropeptides: Insights from Deuterostomian Invertebrates

    PubMed Central

    Elphick, Maurice R.; Mirabeau, Olivier

    2014-01-01

    Five families of neuropeptides that have a C-terminal RFamide motif have been identified in vertebrates: (1) gonadotropin-inhibitory hormone (GnIH), (2) neuropeptide FF (NPFF), (3) pyroglutamylated RFamide peptide (QRFP), (4) prolactin-releasing peptide (PrRP), and (5) Kisspeptin. Experimental demonstration of neuropeptide–receptor pairings combined with comprehensive analysis of genomic and/or transcriptomic sequence data indicate that, with the exception of the deuterostomian PrRP system, the evolutionary origins of these neuropeptides can be traced back to the common ancestor of bilaterians. Here, we review the occurrence of homologs of vertebrate RFamide-type neuropeptides and their receptors in deuterostomian invertebrates – urochordates, cephalochordates, hemichordates, and echinoderms. Extending analysis of the occurrence of the RFamide motif in other bilaterian neuropeptide families reveals RFamide-type peptides that have acquired modified C-terminal characteristics in the vertebrate lineage (e.g., NPY/NPF), neuropeptide families where the RFamide motif is unique to protostomian members (e.g., CCK/sulfakinins), and RFamide-type peptides that have been lost in the vertebrate lineage (e.g., luqins). Furthermore, the RFamide motif is also a feature of neuropeptide families with a more restricted phylogenetic distribution (e.g., the prototypical FMRFamide-related neuropeptides in protostomes). Thus, the RFamide motif is both an ancient and a convergent feature of neuropeptides, with conservation, acquisition, or loss of this motif occurring in different branches of the animal kingdom. PMID:24994999

  8. 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

  9. The neuropeptides Galanin and Galanin(1-15) in depression-like behaviours.

    PubMed

    Millón, Carmelo; Flores-Burgess, Antonio; Narváez, Manuel; Borroto-Escuela, Dasiel O; Gago, Belén; Santín, Luis; Castilla-Ortega, Estela; Narváez, José Ángel; Fuxe, Kjell; Díaz-Cabiale, Zaida

    2017-01-31

    Galanin is a 29 amino acid neuropeptide widely distributed in neurons within the central nervous system. Galanin exerts its biological activities through three different G protein-receptors and participates in a number of functions, including mood regulation. Not only Galanin but also Galanin N-terminal fragments like Galanin(1-15) are active at the central level. In this work, we review the latest findings in studies on Galanin and Galanin(1-15) in depression-related behaviours. Our focus is on animal models for depression, and we pay some attention to research data obtained in human studies. Since Serotonin (5-HT), especially through 5-HT1A, and Galanin receptors interact at both pre-and postsynaptic level, the development of drugs targeting potential GAL1-GAL2-5-HT1A heteroreceptor complexes linked to the raphe-hippocampal 5-HT neurons may represent new treatment strategies in depression.

  10. 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.

  11. [Cloning and analysis of three genes encoding type II CHH family neuropeptides from Fennropenaeus chinensis].

    PubMed

    Wang, Zai-Zhao; Xiang, Jian-Hai

    2003-10-01

    On the basis of sequence similarity, the crustean hyperglycemic hormone (CHH) family peptides have been classified into two types of hormones: type I and type II. Molt-inhibiting hormone (MIH) is a neuropeptide member of type II CHH family. Molting in shrimp is controlled by MIH and ecdysone. By inhibiting the synthesis of ecdysone in the Y-organ, MIH indirectly suppresses the molting activity of shrimp. In this study, we reported the cloning and characterization of 3 gene fragments encoding type II CHH family neuropeptides of the shrimp Fennropenaeus chinensis. According to the complementary DNA sequence of the mult-inhibiting hormone of Fennropenaeus chinensis, 3 primers were designed and synthesized. MP1 and MP2 are sense primers, and MP3 is anti-sense primer. Polymerase chain reaction was performed using genomic DNA of Fennropenaeus chinensis as template. Three PCR products were obtained using primers MP1 and MP3. Their sizes are about 600 bp, 850 bp, 1050 bp, respectively. A 580 bp PCR product was obtained using primers MP2 and MP3. All the 4 PCR products were cloned into pMD18-T vector. The recombinant clones were sequenced using ABI 310 Genetic Analyzer. After sequencing, all the DNA sequences were searched in the GenBank by Blast program to find similar gene sequences. The searching results revealed 3 DNA fragment sequences were of high similarity with CHH family neuropeptide genes from various crustean species. The 3 DNA fragments were named as NP1, NP2, and NP3. Their sizes were 540 bp, 601 bp, and 826 bp, respectively. Using the mRNA sequences with the most similarity to the 3 sequence fragments as reference, the gene structure of the 3 DNA fragment sequences was analyzed. The exons of 3 sequence fragments were aligned with their similar sequences by Clustal W program. Both NP1 and NP2 consisted of 1 intron and 2 exons. NP3 consisted of 2 introns and 3 exons. Sequence analysis suggested that these 3 products belonged to sequence fragments of neuropeptide

  12. 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.

  13. How to contribute to the progress of neuroendocrinology: New insights from discovering novel neuropeptides and neurosteroids regulating pituitary and brain functions.

    PubMed

    Tsutsui, Kazuyoshi

    2016-02-01

    Obtaining new insights by discovering novel neuropeptides and neurosteroids regulating pituitary and brain functions is essential for the progress of neuroendocrinology. At the beginning of 1970s, gonadotropin-releasing hormone (GnRH) was discovered in mammals. Since then, it was generally accepted that GnRH is the only hypothalamic neuropeptide regulating gonadotropin release in vertebrates. In 2000, however, gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide that actively inhibits gonadotropin release, was discovered in quail. The follow-up studies demonstrated that GnIH acts as a new key player for regulation of reproduction across vertebrates. It now appears that GnIH acts on the pituitary and the brain to serve a number of behavioral and physiological functions. On the other hand, a new concept has been established that the brain synthesizes steroids, called neurosteroids. The formation of neurosteroids in the brain was originally demonstrated in mammals and subsequently in other vertebrates. Recently, 7α-hydroxypregnenolone was discovered as a novel bioactive neurosteroid inducing locomotor behavior of vertebrates, indicating that neurosteroidogenesis in the brain is still incompletely elucidated in vertebrates. At the beginning of 2010s, it was further found that the pineal gland actively produces neurosteroids. Pineal neurosteroids act on the brain to regulate locomotor rhythms and neuronal survival. Furthermore, the interaction of neuropeptides and neurosteroids is becoming clear. GnIH decreases aggressive behavior by regulating neuroestrogen synthesis in the brain. This review summarizes these new insights by discovering novel neuropeptides and neurosteroids in the field of neuroendocrinology.

  14. Relationship of the Chemokine, CXCL12, to Effects of Dietary Fat on Feeding-Related Behaviors and Hypothalamic Neuropeptide Systems

    PubMed Central

    Poon, Kinning; Barson, Jessica R.; Ho, Hui T.; Leibowitz, Sarah F.

    2016-01-01

    The intake of a high fat diet (HFD), in addition to stimulating orexigenic neuropeptides in the hypothalamus while promoting overeating and reducing locomotor behavior, is known to increase inflammatory mediators that modulate neuronal systems in the brain. To understand the involvement of chemokines in the effects of a HFD, we examined in rats whether HFD intake affects a specific chemokine, CXCL12, and its receptors, CXCR4 and CXCR7, in the hypothalamus together with the neuropeptides and whether CXCL12 itself acts similarly to a HFD in stimulating the neuropeptides and altering ingestion and locomotor behavior. Compared to low-fat chow, a HFD for 5 days significantly increased the expression of CXCL12 and its receptors, in both the paraventricular nucleus (PVN) where the neuropeptides enkephalin (ENK) and galanin were also stimulated and the perifornical lateral hypothalamus (PFLH) where orexin (OX) and melanin-concentrating hormone (MCH) were increased. In contrast, the HFD had no impact on expression of CXCL12 or its receptors in the arcuate nucleus (ARC) where the carbohydrate-related peptide, neuropeptide Y (NPY), was suppressed. Analysis of protein levels revealed a similar stimulatory effect of a HFD on CXCL12 levels in the PVN and PFLH, as well as in blood, and an increase in the number of CXCR4-positive cells in the PVN. In the ARC, in contrast, levels of CXCL12 and number of CXCR4-positive cells were too low to measure. When centrally administered, CXCL12 was found to have similar effects to a HFD. Injection of CXCL12 into the third cerebral ventricle immediately anterior to the hypothalamus significantly stimulated the ingestion of a HFD, reduced novelty-induced locomotor activity, and increased expression of ENK in the PVN where the CXCR4 receptors were dense. It had no impact, however, on NPY in the ARC or on OX and MCH in the PFLH where the CXCR4 receptors were not detected. These results, showing CXCL12 in the hypothalamus to be stimulated by a HFD

  15. The ion transport peptide is a new functional clock neuropeptide in the fruit fly Drosophila melanogaster.

    PubMed

    Hermann-Luibl, Christiane; Yoshii, Taishi; Senthilan, Pingkalai R; Dircksen, Heinrich; Helfrich-Förster, Charlotte

    2014-07-16

    The clock network of Drosophila melanogaster expresses various neuropeptides, but a function in clock-mediated behavioral control was so far only found for the neuropeptide pigment dispersing factor (PDF). Here, we propose a role in the control of behavioral rhythms for the ion transport peptide (ITP), which is expressed in the fifth small ventral lateral neuron, one dorsal lateral neuron, and in only a few nonclock cells in the brain. Immunocytochemical analyses revealed that ITP, like PDF, is most probably released in a rhythmic manner at projection terminals in the dorsal protocerebrum. This rhythm continues under constant dark conditions, indicating that ITP release is clock controlled. ITP expression is reduced in the hypomorph mutant Clk(AR), suggesting that ITP expression is regulated by CLOCK. Using a genetically encoded RNAi construct, we knocked down ITP in the two clock cells and found that these flies show reduced evening activity and increased nocturnal activity. Overexpression of ITP with two independent timeless-GAL4 lines completely disrupted behavioral rhythms, but only slightly dampened PER cycling in important pacemaker neurons, suggesting a role for ITP in clock output pathways rather than in the communication within the clock network. Simultaneous knockdown (KD) of ITP and PDF made the flies hyperactive and almost completely arrhythmic under constant conditions. Under light-dark conditions, the double-KD combined the behavioral characteristics of the single-KD flies. In addition, it reduced the flies' sleep. We conclude that ITP and PDF are the clock's main output signals that cooperate in controlling the flies' activity rhythms.

  16. MALDI imaging mass spectrometry of neuropeptides in Parkinson's disease.

    PubMed

    Hanrieder, Jörg; Ljungdahl, Anna; Andersson, Malin

    2012-02-14

    MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples(2) (Fig.1). A 12 μm thin tissue section is covered with a MALDI matrix, which facilitates desorption and ionization of intact peptides and proteins that can be detected with a mass analyzer, typically using a MALDI TOF/TOF mass spectrometer. Generally hundreds of peaks can be assessed in a single rat brain tissue section. In contrast to commonly used imaging techniques, this approach does not require prior knowledge of the molecules of interest and allows for unsupervised and comprehensive analysis of multiple molecular species while maintaining high molecular specificity and sensitivity(2). Here we describe a MALDI IMS based approach for elucidating region-specific distribution profiles of neuropeptides in the rat brain of an animal model Parkinson's disease (PD). PD is a common neurodegenerative disease with a prevalence of 1% for people over 65 of age(3,4). The most common symptomatic treatment is based on dopamine replacement using L-DOPA(5). However this is accompanied by severe side effects including involuntary abnormal movements, termed L-DOPA-induced dyskinesias (LID)(1,3,6). One of the most prominent molecular change in LID is an upregulation of the opioid precursor prodynorphin mRNA(7). The dynorphin peptides modulate neurotransmission in brain areas that are essentially involved in movement control(7,8). However, to date the exact opioid peptides that originate from processing of the neuropeptide precursor have not been characterized. Therefore, we utilized MALDI IMS in an animal model of experimental Parkinson's disease and L-DOPA induced dyskinesia. MALDI imaging mass spectrometry proved to be particularly advantageous with respect to neuropeptide characterization, since commonly used antibody based approaches targets known peptide sequences and previously observed post-translational modifications. By

  17. MALDI Imaging Mass Spectrometry of Neuropeptides in Parkinson's Disease

    PubMed Central

    Hanrieder, Jörg; Ljungdahl, Anna; Andersson, Malin

    2012-01-01

    MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 (Fig.1). A 12 μm thin tissue section is covered with a MALDI matrix, which facilitates desorption and ionization of intact peptides and proteins that can be detected with a mass analyzer, typically using a MALDI TOF/TOF mass spectrometer. Generally hundreds of peaks can be assessed in a single rat brain tissue section. In contrast to commonly used imaging techniques, this approach does not require prior knowledge of the molecules of interest and allows for unsupervised and comprehensive analysis of multiple molecular species while maintaining high molecular specificity and sensitivity2. Here we describe a MALDI IMS based approach for elucidating region-specific distribution profiles of neuropeptides in the rat brain of an animal model Parkinson's disease (PD). PD is a common neurodegenerative disease with a prevalence of 1% for people over 65 of age3,4. The most common symptomatic treatment is based on dopamine replacement using L-DOPA5. However this is accompanied by severe side effects including involuntary abnormal movements, termed L-DOPA-induced dyskinesias (LID)1,3,6. One of the most prominent molecular change in LID is an upregulation of the opioid precursor prodynorphin mRNA7. The dynorphin peptides modulate neurotransmission in brain areas that are essentially involved in movement control7,8. However, to date the exact opioid peptides that originate from processing of the neuropeptide precursor have not been characterized. Therefore, we utilized MALDI IMS in an animal model of experimental Parkinson's disease and L-DOPA induced dyskinesia. MALDI imaging mass spectrometry proved to be particularly advantageous with respect to neuropeptide characterization, since commonly used antibody based approaches targets known peptide sequences and previously observed post-translational modifications. By contrast MALDI

  18. CGRP as a neuropeptide in migraine: lessons from mice

    PubMed Central

    Russo, Andrew F

    2015-01-01

    Migraine is a neurological disorder that is far more than just a bad headache. A hallmark of migraine is altered sensory perception. A likely contributor to this altered perception is the neuropeptide calcitonin gene-related peptide (CGRP). Over the past decade, CGRP has become firmly established as a key player in migraine. Although the mechanisms and sites of action by which CGRP might trigger migraine remain speculative, recent advances with mouse models provide some hints. This brief review focuses on how CGRP might act as both a central and peripheral neuromodulator to contribute to the migraine-like symptom of light aversive behaviour in mice. PMID:26032833

  19. Simultaneous demonstrations of neuropeptide Y gene expression and peptide storage in single neurons of the human brain

    SciTech Connect

    Chan-Palay, V.; Yasargil, G.; Hamid, Q.; Polak, J.M.; Palay, S.L.

    1988-05-01

    A combination of in situ hybridization for neuropeptide Y mRNA that used a /sup 32/P-labeled complementary RNA probe and immunocytochemistry with polyclonal antibodies against neuropeptide Y were applied to human cortical brain samples to simultaneously localize neuropeptide Y and its mRNA. These two techniques allowed simultaneous identification of neuropeptide Y gene expression and peptide storage in single neutrons of the human brain.

  20. 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.

  1. Increased prepubertal body weight enhances leptin sensitivity in proopiomelanocortin and neuropeptide y neurons before puberty onset in female rats.

    PubMed

    Castro-González, David; Fuente-Martín, Esther; Sánchez-Garrido, Miguel A; Argente-Arizón, Pilar; Tena-Sempere, Manuel; Barrios, Vicente; Chowen, Julie A; Argente, Jesús

    2015-04-01

    Pubertal onset may be advanced by obesity, with leptin potentially acting as a permissive factor. We hypothesized that having increased body weight (BW) prepubertally affects the ability of leptin to activate intracellular signaling pathways and modulate the expression of hypothalamic neuropeptides involved in reproduction and metabolism. Because being raised in small litters (SLs) tends to increase BW at weaning, female rats were raised in litters of 4 or large litters (LLs) of 12 pups. Leptin (3 μg/g BW) or vehicle (saline) was injected sc at postnatal day (PND) 21 and 30. Rats raised in SLs weighed more at both ages, but relative visceral and subcutaneous fat was increased only on PND21. Serum leptin levels were not different at PND21 or PND30. At PND21, key elements of intracellular leptin signaling (phosphorylated signal transducer and activator of transcription 3 and phosphorylated Akt [p-Akt]) were lower in SL than in LL rats. Leptin injection stimulated phosphorylated signal transducer and activator of transcription 3 in both groups, with a greater increase in LL, whereas p-Akt rose only in SL rats. At PND30, basal leptin signaling did not differ between LL and SL rats. Leptin activation of Akt was similar at 45 minutes, but at 2 hours p-AKT levels were higher in SL than in LL rats, as was the decrease in neuropeptide Y mRNA and increase in pro-opiomelanocortin mRNA levels. No change in the reproductive axis was found. Thus, being raised in SLs increases BW and visceral body fat content, fails to increase plasma leptin concentrations, and increases the leptin responsiveness of both neuropeptide Y and pro-opiomelanocortin cells in the prepubertal hypothalamus.

  2. Neuropeptide Control of Feeding Behavior in Birds and Its Difference with Mammals

    PubMed Central

    Tachibana, Tetsuya; Tsutsui, Kazuyoshi

    2016-01-01

    Feeding is an essential behavior for animals to sustain their lives. Over the past several decades, many neuropeptides that regulate feeding behavior have been identified in vertebrates. These neuropeptides are called “feeding regulatory neuropeptides.” There have been numerous studies on the role of feeding regulatory neuropeptides in vertebrates including birds. Some feeding regulatory neuropeptides show different effects on feeding behavior between birds and other vertebrates, particularly mammals. The difference is marked with orexigenic neuropeptides. For example, melanin-concentrating hormone, orexin, and motilin, which are regarded as orexigenic neuropeptides in mammals, have no effect on feeding behavior in birds. Furthermore, ghrelin and growth hormone-releasing hormone, which are also known as orexigenic neuropeptides in mammals, suppress feeding behavior in birds. Thus, it is likely that the feeding regulatory mechanism has changed during the evolution of vertebrates. This review summarizes the recent knowledge of peptidergic feeding regulatory factors in birds and discusses the difference in their action between birds and other vertebrates. PMID:27853416

  3. 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.

  4. Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y.

    PubMed

    Sabban, Esther L; Laukova, Marcela; Alaluf, Lishay G; Olsson, Emelie; Serova, Lidia I

    2015-12-01

    Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments. Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze

  5. Neuropeptides Modulate Female Chemosensory Processing upon Mating in Drosophila

    PubMed Central

    Zhang, Mo; Loschek, Laura F.; Grunwald Kadow, Ilona C.

    2016-01-01

    A female’s reproductive state influences her perception of odors and tastes along with her changed behavioral state and physiological needs. The mechanism that modulates chemosensory processing, however, remains largely elusive. Using Drosophila, we have identified a behavioral, neuronal, and genetic mechanism that adapts the senses of smell and taste, the major modalities for food quality perception, to the physiological needs of a gravid female. Pungent smelling polyamines, such as putrescine and spermidine, are essential for cell proliferation, reproduction, and embryonic development in all animals. A polyamine-rich diet increases reproductive success in many species, including flies. Using a combination of behavioral analysis and in vivo physiology, we show that polyamine attraction is modulated in gravid females through a G-protein coupled receptor, the sex peptide receptor (SPR), and its neuropeptide ligands, MIPs (myoinhibitory peptides), which act directly in the polyamine-detecting olfactory and taste neurons. This modulation is triggered by an increase of SPR expression in chemosensory neurons, which is sufficient to convert virgin to mated female olfactory choice behavior. Together, our data show that neuropeptide-mediated modulation of peripheral chemosensory neurons increases a gravid female’s preference for important nutrients, thereby ensuring optimal conditions for her growing progeny. PMID:27145127

  6. Pressor and tachycardic responses to intrathecal administration of neuropeptide FF in anesthetized rats.

    PubMed

    Fang, Quan; Li, Ning; Jiang, Tian-nan; Liu, Qian; Li, Yu-lin; Wang, Rui

    2010-04-01

    Neuropeptide FF (NPFF) belongs to a neuropeptide family including two precursors (pro-NPFF(A) and pro-NPFF(B)) and two receptors (NPFF(1) and NPFF(2)). NPFF and NPFF receptor mRNAs have been reported to be highly expressed and localized in the rat and human spinal cord. In the present study, the i.t. action of NPFF system on blood pressure and heart rate were examined using NPFF and two related agonists, NPVF and dNPA, which exhibit highest selectivities for NPFF(1) and NPFF(2) receptors, respectively. In urethane-anesthetized rats, NPFF and related peptides (5-40 nmol, i.t.) produced significant pressor and tachycardic responses at the spinal cord level. These effects were dose-dependent and similar with respect to time-course for the three peptides. Furthermore, i.t. injection of RF9 (20 nmol), a selective NPFF antagonist, significantly antagonized the cardiovascular responses to 20 nmol NPFF and related peptides (i.t.). Moreover, pretreatment of the rats with alpha-adrenoceptor antagonist phentolamine (1mg/kg, i.v.) significantly reduced the pressor effects of NPFF. Nevertheless, pretreatment with muscarinic receptor and adrenoceptor antagonists (i.v.) could block the tachycardic effects induced by NPFF. Collectively, our results suggested that i.t. administration of NPFF and related peptides increased MAP and HR which were possibly mediated by the activation of both NPFF(1) and NPFF(2) receptors in the rat spinal cord. In addition, our results showed that the muscarinic receptor and adrenoceptor participated in the tachycardic response to i.t. NPFF, while alpha-adrenoceptor played an important role in the regulation of pressor effect of NPFF.

  7. Immunohistochemical localization of the neuropeptide S receptor in the rat central nervous system.

    PubMed

    Leonard, S K; Ring, R H

    2011-01-13

    The neuropeptide S receptor (NPSR) is a G-protein coupled receptor that is potently activated by the linear 20 amino acid peptide, neuropeptide S (NPS). Central administration of NPS promotes arousal and anxiolytic-like effects in rodents, and fails to promote such effects in NPSR knockout animals or in the presence of NPSR-selective antagonists. In situ hybridization (ISH) studies in rat brain have revealed that the mRNAs encoding the NPS precursor and the NPS receptor are expressed at high levels in discrete regions of the rat CNS. The distribution of the NPSR protein in brain has not been reported due to a lack of available antibodies. We have generated and validated a NPSR-specific antibody and used it to determine the distribution of the NPSR in male Sprague-Dawley (SD) rat brain. The anti-NPSR antibody identified a single protein by Western blot with an estimated molecular weight of 65 kD, which was prevented by pre-incubation of the antibody with the immunizing peptide. The protein distribution identified with this antibody in rat brain was consistent both with the mRNA distribution identified by in situ hybridization, and to the localization pattern identified by a second NPSR-specific antibody against a distinct NPSR epitope. NPSR protein was identified in the medial amygdala (MeA), substantia nigra pars compacta, subiculum, dorsal raphe, and several hypothalamic and thalamic regions. Additionally, NPSR protein was localized in the pyramidal cell layer of the ventral hippocampus, the medial habenula (MHb), and was widely distributed in the cortex. The distribution of NPSR protein provides further insight into the organization of the NPS system and may guide future studies on the role of the NPSR in brain.

  8. The neuropeptide catestatin promotes vascular smooth muscle cell proliferation through the Ca{sup 2+}-calcineurin-NFAT signaling pathway

    SciTech Connect

    Guo, Xiaoxia; Zhou, Chunyan; Sun, Ningling

    2011-04-22

    Highlights: {yields} Catestatin stimulates proliferation of vascular smooth muscle cells in a dose-dependent manner. {yields} Catestatin provokes sustained increase in intracellular Ca{sup 2+}. {yields} Catestatin produces increased activation of calcineurin and promotes NFATc1 translocation into the nucleus. -- Abstract: The Chromogranin A-derived neuropeptide catestatin is an endogenous nicotinic cholinergic antagonist that acts as a pleiotropic hormone. Since catestatin shares several functions with other members derived from the chromogranin/secretogranin protein family and other neuropeptides which exert proliferative effects on vascular smooth muscle cells (VSMCs), we therefore hypothesized that catestatin would regulate VSMC proliferation. The present study demonstrates that catestatin caused a dose-dependent induction of proliferation in rat aortic smooth muscle cells and furthermore evoked a sustained increase in intracellular calcium. This subsequently leaded to enhanced activation of the Ca{sup 2+}/calmodulin-dependent phosphatase, calcineurin and resulted in an activation of the Ca{sup 2+}-dependent transcription factor, nuclear factor of activated T cells (NFAT), initiating transcription of proliferative genes. In addition, cyclosporin A (CsA), a potent inhibitor of calcineurin, abrogated catestatin-mediated effect on VSMCs, indicating that the calcineurin-NFAT signaling is strongly required for catestatin-induced growth of VSMCs. The present study establishes catestatin as a novel proliferative cytokine on vascular smooth muscle cells and this effect is mediated by the Ca{sup 2+}-calcineurin-NFAT signaling pathway.

  9. [Neuropeptides and psychiatry report presented at the French-Swiss Psychiatric meeting in Bel-Air, Geneva, 4 May 1980].

    PubMed

    Taban, C H

    1981-01-01

    In this mini-review the definition, some localizations and effects of 18 neuropeptides (as known at the beginning of 1980) are recalled, as well as some of the methods used. The hypothesis that neuropeptides may modify both functions and structures is presented. After a brief comment on the neuropeptides/monoamines relations and on some pharmacological results, the possible implications of neuropeptides dysfunctions in various psychiatric disorders are discussed. Some facts leading to the suspicion that both substance P and endorphines are increased in some psychoses are mentioned. The results of therapeutic trials are discussed. The importance of neuropeptides for the maintenance of internal homeostasis and behavioural adjustments is stressed.

  10. 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

  11. Cloning, expression and processing of the CP2 neuropeptide precursor of Aplysia.

    PubMed

    Vilim, F S; Alexeeva, V; Moroz, L L; Li, L; Moroz, T P; Sweedler, J V; Weiss, K R

    2001-12-01

    The cDNA sequence encoding the CP2 neuropeptide precursor is identified and encodes a single copy of the neuropeptide that is flanked by appropriate processing sites. The distribution of the CP2 precursor mRNA is described and matches the CP2-like immunoreactivity described previously. Single cell RT-PCR independently confirms the presence of CP2 precursor mRNA in selected neurons. MALDI-TOF MS is used to identify additional peptides derived from the CP2 precursor in neuronal somata and nerves, suggesting that the CP2 precursor may give rise to additional bioactive neuropeptides.

  12. Overexpression of neuropeptide Y induced by brain-derived neurotrophic factor in the rat hippocampus is long lasting.

    PubMed

    Reibel, S; Vivien-Roels, B; Lê, B T; Larmet, Y; Carnahan, J; Marescaux, C; Depaulis, A

    2000-02-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal neuroplasticity. In particular, BDNF upregulation in the hippocampus by epileptic seizures suggests its involvement in the neuronal rearrangements accompanying epileptogenesis. We have shown previously that chronic infusion of BDNF in the hippocampus induces a long-term delay in hippocampal kindling progression. Although BDNF has been shown to enhance the excitability of this structure upon acute application, long-term transcriptional regulations leading to increased inhibition within the hippocampus may account for its suppressive effects on epileptogenesis. Therefore, the long-term consequences of a 7-day chronic intrahippocampal infusion of BDNF (12 microg/day) were investigated up to 2 weeks after the end of the infusion, on the expression of neurotransmitters contained in inhibitory hippocampal interneurons and which display anti-epileptic properties. Our results show that BDNF does not modify levels of immunostaining for glutamic acid decarboxylase, the rate-limiting enzyme for gamma-aminobutyric acid (GABA) synthesis, and somatostatin. Conversely, BDNF induces a long-lasting increase of neuropeptide Y (NPY) in the hippocampus, measured by immunohistochemistry and radioimmunoassay, outlasting the end of the infusion by at least 7 days. The distribution of BDNF-induced neuropeptide Y immunoreactivity is similar to the pattern observed in animals submitted to hippocampal kindling, with the exception of mossy fibres which only become immunoreactive following seizure activity. The enduring increase of neuropeptide Y expression induced by BDNF in the hippocampus suggests that this neurotrophin can trigger long-term genomic effects, which may contribute to the neuroplasticity of this structure, in particular during epileptogenesis.

  13. Neuropeptide Y induces fasted pattern of duodenal motility via Y(2) receptors in conscious fed rats.

    PubMed

    Fujimiya, M; Itoh, E; Kihara, N; Yamamoto, I; Fujimura, M; Inui, A

    2000-01-01

    Neuropeptide Y (NPY), a 36-amino acid peptide abundantly expressed in the brain, has been implicated in the regulation of feeding and visceral functions. The present study was designed to investigate whether or not NPY specifically regulates duodenal motility. The manometric method was used to measure duodenal motility in conscious, freely moving rats. The rat duodenum showed phasic contractions mimicking the migrating motor complex in the fasted state that were replaced by irregular contractions after the ingestion of food. NPY powerfully affected the contractile activity after intracerebroventricular (i.c.v.) administration, changing fed (postprandial) patterns into phasic contractions characterized as fasted (interdigestive) patterns. This effect was mediated via receptors with pharmacological profiles similar to rat Y(2) and Y(4) receptors, although neither Y(1) nor Y(5) agonists had any effects on motility despite potent feeding-stimulatory effects. Immunoneutralization with anti-NPY antiserum administered i.c.v. abolished fasted patterns and induced fed-like motor activities. An i.c.v. dose of peptide YY produced a different effect from NPY, with increase in the motor activities of both fed and fasted patterns. These results indicate that fasted and fed motor activities are regulated processes and that NPY induces fasted activity through Y(2), and possibly Y(4), receptors, which may represent an integrated mechanism linked to the onset of feeding behavior.

  14. Neuropeptide Receptor Transcript Expression Levels and Magnitude of Ionic Current Responses Show Cell Type-Specific Differences in a Small Motor Circuit

    PubMed Central

    Garcia, Veronica J.; Daur, Nelly; Temporal, Simone; Schulz, David J.

    2015-01-01

    We studied the relationship between neuropeptide receptor transcript expression and current responses in the stomatogastric ganglion (STG) of the crab, Cancer borealis. We identified a transcript with high sequence similarity to crustacean cardioactive peptide (CCAP) receptors in insects and mammalian neuropeptide S receptors. This transcript was expressed throughout the nervous system, consistent with the role of CCAP in a range of different behaviors. In the STG, single-cell qPCR showed expression in only a subset of neurons. This subset had previously been shown to respond to CCAP with the activation of a modulator-activated inward current (IMI), with one exception. In the one cell type that showed expression but no IMI responses, we found CCAP modulation of synaptic currents. Expression levels within STG neuron types were fairly variable, but significantly different between some neuron types. We tested the magnitude and concentration dependence of IMI responses to CCAP application in two identified neurons, the lateral pyloric (LP) and the inferior cardiac (IC) neurons. LP had several-fold higher expression and showed larger current responses. It also was more sensitive to low CCAP concentrations and showed saturation at lower concentrations, as sigmoid fits showed smaller EC50 values and steeper slopes. In addition, occlusion experiments with proctolin, a different neuropeptide converging onto IMI, showed that saturating concentrations of CCAP activated all available IMI in LP, but only approximately two-thirds in IC, the neuron with lower receptor transcript expression. The implications of these findings for comodulation are discussed. PMID:25926455

  15. Dcf1 regulates neuropeptide expression and maintains energy balance.

    PubMed

    Liu, Qiang; Chen, Yu; Li, Qian; Wu, Liang; Wen, Tieqiao

    2017-04-01

    Neuropeptide Y (NPY) is an important neurotransmitter in the brain that plays a pivotal role in food intake and energy storage. Although many studies have focused on these functions, the regulation of NPY expression remains unclear. Here we showed that dendritic cell factor 1 (Dcf1) regulates NPY expression and maintains energy balance. We found that NPY expression is significantly reduced in the hypothalamus of Dcf1 knockout (Dcf1(-/-), KO) mice. In contrast, Dcf1 overexpression significantly increases NPY expression in the cell line. We also found that Dcf1 acts upstream of the NPY gene to regulate NPY expression and modulates the NPY-NPY receptor 1-GABA signal. Notably, we observed a significant increase in the ATP concentration in Dcf1(-/-) mice, suggesting a greater demand for energy in the absence of Dcf1. We studied the relationship between Dcf1 and NPY and revealed that Dcf1 plays a critical role in energy balance.

  16. The effect of obesogenic diets on brain Neuropeptide Y.

    PubMed

    Gumbs, Myrtille C R; van den Heuvel, José K; la Fleur, Susanne E

    2016-08-01

    Obesity is a major health problem characterized by accumulated fat mass. The availability of an energy-dense, highly palatable diet plays an important role in obesity development. Neuropeptide Y (NPY), an orexigenic peptide, is affected by dietary composition and NPY can affect dietary preference. The hypothalamic NPY system is well characterized and has been studied in several models of obesity. However, findings from models of diet-induced obesity are not straightforward. In addition, NPY plays a role in (food-)motivated behaviors and interacts with the mesolimbic dopamine system, both of which are altered in obesity. We here review the effect of obesogenic diets on NPY levels in the hypothalamus and reward-related regions.

  17. A d-Amino Acid-Containing Neuropeptide Discovery Funnel

    PubMed Central

    2016-01-01

    A receptor binding class of d-amino acid-containing peptides (DAACPs) is formed in animals from an enzymatically mediated post-translational modification of ribosomally translated all-l-amino acid peptides. Although this modification can be required for biological actions, detecting it is challenging because DAACPs have the same mass as their all-l-amino acid counterparts. We developed a suite of mass spectrometry (MS) protocols for the nontargeted discovery of DAACPs and validated their effectiveness using neurons from Aplysia californica. The approach involves the following three steps, with each confirming and refining the hits found in the prior step. The first step is screening for peptides resistant to digestion by aminopeptidase M. The second verifies the presence of a chiral amino acid via acid hydrolysis in deuterium chloride, labeling with Marfey’s reagent, and liquid chromatography–mass spectrometry to determine the chirality of each amino acid. The third involves synthesizing the putative DAACPs and comparing them to the endogenous standards. Advantages of the method, the d-amino acid-containing neuropeptide discovery funnel, are that it is capable of detecting the d-form of any common chiral amino acid, and the first two steps do not require peptide standards. Using these protocols, we report that two peptides from the Aplysia achatin-like neuropeptide precursor exist as GdYFD and SdYADSKDEESNAALSDFA. Interestingly, GdYFD was bioactive in the Aplysia feeding and locomotor circuits but SdYADSKDEESNAALSDFA was not. The discovery funnel provides an effective means to characterize DAACPs in the nervous systems of animals in a nontargeted manner. PMID:27788334

  18. Patterns of bromodeoxyuridine incorporation and neuropeptide immunoreactivity during arm regeneration in the starfish Asterias rubens

    PubMed Central

    Moss, C.

    1998-01-01

    Regeneration of the arm of the starfish, Asterias rubens (L.) (Echinodermata: Asteroidea) was examined using two preparations. The first involved regeneration of the entire arm tip and its associated sensory structures and the second examined regeneration of a small section of radial nerve cord in the mid-arm region. Cell cycle activity was investigated by incorporation of the thymidine analogue, bromodeoxyuridine (BrdU). Details of neuroanatomy were obtained by immunocytochemistry (ICC) using an antiserum to the recently isolated starfish neuropeptide, GFNSALMFamide (S1). BrdU labelling indicated that initial events occur by morphallaxis, with cell cycle activity first apparent after formation of a wound epidermis. As regeneration proceeded, BrdU immunoreactive (IR) nuclei revealed cell cycle activity in cells at the distal ends of the radial nerve cord epidermis, in the coelomic epithelium, the perihaemal and water vascular canal epithelia, and in the forming tube feet of both preparations. By varying the time between BrdU pulses and tissue fixation, the possible migration or differentiation of labelled cells was investigated. Neuropeptide ICC indicated the extension of S1-IR nerve fibres into the regenerating area, soon after initial wound healing processes were complete. These fibres were varicose and disorganized in appearance, when compared to the normal pattern of S1-IR in the radial nerve. S1-IR was also observed in cell bodies, which reappeared in the reforming optic cushion and radial nerve at later stages of regeneration. Double labelling studies with anti-BrdU and anti-S1 showed no co-localization in these cell bodies, in all the stages examined. It appeared that S1-IR cells were not undergoing, and had not recently undergone, cell cycle activity. It cannot be confirmed whether S1-IR neurons were derived from proliferating cells of epithelial origin, or from transdifferentiation of epithelial cells, although the former mechanism is suggested

  19. Co-regulation of cold-resistant food acquisition by insulin- and neuropeptide Y-like systems in Drosophila melanogaster.

    PubMed

    Lingo, P R; Zhao, Z; Shen, P

    2007-08-24

    To survive, food-deprived animals may be forced to forage under hostile conditions. We attempt to use genetically tractable Drosophila melanogaster as a model to elucidate molecular and neural mechanisms that drive a forager to engage in risk-prone food acquisition. Here we describe a paradigm for assessing hunger-driven food acquisition by fly larvae at a deleteriously cold temperature. Genetic analyses reveal that the neural activity of NPFR1, a receptor of neuropeptide F (NPF, the sole fly homolog of neuropeptide Y or NPY), was required for cold-resistant feeding behavior of fasted larvae. Conversely, NPFR1 overexpression in fed larvae was sufficient to trigger cold-resistant feeding activity normally associated with fasted larvae. Furthermore, the fly insulin-like system, implicated in the transduction of hunger signals to the CNS, regulated negatively larval cold-resistant food acquisition. The results from this and our previous studies suggest that the fly NPY-like system is a central mediator of hunger-elicited resistance to diverse stressors that can be of thermal, gustatory or mechanical form.

  20. Neuropeptide S receptor gene variation and neural correlates of cognitive emotion regulation

    PubMed Central

    Domschke, Katharina; Müller, Laura D.; Dresler, Thomas; Eff, Florian; Kopf, Juliane; Deckert, Jürgen; Reif, Andreas; Herrmann, Martin J.

    2015-01-01

    The neuropeptide S (NPS) and its receptor NPSR have captured attention in the pathogenesis of anxiety disorders. Here, a functional polymorphism in the NPSR1 gene has been linked to deviant cortico–limbic interactions in response to negative stimuli. While healthy T allele carriers exhibited increased amygdala and prefrontal cortex activity, panic disorder patients carrying the T risk allele displayed hypofrontality possibly reflecting insufficient prefrontal inhibition of limbic reactivity. In order to study multi-level effects of genotype and anxiety, prefrontal cortex activity during an emotional n-back task was measured in 66 volunteers genotyped for the NPSR1 rs324981 A/T variant (AA homozygotes vs. T allele carriers) by means of functional near-infrared spectroscopy. For a high working memory load (3-back), T allele carriers showed a signal increase to negative pictures in the dorsolateral and medial prefrontal cortex while AA homozygotes displayed a signal decrease. Since groups did not differ on skin conductance level and behavioral parameters, this effect in the risk group in line with results from fMRI studies is speculated to represent an adaptive mechanism to compensate for presumably increased subcortical activity driven by an overactive NPS system. However, anxiety sensitivity correlated negatively with prefrontal activity in T allele carriers possibly suggesting a decompensation of the adaptive compensatory upregulation. PMID:25971599

  1. Neuropeptide y and neuropeptide y y5 receptor interaction restores impaired growth potential of aging bone marrow stromal cells.

    PubMed

    Igura, Koichi; Haider, Husnain Kh; Ahmed, Rafeeq P H; Sheriff, Sulaiman; Ashraf, Muhammad

    2011-08-01

    Abstract improved growth characteristics of the aging bone marrow cells subsequent to neuropeptide Y (NPY)/neuropeptide Y Y5 receptor (NPY Y5R) ligand-receptor interaction. Bone marrow cells were isolated from neonatal (2-3 weeks), young (8-12 weeks), and old (24-28 months) rats on the basis of their preferential adherence to plastic surface. After culturing the cells at initial seeding density of 1×10(4) cells/cm(2), we found that the proliferation potential of bone marrow cells declined with age. Real-time polymerase chain reaction (PCR) and Western blotting showed that bone marrow cells in different age groups constitutively expressed NPY and NPY receptor subtypes (Y1R, Y2R, and Y5R). However, NPY and Y5R expression increased by more than 130-fold and decreased by 28-fold, respectively, in old bone marrow cells as compared to young bone marrow cells. NPY (10 nM) stimulated the proliferation of all bone marrow cells age groups, and their proliferation was blocked by Y5R antagonist. However, the pro-proliferative effect of NPY on old bone marrow cells was weaker than other cell groups due to lower Y5R expression. Y5R gene transfection of old bone marrow cells with subsequent NPY(3-36) (10 nM) treatment significantly increased proliferation of old bone marrow cells (>56%) as compared to green fluorescence protein-transfected control old bone marrow cells. Stimulation of old bone marrow cells by NPY treatment rejuvenated the growth characteristics of aging bone marrow cells as a result of Y5R overexpression.

  2. Neuronal Expression of the Human Neuropeptide S Receptor NPSR1 Identifies NPS-Induced Calcium Signaling Pathways

    PubMed Central

    Erdmann, Frank; Kügler, Sebastian; Blaesse, Peter; Lange, Maren D.; Skryabin, Boris V.; Pape, Hans-Christian; Jüngling, Kay

    2015-01-01

    The neuropeptide S (NPS) system was discovered as a novel neurotransmitter system a decade ago and has since been identified as a key player in the modulation of fear and anxiety. Genetic variations of the human NPS receptor (NPSR1) have been associated with pathologies like panic disorders. However, details on the molecular fundamentals of NPSR1 activity in neurons remained elusive. We expressed NPSR1 in primary hippocampal cultures. Using single-cell calcium imaging we found that NPSR1 stimulation induced calcium mobilization from the endoplasmic reticulum via activation of IP3 and ryanodine receptors. Store-operated calcium channels were activated in a downstream process mediating entry of extracellular calcium. We provide the first detailed analysis of NPSR1 activity and the underlying intracellular pathways with respect to calcium mobilization in neurons. PMID:25714705

  3. Neuropeptides and central control of sexual behaviour from the past to the present: a review.

    PubMed

    Argiolas, Antonio; Melis, Maria Rosaria

    2013-09-01

    Of the numerous neuropeptides identified in the central nervous system, only a few are involved in the control of sexual behaviour. Among these, the most studied are oxytocin, adrenocorticotropin, α-melanocyte stimulating hormone and opioid peptides. While opioid peptides inhibit sexual performance, the others facilitate sexual behaviour in most of the species studied so far (rats, mice, monkeys and humans). However, evidence for a sexual role of gonadotropin-releasing hormone, corticotropin releasing factor, neuropeptide Y, galanin and galanin-like peptide, cholecystokinin, substance P, vasoactive intestinal peptide, vasopressin, angiotensin II, hypocretins/orexins and VGF-derived peptides are also available. Corticotropin releasing factor, neuropeptide Y, cholecystokinin, vasopressin and angiotensin II inhibit, while substance P, vasoactive intestinal peptide, hypocretins/orexins and some VGF-derived peptide facilitate sexual behaviour. Neuropeptides influence sexual behaviour by acting mainly in the hypothalamic nuclei (i.e., lateral hypothalamus, paraventricular nucleus, ventromedial nucleus, arcuate nucleus), in the medial preoptic area and in the spinal cord. However, it is often unclear whether neuropeptides influence the anticipatory phase (sexual arousal and/or motivation) or the consummatory phase (performance) of sexual behaviour, except in a few cases (e.g., opioid peptides and oxytocin). Unfortunately, scarce information has been added in the last 15 years on the neural mechanisms by which neuropeptides influence sexual behaviour, most studied neuropeptides apart. This may be due to a decreased interest of researchers on neuropeptides and sexual behaviour or on sexual behaviour in general. Such a decrease may be related to the discovery of orally effective, locally acting type V phosphodiesterase inhibitors for the therapy of erectile dysfunction.

  4. 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.

  5. Differential plasma catecholamine and neuropeptide Y responses to acute stress in rats

    SciTech Connect

    Zukowska-Grojec, Z.; Konarska, M.; McCarty, R.

    1988-01-01

    Neuropeptide Y (NPY) is a vasoconstrictor present in the sympatho-adrenomedullary system and may be co-released with norepinephrine (NE) and epinephrine (EPI) during sympathetic activation. The authors studied plasma NPY-immunoreactivity (-ir, radioimmunoassay) and catecholamine (radioenzymatic) responses during two acute stress paradigms that differ in character, intensity, and duration. The intermittent stress of footshock evoked intensity-dependent immediate increments in plasma NE and EPI, and a delayed NPY-ir response. Prolonged immobilization caused greater increases in plasma NE and EPI levels and no changes in plasma NPY-ir until the end of the stress session. Plasma NPY-ir responses correlated with those of NE but not with EPI suggesting a sympathetic origin for the release of the peptide. Relatively greater NPY-ir responses to footshock than to immobilization may be consistent with a preferential release of the peptide by a bursting but not continuous mode of sympathetic activation. However, it may also be due to a differential activation of the sympathetic nerves and adrenal medulla by these two stress situations.

  6. Cell type-dependent trafficking of neuropeptide Y-containing dense core granules in CNS neurons.

    PubMed

    Ramamoorthy, Prabhu; Wang, Qian; Whim, Matthew D

    2011-10-12

    Neuropeptide transmitters are synthesized throughout the CNS and play important modulatory roles. After synthesis in the neuronal cell body, it is generally assumed that peptides are transported to nonspecialized sites of release. However, apart from a few cases, this scenario has not been thoroughly examined. Using wild-type and NPY(GFP) transgenic mice, we have studied the subcellular distribution of neuropeptide Y (NPY), a prototypical and broadly expressed neuropeptide. NPY puncta were found in the dendrites and axons of hippocampal GABAergic interneurons in situ. In contrast in hypothalamic GABAergic interneurons, NPY was restricted to the axon. Surprisingly this differential trafficking was preserved when the neurons were maintained in vitro. When hippocampal and hypothalamic neurons were transfected with NPY-Venus, the distribution of the fluorescent puncta replicated the cell type-specific distribution of endogenous neuropeptide Y. The NPY puncta in the axons of hippocampal and hypothalamic neurons colocalized with the sites of classical transmitter release (identified by staining for synapsin and the vesicular GABAergic transporter, VGAT). In hippocampal neurons, most of the postsynaptic NPY puncta were clustered opposite synapsin-containing varicosities. When neurons were stained for a second neuropeptide, agouti-related protein, immunoreactivity was found in the axon and dendrites of hippocampal neurons but only in the axons of hypothalamic neurons, thus mimicking the polarized distribution of NPY. These results indicate that the trafficking of neuropeptide-containing dense core granules is markedly cell type specific and is not determined entirely by the characteristics of the particular peptide per se.

  7. The endoparasitoid, Cotesia vestalis, regulates host physiology by reprogramming the neuropeptide transcriptional network.

    PubMed

    Shi, Min; Dong, Shuai; Li, Ming-tian; Yang, Yan-yan; Stanley, David; Chen, Xue-xin

    2015-02-02

    Endoparasitoids develop inside another insect by regulating host immunity and development via maternal factors injected into hosts during oviposition. Prior results have provided insights into parasitism-induced immunosuppression, including the neuropeptide accumulation in parasitized insects. Nonetheless, our understanding of neuropeptide influence on host development and behavior is not yet complete. We posed the hypothesis that parasitization alters expression of genes encoding pro-neuropeptides and used larvae of Plutella xylostella and its endoparasitoid, Cotesia vestalis to test our hypothesis. We prepared transcriptomes from the larval P. xylostella brain-CC-CA complex and identified transcripts encoding 19 neuropeptides. All corresponding cDNAs were confirmed by RACE. Our results demonstrate that parasitism significantly down-regulated, or delayed, expression of genes encoding pro-neuropeptides within 48 h post-parasitization. Changing expression of these genes may account for the previously reported decreased feeding behavior, reduced growth rates and aborted development in the host larvae. In effect, parasitization may operate at the molecular level within the CNS to create global changes in larval host biology. The significance of our finding is that, in addition to the known effects on immunity, parasitoids influence host pro-neuropeptide gene transcription. This finding reveals a new mechanism operating in host-parasitoid relationships to the advantage of the parasitoid.

  8. Inter-phyla studies on neuropeptides: the potential for broad-spectrum anthelmintic and/or endectocide discovery.

    PubMed

    Mousley, A; Maule, A G; Halton, D W; Marks, N J

    2005-01-01

    Flatworm, nematode and arthropod parasites have proven their ability to develop resistance to currently available chemotherapeutics. The heavy reliance on chemotherapy and the ability of target species to develop resistance has prompted the search for novel drug targets. In view of its importance to parasite/pest survival, the neuromusculature of parasitic helminths and pest arthropod species remains an attractive target for the discovery of novel endectocide targets. Exploitation of the neuropeptidergic system in helminths and arthropods has been hampered by a limited understanding of the functional roles of individual peptides and the structure of endogenous targets, such as receptors. Basic research into these systems has the potential to facilitate target characterization and its offshoots (screen development and drug identification). Of particular interest to parasitologists is the fact that selected neuropeptide families are common to metazoan pest species (nematodes, platyhelminths and arthropods) and fulfil specific roles in the modulation of muscle function in each of the three phyla. This article reviews the inter-phyla activity of two peptide families, the FMRFamide-like peptides and allatostatins, on motor function in helminths and arthropods and discusses the potential of neuropeptide signalling as a target system that could uncover novel endectocidal agents.

  9. Secretory granule biogenesis and neuropeptide sorting to the regulated secretory pathway in neuroendocrine cells.

    PubMed

    Loh, Y Peng; Kim, Taeyoon; Rodriguez, Yazmin M; Cawley, Niamh X

    2004-01-01

    Neuropeptide precursors synthesized at the rough endoplasmic reticulum are transported and sorted at the trans-Golgi network (TGN) to the granules of the regulated secretory pathway (RSP) of neuroendocrine cells. They are then processed into active peptides and stored in large dense-core granules (LDCGs) until secreted upon stimulation. We have studied the regulation of biogenesis of the LDCGs and the mechanism by which neuropeptide precursors, such as pro-opiomelanocortin (POMC), are sorted into these LDCGs of the RSP in neuroendocrine and endocrine cells. We provide evidence that chromogranin A (CgA), one of the most abundant acidic glycoproteins ubiquitously present in neuroendocrine/endocrine cells, plays an important role in the regulation of LDCG biogenesis. Specific depletion of CgA expression by antisense RNAs in PC12 cells led to a profound loss of secretory granule formation. Exogenously expressed POMC was neither stored nor secreted in a regulated manner in these CgA-deficient PC12 cells. Overexpression of CgA in a CgA- and LDCG-deficient endocrine cell line, 6T3, restored regulated secretion of transfected POMC and the presence of immunoreactive CgA at the tips of the processes of these cells. Unlike CgA, CgB, another granin protein, could not substitute for the role of CgA in regulating LDCG biogenesis. Thus, we conclude that CgA is a key player in the regulation of the biogenesis of LDCGs in neuroendocrine cells. To examine the mechanism of sorting POMC to the LDCGs, we carried out site-directed mutagenesis, transfected the POMC mutants into PC12 cells, and assayed for regulated secretion. Our previous molecular modeling studies predicted a three-dimensional sorting motif in POMC that can bind to a sorting receptor, membrane carboxypeptidase E (CPE). The sorting signal consists of four conserved residues at the N-terminal loop structure of POMC: two acidic residues and two hydrophobic residues. The two acidic residues were predicted to bind to a

  10. Reproduction Symposium: hypothalamic neuropeptides and the nutritional programming of puberty in heifers.

    PubMed

    Amstalden, M; Cardoso, R C; Alves, B R C; Williams, G L

    2014-08-01

    Nutrition during the juvenile period has a major impact on timing reproductive maturity in heifers. Restricted growth delays puberty, whereas elevated BW gain advances the onset of puberty. The initiation of high-frequency episodic release of GnRH and, consequently, LH during the peripubertal period is crucial for maturation of the reproductive axis and establishment of normal estrous cycles. Nutritional signals are perceived by metabolic-sensing cells in the hypothalamus, which interact with estradiol-receptive neurons to regulate the secretory activity of GnRH neurons. The orexigenic peptide, neuropeptide Y (NPY), and the anorexigenic peptide derived from the proopiomelanocortin (POMC) gene, melanocyte-stimulating hormone α (αMSH), are believed to be major afferent pathways that transmit inhibitory (NPY) and excitatory (αMSH) inputs to GnRH neurons. The neuropeptide kisspeptin is considered a major stimulator of GnRH secretion and has been shown to mediate estradiol's effect on GnRH neuronal activity. Kisspeptin may also integrate the neuronal pathways mediating the metabolic and gonadal steroid hormone control of gonadotropin secretion. Recent studies in our laboratories indicate that functional and structural changes in the pathways involving NPY, POMC, and kisspeptin neurons occur in response to high rates of BW gain during the juvenile period in heifers. Changes include regulation of expression in NPY, POMC, and KISS1 and plasticity in the neuronal projections to GnRH neurons and within the neuronal network comprising these cells. Moreover, an intricate pattern of differential gene expression in the arcuate nucleus of the hypothalamus occurs in response to feeding high concentrate diets that promote elevated BW gain. Genes involved include those controlling feeding intake and cell metabolism, neuronal growth and remodeling, and synaptic transmission. Characterizing the cellular pathways and molecular networks involved in the mechanisms that control the

  11. 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

  12. Receptor-mediated uptake of boron-rich neuropeptide y analogues for boron neutron capture therapy.

    PubMed

    Ahrens, Verena M; Frank, René; Boehnke, Solveig; Schütz, Christian L; Hampel, Gabriele; Iffland, Dorothée S; Bings, Nicolas H; Hey-Hawkins, Evamarie; Beck-Sickinger, Annette G

    2015-01-01

    Peptidic ligands selectively targeting distinct G protein-coupled receptors that are highly expressed in tumor tissue represent a promising approach in drug delivery. Receptor-preferring analogues of neuropeptide Y (NPY) bind and activate the human Y1 receptor subtype (hY1 receptor), which is found in 90% of breast cancer tissue and in all breast-cancer-derived metastases. Herein, novel highly boron-loaded Y1 -receptor-preferring peptide analogues are described as smart shuttle systems for carbaboranes as (10) B-containing moieties. Various positions in the peptide were screened for their susceptibility to carbaborane modification, and the most promising positions were chosen to create a multi-carbaborane peptide containing 30 boron atoms per peptide with excellent activation and internalization patterns at the hY1 receptor. Boron uptake studies by inductively coupled plasma mass spectrometry revealed successful uptake of the multi-carbaborane peptide into hY1 -receptor-expressing cells, exceeding the required amount of 10(9) boron atoms per cell. This result demonstrates that the NPY/hY receptor system can act as an effective transport system for boron-containing moieties.

  13. Mutations in arrestin-3 differentially affect binding to neuropeptide Y receptor subtypes.

    PubMed

    Gimenez, Luis E; Babilon, Stefanie; Wanka, Lizzy; Beck-Sickinger, Annette G; Gurevich, Vsevolod V

    2014-07-01

    Based on the identification of residues that determine receptor selectivity in arrestins and the phylogenetic analysis of the arrestin (arr) family, we introduced fifteen mutations of receptor-discriminator residues in arr-3, which were identified previously using mutagenesis, in vitro binding, and BRET-based recruitment assay in intact cells. The effects of these mutations were tested using neuropeptide Y receptors Y1R and Y2R. NPY-elicited arr-3 recruitment to Y1R was not affected by these mutations, or even alanine substitution of all ten residues (arr-3-NCA), which prevented arr-3 binding to other receptors tested so far. However, NCA and two other mutations prevented agonist-independent arr-3 pre-docking to Y1R. In contrast, eight out of 15 mutations significantly reduced agonist-dependent arr-3 recruitment to Y2R. NCA eliminated arr-3 binding to active Y2R, whereas Tyr239Thr reduced it ~7-fold. Thus, manipulation of key residues on the receptor-binding surface generates arr-3 with high preference for Y1R over Y2R. Several mutations differentially affect arr-3 pre-docking and agonist-induced recruitment. Thus, arr-3 recruitment to the receptor involves several mechanistically distinct steps. Targeted mutagenesis can fine-tune arrestins directing them to specific receptors and particular activation states of the same receptor.

  14. Neuroendocrine-Autonomic Integration in the Paraventricular Nucleus: Novel Roles for Dendritically Released Neuropeptides

    PubMed Central

    Stern, J. E.

    2015-01-01

    Communication between pairs of neurones in the central nervous system typically involves classical ‘hard-wired’ synaptic transmission, characterised by high temporal and spatial precision. Over the last two decades, however, knowledge regarding the repertoire of communication modalities used in the brain has notably expanded to include less conventional forms, characterised by a diffuse and less temporally precise transfer of information. These forms are best suited to mediate communication among entire neuronal populations, now recognised to be a fundamental process in the brain for the generation of complex behaviours. In response to an osmotic stressor, the hypothalamic paraventricular nucleus (PVN) generates a multimodal homeostatic response that involves orchestrated neuroendocrine (i.e. systemic release of vasopressin) and autonomic (i.e. sympathetic outflow to the kidneys) components. The precise mechanisms that underlie interpopulation cross-talk between these two distinct neuronal populations, however, remain largely unknown. The present review summarises and discusses a series of recent studies that have identified the dendritic release of neuropeptides as a novel interpopulation signalling modality in the PVN. A current working model is described in which it is proposed that the activity-dependent dendritic release of vasopressin from neurosecretory neurones in the PVN acts in a diffusible manner to increase the activity of distant presympathetic neurones, resulting in an integrated sympathoexcitatory population response, particularly within the context of a hyperosmotic challenge. The cellular mechanism underlying this novel form of intercellular communication, as well as its physiological and pathophysiological implications, is discussed. PMID:25546497

  15. Mutations in arrestin-3 differentially affect binding to neuropeptide Y receptor subtypes

    PubMed Central

    Gimenez, Luis E.; Babilon, Stefanie; Wanka, Lizzy; Beck-Sickinger, Annette G.; Gurevich, Vsevolod V.

    2014-01-01

    Based on the identification of residues that determine receptor selectivity in arrestins and the phylogenetic analysis of the arrestin (arr) family, we introduced fifteen mutations of receptor-discriminator residues in arr-3, which were identified previously using mutagenesis, in vitro binding, and BRET-based recruitment assay in intact cells. The effects of these mutations were tested using neuropeptide Y receptors Y1R and Y2R. NPY-elicited arr-3 recruitment to Y1R was not affected by these mutations, or even alanine substitution of all ten residues (arr-3-NCA), which prevented arr-3 binding to other receptors tested so far. However, NCA and two other mutations prevented agonist-independent arr-3 pre-docking to Y1R. In contrast, eight out of 15 mutations significantly reduced agonist-dependent arr-3 recruitment to Y2R. NCA eliminated arr-3 binding to active Y2R, whereas Tyr239Thr reduced it ~7-fold. Thus, manipulation of key residues on the receptor-binding surface generates arr-3 with high preference for Y1R over Y2R. Several mutations differentially affect arr-3 pre-docking and agonist-induced recruitment. Thus, arr-3 recruitment to the receptor involves several mechanistically distinct steps. Targeted mutagenesis can fine-tune arrestins directing them to specific receptors and particular activation states of the same receptor. PMID:24686081

  16. Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review of recent research strategies in depression.

    PubMed

    Hatzinger, M

    2000-04-01

    Depressed patients show a variety of alterations in hypothalamic-pituitary-adrenocortical (HPA) system regulation which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function tests. The latter include the combined dexamethasone (DEX) suppression/corticotropin-releasing hormone (CRH) challenge test, in which CRH was able to override DEX induced suppression of ACTH and cortisol secretion. Whereas the abnormal HPA activation in these patients improved in parallel with clinical remission, persistent HPA dysregulation was associated with an increased risk of relapse. Moreover, healthy subjects at high genetic risk for depression also showed this phenomenon as a trait marker. In consequence, it has been concluded that HPA alteration and development as well as course of depression may be causally related. As evidenced from clinical and preclinical studies, underlying mechanisms of these abnormalities involve impairment of central corticosteroid receptor function which leads to enhanced activity of hypothalamic neurons synthesising and releasing vasopressin and CRH. These neuropeptides mediate not only neuroendocrine but also behavioural effects. Recent research provided evidence that CRH can induce depression-like symptoms in animals and that these signs are mediated through the CRH1 receptor subtype. Hence, therapeutical application of new compounds acting more specifically on the HPA system such as CRH1 receptor antagonists appear to be a promising approach for future treatment options of depression. In conclusion, research in neuroendocrinology provided new insights into the underlying pathophysiology of depression and, in consequence, may lead to the development of new therapeutic tools.

  17. Neuropeptide Y reduces ovarian blood flow in the rabbit

    SciTech Connect

    Jorgensen, J.C.; Sejrsen, P. )

    1990-05-01

    Neuropeptide Y-containing nerve fibers have previously been demonstrated to innervate the mammalian ovary. These nerve fibers innervate primarily the vasculature. In this study we have developed a method for in vivo measurement of the ovary blood flow rate by means of the {sup 133}Xe method. Using this technique we measured the ovary blood flow rate and investigated the dose-response relationship between close intraarterial-injected NPY and the ovary blood flow rate. A monoexponential washout curve for {sup 133}Xe was found for the whole washout process, ensuring that the blood flow rate at any time could be calculated from the curve. We found a mean blood flow rate in the nonpregnant rabbit ovary at 43.6 +/- 4.4 ml.(100 g)-1.min-1 (mean +/- SEM). Injection of NPY (20, 200, 2000 pM) in the aorta close to a. ovarica resulted in a dose-dependent decrease in the ovarian blood flow rate with a maximum reduction to 40.7 +/- 6.3% (mean +/- SEM) of the control blood flow rate. These findings make it likely that receptors able to interact with NPY are present in the vasculature of the rabbit ovary.

  18. The effect of tachykinin neuropeptides on amyloid {beta} aggregation

    SciTech Connect

    Flashner, Efrat; Raviv, Uri; Friedler, Assaf

    2011-04-01

    Research highlights: {yields} Mechanistic explanation of how tachykinin neuropeptides reduce A{beta}-induced neurotoxicity. {yields} Biophysical studies suggest that tachykinins do not modulate the distribution of A{beta} oligomeric states, but rather may incorporate into the fibrils. {yields} A possible strategy to inhibit toxicity of amyloid fibrils. -- Abstract: A hallmark of Alzheimer's disease is production of amyloid {beta} peptides resulting from aberrant cleavage of the amyloid precursor protein. Amyloid {beta} assembles into fibrils under physiological conditions, through formation of neurotoxic intermediate oligomers. Tachykinin peptides are known to affect amyloid {beta} neurotoxicity in cells. To understand the mechanism of this effect, we studied how tachykinins affect A{beta}(1-40) aggregation in vitro. Fibrils grown in the presence of tachykinins exhibited reduced thioflavin T (ThT) fluorescence, while their morphology, observed in transmission electron microscopy (TEM), did not alter. Cross linking studies revealed that the distribution of low molecular weight species was not affected by tachykinins. Our results suggest that there may be a specific interaction between tachykinins and A{beta}(1-40) that allows them to co-assemble. This effect may explain the reduction of A{beta}(1-40) neurotoxicity in cells treated with tachykinins.

  19. Neuropeptides degranulate serous cells of ferret tracheal glands

    SciTech Connect

    Gashi, A.A.; Borson, D.B.; Finkbeiner, W.E.; Nadel, J.A.; Basbaum, C.B.

    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 P 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.

  20. Environmental enrichment induces behavioural disturbances in neuropeptide Y knockout mice

    PubMed Central

    Reichmann, Florian; Wegerer, Vanessa; Jain, Piyush; Mayerhofer, Raphaela; Hassan, Ahmed M.; Fröhlich, Esther E.; Bock, Elisabeth; Pritz, Elisabeth; Herzog, Herbert; Holzer, Peter; Leitinger, Gerd

    2016-01-01

    Environmental enrichment (EE) refers to the provision of a complex and stimulating housing condition which improves well-being, behaviour and brain function of laboratory animals. The mechanisms behind these beneficial effects of EE are only partially understood. In the current report, we describe a link between EE and neuropeptide Y (NPY), based on findings from NPY knockout (KO) mice exposed to EE. Relative to EE-housed wildtype (WT) animals, NPY KO mice displayed altered behaviour as well as molecular and morphological changes in amygdala and hippocampus. Exposure of WT mice to EE reduced anxiety and decreased central glucocorticoid receptor expression, effects which were absent in NPY KO mice. In addition, NPY deletion altered the preference of EE items, and EE-housed NPY KO mice responded to stress with exaggerated hyperthermia, displayed impaired spatial memory, had higher hippocampal brain-derived neurotrophic factor mRNA levels and altered hippocampal synaptic plasticity, effects which were not seen in WT mice. Accordingly, these findings suggest that NPY contributes to the anxiolytic effect of EE and that NPY deletion reverses the beneficial effects of EE into a negative experience. The NPY system could thus be a target for “enviromimetics”, therapeutics which reproduce the beneficial effects of enhanced environmental stimulation. PMID:27305846

  1. Identification and expression profiles of neuropeptides and their G protein-coupled receptors in the rice stem borer Chilo suppressalis.

    PubMed

    Xu, Gang; Gu, Gui-Xiang; Teng, Zi-Wen; Wu, Shun-Fan; Huang, Jia; Song, Qi-Sheng; Ye, Gong-Yin; Fang, Qi

    2016-06-29

    In insects, neuropeptides play important roles in the regulation of multiple physiological processes by binding to their corresponding receptors, which are primarily G protein-coupled receptors (GPCRs). The genes encoding neuropeptides and their associated GPCRs in the rice stem borer Chilo suppressalis were identified by a transcriptomic analysis and were used to identify potential targets for the disruption of physiological processes and the protection of crops. Forty-three candidate genes were found to encode the neuropeptide precursors for all known insect neuropeptides except for arginine-vasopressin-like peptide (AVLP), CNMamide, neuropeptide-like precursors 2-4 (NPLP2-4), and proctolin. In addition, novel alternative splicing variants of three neuropeptide genes (allatostatin CC, CCHamide 1, and short neuropeptide F) are reported for the first time, and 51 putative neuropeptide GPCRs were identified. Phylogenetic analyses demonstrated that 44 of these GPCRs belong to the A-family (or rhodopsin-like), 5 belong to the B-family (or secretin-like), and 2 are leucine-rich repeat-containing GPCRs. These GPCRs and their likely ligands were also described. qRT-PCR analyses revealed the expression profiles of the neuropeptide precursors and GPCR genes in various tissues of C. suppressalis. Our study provides fundamental information that may further our understanding of neuropeptidergic signaling systems in Lepidoptera and aid in the design of peptidomimetics, pseudopeptides or small molecules capable of disrupting the physiological processes regulated by these signaling molecules and their receptors.

  2. Identification and expression profiles of neuropeptides and their G protein-coupled receptors in the rice stem borer Chilo suppressalis

    PubMed Central

    Xu, Gang; Gu, Gui-Xiang; Teng, Zi-Wen; Wu, Shun-Fan; Huang, Jia; Song, Qi-Sheng; Ye, Gong-Yin; Fang, Qi

    2016-01-01

    In insects, neuropeptides play important roles in the regulation of multiple physiological processes by binding to their corresponding receptors, which are primarily G protein-coupled receptors (GPCRs). The genes encoding neuropeptides and their associated GPCRs in the rice stem borer Chilo suppressalis were identified by a transcriptomic analysis and were used to identify potential targets for the disruption of physiological processes and the protection of crops. Forty-three candidate genes were found to encode the neuropeptide precursors for all known insect neuropeptides except for arginine-vasopressin-like peptide (AVLP), CNMamide, neuropeptide-like precursors 2-4 (NPLP2-4), and proctolin. In addition, novel alternative splicing variants of three neuropeptide genes (allatostatin CC, CCHamide 1, and short neuropeptide F) are reported for the first time, and 51 putative neuropeptide GPCRs were identified. Phylogenetic analyses demonstrated that 44 of these GPCRs belong to the A-family (or rhodopsin-like), 5 belong to the B-family (or secretin-like), and 2 are leucine-rich repeat-containing GPCRs. These GPCRs and their likely ligands were also described. qRT-PCR analyses revealed the expression profiles of the neuropeptide precursors and GPCR genes in various tissues of C. suppressalis. Our study provides fundamental information that may further our understanding of neuropeptidergic signaling systems in Lepidoptera and aid in the design of peptidomimetics, pseudopeptides or small molecules capable of disrupting the physiological processes regulated by these signaling molecules and their receptors. PMID:27353701

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

    PubMed Central

    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

    2016-01-01

    Background Molecular and cellular mechanisms of neuropeptide-Y (NPY)-mediated gender-difference in blood pressure (BP) regulation are largely unknown. Methods 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. Results 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. Conclusions Sex- and afferent-specific expression of Neuropeptide-Y receptors in baroreflex afferent pathway may contribute to sexual-dimorphic neurocontrol of BP regulation. PMID:27623075

  4. Neuropeptide Y inhibits the trigeminovascular pathway through NPY Y1 receptor: implications for migraine

    PubMed Central

    Oliveira, Margarida-Martins; Akerman, Simon; Tavares, Isaura; Goadsby, Peter J.

    2016-01-01

    Abstract Migraine is a painful neurologic disorder with premonitory symptomatology that can include disturbed appetite. Migraine pathophysiology involves abnormal activation of trigeminocervical complex (TCC) neurons. Neuropeptide Y (NPY) is synthesized in the brain and is involved in pain modulation. NPY receptors are present in trigeminal ganglia and trigeminal nucleus caudalis suggesting a role in migraine pathophysiology. The present study aimed to determine the effect of systemic administration of NPY on TCC neuronal activity in response to dural nociceptive trigeminovascular activation. We performed in vivo electrophysiology in anesthetized rats, administered NPY (10, 30, and 100 µg·kg−1), and investigated the receptors involved by studying NPY Y1 (30 µg·kg−1), Y2 (30 µg·kg−1), and Y5 receptor agonists (100·µg·kg−1), and NPY Y1 receptor antagonist (30 µg·kg−1). NPY (30 and 100 µg·kg−1) significantly reduced TCC neuronal firing in response to dural-evoked trigeminovascular activation, but only NPY (30 µg·kg−1) significantly reduced spontaneous trigeminal firing. NPY Y1 receptor agonist also significantly reduced dural-evoked and spontaneous TCC neuronal firing. NPY (10 µg·kg−1), NPY Y2, and Y5 receptor agonists, and the NPY Y1 receptor antagonist had no significant effects on nociceptive dural-evoked neuronal firing in the TCC or spontaneous trigeminal firing. This study demonstrates that NPY dose dependently inhibits dural-evoked trigeminal activity, through NPY Y1 receptor activation, indicating antinociceptive actions of NPY in a migraine animal model. Based on the role of NPY in appetite regulation, it is possible that disruption of the NPY system might explain changes of appetite in migraineurs. PMID:27023421

  5. Toward a single-cell-based analysis of neuropeptide expression in Periplaneta americana antennal lobe neurons.

    PubMed

    Neupert, Susanne; Fusca, Debora; Schachtner, Joachim; Kloppenburg, Peter; Predel, Reinhard

    2012-03-01

    A multitude of potential neurotransmitters and neuromodulators, including peptides, have been detected in the antennal lobe (AL), the first synaptic relay of the central olfactory pathway in the insect brain. However, the functional role of neuropeptides in this system has yet to be revealed. An important prerequisite to understanding the role of neuropeptides is to match the functionally different cell types in the AL with their peptide profiles by using electrophysiological recordings combined with immunocytochemical studies and/or single-cell mass spectrometry. The olfactory system of Periplaneta americana is particularly well suited to accomplish this goal because several physiologically distinct neuron types can be unequivocally identified. With the aim to analyze the neuropeptide inventory of the P. americana AL, this study is an essential step in this direction. First, we systematically analyzed different parts of the AL by matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry to obtain the complete set of neuropeptides present. Altogether, 56 ion signals could be assigned to products of 10 neuropeptide genes (allatostatins A, B, C, SIFamide, allatotropin, FMRFamide-related peptides [myosuppressin, short neuropeptides F, extended FMRFamides], crustacean cardioactive peptide, tachykinin-related peptides). In a second step, a combination of immunocytochemistry and mass spectrometric profiling of defined AL compartments was used to reveal the spatial distribution of neuropeptide-containing cells. Finally, we demonstrated the feasibility of MALDI-TOF mass spectrometric profiling of single AL neurons, which is an important precondition for combining electrophysiology with peptide profiling at the single-cell level.

  6. Mapping of Neuropeptides in the Crustacean Stomatogastric Nervous System by Imaging Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Ye, Hui; Hui, Limei; Kellersberger, Katherine; Li, Lingjun

    2013-01-01

    Considerable effort has been devoted to characterizing the crustacean stomatogastric nervous system (STNS) with great emphasis on comprehensive analysis and mapping distribution of its diverse neuropeptide complement. Previously, immunohistochemistry (IHC) has been applied to this endeavor, yet with identification accuracy and throughput compromised. Therefore, molecular imaging methods are pursued to unequivocally determine the identity and location of the neuropeptides at a high spatial resolution. In this work, we developed a novel, multi-faceted mass spectrometric strategy combining profiling and imaging techniques to characterize and map neuropeptides from the blue crab Callinectes sapidus STNS at the network level. In total, 55 neuropeptides from 10 families were identified from the major ganglia in the C. sapidus STNS for the first time, including the stomatogastric ganglion (STG), the paired commissural ganglia (CoG), the esophageal ganglion (OG), and the connecting nerve stomatogastric nerve ( stn) using matrix-assisted laser desorption/ionization tandem time-of-flight (MALDI-TOF/TOF) and the MS/MS capability of this technique. In addition, the locations of multiple neuropeptides were documented at a spatial resolution of 25 μm in the STG and upstream nerve using MALDI-TOF/TOF and high-mass-resolution and high-mass-accuracy MALDI-Fourier transform ion cyclotron resonance (FT-ICR) instrument. Furthermore, distributions of neuropeptides in the whole C. sapidus STNS were examined by imaging mass spectrometry (IMS). Different isoforms from the same family were simultaneously and unambiguously mapped, facilitating the functional exploration of neuropeptides present in the crustacean STNS and exemplifying the revolutionary role of this novel platform in neuronal network studies.

  7. New insights on the neuropeptide Y system in the larval lamprey brain: neuropeptide Y immunoreactive neurons, descending spinal projections and comparison with tyrosine hydroxylase and GABA immunoreactivities.

    PubMed

    Barreiro-Iglesias, A; Anadón, R; Rodicio, M C

    2010-05-05

    Lampreys are useful models for studying the evolution of the nervous system of vertebrates. Here we used immunofluorescence and tract-tracing methods to study new aspects of the neuropeptide Y-immunoreactive (NPY-ir) system in larval sea lampreys. NPY-ir neurons were observed in brain nuclei that contain NPY-ir cells in other lamprey species. Moreover, a group of NPY-ir cells that migrated away the periventricular layer was observed in the lateral part of the dorsal hypothalamus, which suggests a role for NPY in feeding behavior in lampreys. We also report NPY-ir cells in the dorsal column nucleus, which appears to be unique among vertebrates, and in the habenula. A combination of tract-tracing and immunohistochemical labeling demonstrated the presence of spinal projecting NPY-ir reticular cells in the anterior rhombencephalic reticular formation, and the relationships between the NPY-ir system and the reticulospinal nuclei and some afferent systems. The colocalization of catecholamines and GABA in lamprey NPY-ir neurons was investigated by double immunofluorescence methods. Colocalization of tyrosine hydroxylase (TH) and NPY immunoreactivities was not observed in any brain neuron, although reported in amphibians and mammals. The frequent presence of NPY-ir terminals on TH-ir cells suggests that NPY modulates the activity of some dopaminergic nuclei in lampreys. Colocalization of NPY and GABA immunoreactivities was frequently observed in neurons of different rhombencephalic and diencephalic NPY-ir populations. These results in lampreys suggest that the coexpression of NPY and GABA in neurons appeared early on in the brains of vertebrates.

  8. Control of chronic excessive alcohol drinking by genetic manipulation of the Edinger–Westphal nucleus urocortin-1 neuropeptide system

    PubMed Central

    Giardino, W J; Rodriguez, E D; Smith, M L; Ford, M M; Galili, D; Mitchell, S H; Chen, A; Ryabinin, A E

    2017-01-01

    Midbrain neurons of the centrally projecting Edinger–Westphal nucleus (EWcp) are activated by alcohol, and enriched with stress-responsive neuropeptide modulators (including the paralog of corticotropin-releasing factor, urocortin-1). Evidence suggests that EWcp neurons promote behavioral processes for alcohol-seeking and consumption, but a definitive role for these cells remains elusive. Here we combined targeted viral manipulations and gene array profiling of EWcp neurons with mass behavioral phenotyping in C57BL/6 J mice to directly define the links between EWcp-specific urocortin-1 expression and voluntary binge alcohol intake, demonstrating a specific importance for EWcp urocortin-1 activity in escalation of alcohol intake. PMID:28140406

  9. An Indirect Action Contributes to C-Fos Induction in Paraventricular Hypothalamic Nucleus by Neuropeptide Y

    PubMed Central

    Fan, Shengjie; Dakshinamoorthy, Janani; Kim, Eun Ran; Xu, Yong; Huang, Cheng; Tong, Qingchun

    2016-01-01

    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 to examine the underlying NPY orexigenic neural pathways. However, PVH C-Fos induction is in discordance with the abundant expression of NPY receptors, a group of inhibitory Gi protein coupled receptors in the PVH, and with the overall role of PVH neurons in feeding inhibition, suggesting a mechanism of indirect action. Here we showed that the ability of NPY on C-Fos induction in the PVH was blunted in conditions of insulin deficiency and fasting, a condition associated with a high level of NPY and a low level of insulin. Moreover, insulin insufficiency blunted C-Fos induction in the PVH by fasting-induced re-feeding, and insulin and NPY induced c-Fos induction in the same group of PVH neurons. Finally, NPY produced normal C-Fos induction in the PVH with disruption of GABA-A receptors. Thus, our results revealed that PVH C-Fos induction by NPY is mediated by an indirect action, which is at least partially mediated by insulin action, but not GABA-A receptors. PMID:26813148

  10. Functional characterization of the short neuropeptide F receptor in the desert locust, Schistocerca gregaria.

    PubMed

    Dillen, Senne; Zels, Sven; Verlinden, Heleen; Spit, Jornt; Van Wielendaele, Pieter; Vanden Broeck, Jozef

    2013-01-01

    Whereas short neuropeptide F (sNPF) has already been reported to stimulate feeding behaviour in a variety of insect species, the opposite effect was observed in the desert locust. In the present study, we cloned a G protein-coupled receptor (GPCR) cDNA from the desert locust, Schistocerca gregaria. Cell-based functional analysis of this receptor indicated that it is activated by both known isoforms of Schgr-sNPF in a concentration dependent manner, with EC(50) values in the nanomolar range. This Schgr-sNPF receptor constitutes the first functionally characterized peptide GPCR in locusts. The in vivo effects of the sNPF signalling pathway on the regulation of feeding in locusts were further studied by knocking down the newly identified Schgr-sNPF receptor by means of RNA interference, as well as by means of peptide injection studies. While injection of sNPF caused an inhibitory effect on food uptake in the desert locust, knocking down the corresponding peptide receptor resulted in an increase of total food uptake when compared to control animals. This is the first comprehensive study in which a clearly negative correlation is described between the sNPF signalling pathway and feeding, prompting a reconsideration of the diverse roles of sNPFs in the physiology of insects.

  11. Neuroprotection by neuropeptide Y in cell and animal models of Parkinson's disease.

    PubMed

    Decressac, Mickael; Pain, Stéphanie; Chabeauti, Pierre-Yves; Frangeul, Laura; Thiriet, Nathalie; Herzog, Herbert; Vergote, Jackie; Chalon, Sylvie; Jaber, Mohamed; Gaillard, Afsaneh

    2012-09-01

    This study was aimed to investigate the potential neuroprotective effect of neuropeptide Y (NPY) on the survival of dopaminergic cells in both in vitro and in animal models of Parkinson's disease (PD). NPY protected human SH-SY5Y dopaminergic neuroblastoma cells from 6-hydroxydopamine-induced toxicity. In rat and mice models of PD, striatal injection of NPY preserved the nigrostriatal dopamine pathway from degeneration as evidenced by quantification of (1) tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, levels of (2) striatal tyrosine hydroxylase and dopamine transporter, (3) dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) as well as (4) rotational behavior. NPY had no neuroprotective effects in mice treated with Y(2) receptor antagonist or in transgenic mice deficient for Y(2) receptor suggesting that NPY effects are mediated through this receptor. Stimulation of Y(2) receptor by NPY triggered the activation of both the ERK1/2 and Akt pathways but did not modify levels of brain derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor. These results open new perspectives in neuroprotective therapies using NPY and suggest potential beneficial effects in PD.

  12. Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness

    PubMed Central

    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.

    2016-01-01

    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. PMID:27088802

  13. Involvement of neuropeptide Y Y1 receptor in the regulation of amphetamine-mediated appetite suppression.

    PubMed

    Kuo, Dong-Yih; Chen, Pei-Ni; Yu, Ching-Han; Kuo, Meng-Hsien; Hsieh, Yih-Shou; Chu, Shu-Chen

    2012-10-01

    Recently, we reported that an initial decrease followed by recovery of food intake was observed during four days of amphetamine (AMPH) treatment and suggested that these changes in response were mediated by changes in neuropeptide Y (NPY) and proopiomelanocortin (POMC). Here we investigated if Y1 receptor (Y1R) and/or Y5 receptor (Y5R) might be involved in this regulation. Rats were treated daily with AMPH for four days. Changes in the expression levels of Y1R, Y5R, melanocortin receptor 3 (MC3R), and NPY were assessed and compared. Results showed that Y1R and MC3R increased, with a maximal increase of about 210% on Day 2 but with a restoration to the normal level on Day 4. In contrast, NPY decreased with a biggest reduction of about 45% on Day 2 and the pattern of expression during AMPH treatment was opposite to those of Y1R and MC3R, while the expression of Y5R was not changed. Central inhibitions of NPY formation or Y1R activity modulated the anorectic response of AMPH and the reciprocal regulation of NPY and MC3R, revealing a crucial role of Y1R in this action. It is suggested that Y1R participates in the reciprocal regulation of NPY- and MC3R-containing neurons in the hypothalamus during the anorectic effect of AMPH. These results may further the understanding of Y1R in the control of eating.

  14. Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

    PubMed Central

    Behnke, Joseph; Cheedalla, Aneesha; Bhatt, Vatsal; Bhat, Maysa; Teng, Shavonne; Palmieri, Alicia; Windon, Charles Christian; Thakker-Varia, Smita; Alder, Janet

    2017-01-01

    The neuropeptide VGF (non-acronymic) is induced by brain-derived neurotrophic factor and promotes hippocampal neurogenesis, as well as synaptic activity. However, morphological changes induced by VGF have not been elucidated. Developing hippocampal neurons were exposed to VGF through bath application or virus-mediated expression in vitro. VGF-derived peptide, TLQP-62, enhanced dendritic branching, and outgrowth. Furthermore, VGF increased dendritic spine density and the proportion of immature spines. Spine formation was associated with increased synaptic protein expression and co-localization of pre- and postsynaptic markers. Three non-synonymous single nucleotide polymorphisms (SNPs) were selected in human VGF gene. Transfection of N2a cells with plasmids containing these SNPs revealed no relative change in protein expression levels and normal protein size, except for a truncated protein from the premature stop codon, E525X. All three SNPs resulted in a lower proportion of N2a cells bearing neurites relative to wild-type VGF. Furthermore, all three mutations reduced the total length of dendrites in developing hippocampal neurons. Taken together, our results suggest VGF enhances dendritic maturation and that these effects can be altered by common mutations in the VGF gene. The findings may have implications for people suffering from psychiatric disease or other conditions who may have altered VGF levels. PMID:28287464

  15. 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

  16. Effects of loratadine and cetirizine on serum levels of neuropeptides in patients with chronic urticaria.

    PubMed

    Başak, Pinar Y; Vural, Huseyin; Kazanoglu, Oya O; Erturan, Ijlal; Buyukbayram, Halil I

    2014-12-01

    H1-receptor inhibiting drugs, namely loratadine and cetirizine, were frequently used in treatment of chronic urticaria. Urticarial weal and flare reactions, a neurogenic reflex due to neuropeptides, were reported to be more effectively inhibited by cetirizine than loratadine. The aim of this study was to determine and compare the effects of systemic loratadine and cetirizine treatments on serum levels of selected neuropeptides in chronic urticaria. Treatment groups of either systemic loratadine or cetirizine (10 mg/d), consisting of 16 and 22 patients, respectively, were included. Serum levels of stem cell factor (SCF), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), vasoactive intestinal peptide (VIP), and substance P (SP) were detected before and after one week of treatment with antihistamines. Serum NPY and VIP levels were significantly decreased when compared before and after treatment with antihistamines (P < 0.001 and P < 0.01, respectively). SCF and NGF values were also decreased after antihistamine treatment (P < 0.05). Post-treatment levels of CGRP were significantly higher compared with pretreatment values, while no significant difference was detected between pre and post treatment levels of SP. Cetirizine was significantly more effective than loratadine on lowering serum levels of SCF among the other neuropeptides. Systemic loratadine and cetirizine treatments in patients with chronic urticaria precisely caused variations in serum levels of neuropeptides. The predominant effect of cetirizine compared to loratadine on reducing serum SCF levels might be explained with anti-inflammatory properties of cetirizine.

  17. 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.

  18. TRPV1, TRPA1, and CB1 in the isolated vagus nerve--axonal chemosensitivity and control of neuropeptide release.

    PubMed

    Weller, K; Reeh, P W; Sauer, S K

    2011-12-01

    Vagal sensory afferents innervating airways and abdominal tissues express TRPV1 and TRPA1, two depolarizing calcium permeable ion channels playing a major role in sensing environmental irritants and endogenous metabolites which cause neuropeptide release and neurogenic inflammation. Here we have studied axonal chemosensitivity and control of neuropeptide release from the isolated rat and mouse vagus nerve by using prototypical agonists of these transduction channels - capsaicin, mustard oil and the specific endogenous activators, anandamide (methyl arachidonyl ethanolamide, mAEA), and acrolein, respectively. Capsaicin evoked iCGRP release from the rat vagus nerve with an EC₅₀ of 0.12 μM. Co-application of mAEA had a dual effect: nanomolar concentrations of mAEA (0.01 μM) significantly reduced capsaicin-evoked iCGRP release while concentrations ≥ 1 μM mAEA had sensitizing effects. Only 100 μM mAEA directly augmented iCGRP release by itself. In the mouse, 310 μM mAEA increased release in wildtype and TRPA1-/- mice which could be inhibited by capsazepine (10 μM) and was completely absent in TRPV1-/- mice. CB1-/- and CB1/CB2 double -/- mice equally displayed increased sensitivity to mAEA (100 μM) and a sensitizing effect to capsaicin, in contrast to wildtypes. Acrolein and mustard oil (MO)--at μM concentrations--induced a TRPA1-dependent iCGRP release; however, millimolar concentrations of mustard oil (>1mM) evoked iCGRP release by activating TRPV1, confirming recent evidence for TRPV1 agonism of high mustard oil concentrations. Taken together, we present evidence for functional expression of excitatory TRPV1, TRPA1, and inhibitory CB1 receptors along the sensory fibers of the vagus nerve which lend pathophysiological relevance to the axonal membrane and the control of neuropeptide release that may become important in cases of inflammation or neuropathy. Sensitization and possible ectopic discharge may contribute to the development of autonomic

  19. A novel functionally distinct subtype of striatal neuropeptide Y interneuron.

    PubMed

    Ibáñez-Sandoval, Osvaldo; Tecuapetla, Fatuel; Unal, Bengi; Shah, Fulva; Koós, Tibor; Tepper, James M

    2011-11-16

    We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic GFP (green fluorescent protein)-NPY reporter mice. In vitro whole-cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical, and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spike (NPY-PLTS) interneurons. The novel NPY interneuron type (NPY-neurogliaform) differed from previously described NPY-PLTS interneurons by exhibiting a significantly lower input resistance and hyperpolarized membrane potential, regular, nonaccommodating spiking in response to depolarizing current injections, and an absence of plateau depolarizations or low-threshold spikes. NPY-neurogliaform interneurons were also easily distinguished morphologically by their dense, compact, and highly branched dendritic and local axonal arborizations that contrasted sharply with the sparse and extended axonal and dendritic arborizations of NPY-PLTS interneurons. Furthermore, NPY-neurogliaform interneurons did not express immunofluorescence for somatostatin or nitric oxide synthase that was ubiquitous in NPY-PLTS interneurons. IPSP/Cs could only rarely be elicited in spiny projection neurons (SPNs) in paired recordings with NPY-PLTS interneurons. In contrast, the probability of SPN innervation by NPY-neurogliaform interneurons was extremely high, the synapse very reliable (no failures were observed), and the resulting postsynaptic response was a slow, GABA(A) receptor-mediated IPSC that has not been previously described in striatum but that has been elicited from NPY-GABAergic neurogliaform interneurons in cortex and hippocampus. These properties suggest unique and distinctive roles for NPY-PLTS and NPY-neurogliaform interneurons in the integrative properties of the neostriatum.

  20. Neuropeptide Regulation of Signaling and Behavior in the BNST

    PubMed Central

    Kash, Thomas L.; Pleil, Kristen E.; Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily G.; Crowley, Nicole; Mazzone, Christopher; Sugam, Jonathan; Hardaway, J. Andrew; McElligott, Zoe A.

    2015-01-01

    Recent technical developments have transformed how neuroscientists can probe brain function. What was once thought to be difficult and perhaps impossible, stimulating a single set of long range inputs among many, is now relatively straight-forward using optogenetic approaches. This has provided an avalanche of data demonstrating causal roles for circuits in a variety of behaviors. However, despite the critical role that neuropeptide signaling plays in the regulation of behavior and physiology of the brain, there have been remarkably few studies demonstrating how peptide release is causally linked to behaviors. This is likely due to both the different time scale by which peptides act on and the modulatory nature of their actions. For example, while glutamate release can effectively transmit information between synapses in milliseconds, peptide release is potentially slower [See the excellent review by Van Den Pol on the time scales and mechanisms of release (van den Pol, 2012)] and it can only tune the existing signals via modulation. And while there have been some studies exploring mechanisms of release, it is still not as clearly known what is required for efficient peptide release. Furthermore, this analysis could be complicated by the fact that there are multiple peptides released, some of which may act in contrast. Despite these limitations, there are a number of groups making progress in this area. The goal of this review is to explore the role of peptide signaling in one specific structure, the bed nucleus of the stria terminalis, that has proven to be a fertile ground for peptide action. PMID:25475545

  1. A neuropeptide speeds circadian entrainment by reducing intercellular synchrony

    PubMed Central

    An, Sungwon; Harang, Rich; Meeker, Kirsten; Granados-Fuentes, Daniel; Tsai, Connie A.; Mazuski, Cristina; Kim, Jihee; Doyle, Francis J.; Petzold, Linda R.; Herzog, Erik D.

    2013-01-01

    Shift work or transmeridian travel can desynchronize the body's circadian rhythms from local light–dark cycles. The mammalian suprachiasmatic nucleus (SCN) generates and entrains daily rhythms in physiology and behavior. Paradoxically, we found that vasoactive intestinal polypeptide (VIP), a neuropeptide implicated in synchrony among SCN cells, can also desynchronize them. The degree and duration of desynchronization among SCN neurons depended on both the phase and the dose of VIP. A model of the SCN consisting of coupled stochastic cells predicted both the phase- and the dose-dependent response to VIP and that the transient phase desynchronization, or “phase tumbling”, could arise from intrinsic, stochastic noise in small populations of key molecules (notably, Period mRNA near its daily minimum). The model also predicted that phase tumbling following brief VIP treatment would accelerate entrainment to shifted environmental cycles. We tested this using a prepulse of VIP during the day before a shift in either a light cycle in vivo or a temperature cycle in vitro. Although VIP during the day does not shift circadian rhythms, the VIP pretreatment approximately halved the time required for mice to reentrain to an 8-h shifted light schedule and for SCN cultures to reentrain to a 10-h shifted temperature cycle. We conclude that VIP below 100 nM synchronizes SCN cells and above 100 nM reduces synchrony in the SCN. We show that exploiting these mechanisms that transiently reduce cellular synchrony before a large shift in the schedule of daily environmental cues has the potential to reduce jet lag. PMID:24167276

  2. Hypothalamic neuropeptide systems and anticipatory weight change in Siberian hamsters.

    PubMed

    Adam, C L; Mercer, J G

    2001-01-01

    Seasonal animals are able both to programme changes in body weight in response to annual changes in photoperiod (anticipatory regulation) and to correct changes in body weight caused by imposed energetic demand (compensatory regulation). Experimental evidence from the Siberian hamster suggests that seasonally appropriate body weight is continually reset according to photoperiodic history, even when actual body weight is driven away from this target weight by manipulation of energy intake. These characteristics constitute the "sliding set point" of seasonal body weight regulation. To define the mechanisms and molecules underlying anticipatory body weight regulation, we are investigating the involvement of hypothalamic systems with an established role in the compensatory defence of body weight. Weight loss or restricted growth induced by short days (SD) results in low circulating leptin compared with long day (LD) controls. However, this chronic low leptin signal is read differently from acute low leptin resulting from food deprivation; leptin receptor gene expression in the hypothalamic arcuate nucleus (ARC) is lower in SD, whereas food deprivation increases expression levels, suggesting changes in sensitivity to leptin feedback. SD alterations in mRNA levels for a number of hypothalamic neuropeptide and receptor genes appear counter-intuitive for a SD body weight trajectory. However, early increases in ARC cocaine-and amphetamine-regulated transcript (CART) gene expression in SDs could be involved in driving body weight loss or growth restriction. The sites of photoperiod interaction with energy balance neuronal circuitry and the neurochemical encoding of body weight set point require full characterisation. Study of anticipatory regulation in seasonal animals offers new insight into body weight regulation across mammalian species, including man.

  3. A neuropeptide speeds circadian entrainment by reducing intercellular synchrony.

    PubMed

    An, Sungwon; Harang, Rich; Meeker, Kirsten; Granados-Fuentes, Daniel; Tsai, Connie A; Mazuski, Cristina; Kim, Jihee; Doyle, Francis J; Petzold, Linda R; Herzog, Erik D

    2013-11-12

    Shift work or transmeridian travel can desynchronize the body's circadian rhythms from local light-dark cycles. The mammalian suprachiasmatic nucleus (SCN) generates and entrains daily rhythms in physiology and behavior. Paradoxically, we found that vasoactive intestinal polypeptide (VIP), a neuropeptide implicated in synchrony among SCN cells, can also desynchronize them. The degree and duration of desynchronization among SCN neurons depended on both the phase and the dose of VIP. A model of the SCN consisting of coupled stochastic cells predicted both the phase- and the dose-dependent response to VIP and that the transient phase desynchronization, or "phase tumbling", could arise from intrinsic, stochastic noise in small populations of key molecules (notably, Period mRNA near its daily minimum). The model also predicted that phase tumbling following brief VIP treatment would accelerate entrainment to shifted environmental cycles. We tested this using a prepulse of VIP during the day before a shift in either a light cycle in vivo or a temperature cycle in vitro. Although VIP during the day does not shift circadian rhythms, the VIP pretreatment approximately halved the time required for mice to reentrain to an 8-h shifted light schedule and for SCN cultures to reentrain to a 10-h shifted temperature cycle. We conclude that VIP below 100 nM synchronizes SCN cells and above 100 nM reduces synchrony in the SCN. We show that exploiting these mechanisms that transiently reduce cellular synchrony before a large shift in the schedule of daily environmental cues has the potential to reduce jet lag.

  4. Development of neuropeptide Y-mediated heart innervation in rats.

    PubMed

    Masliukov, Petr M; Moiseev, Konstantin; Emanuilov, Andrey I; Anikina, Tatyana A; Zverev, Alexey A; Nozdrachev, Alexandr D

    2016-02-01

    Neuropeptide Y (NPY) plays a trophic role in the nervous and vascular systems and in cardiac hypertrophy. However, there is no report concerning the expression of NPY and its receptors in the heart during postnatal development. In the current study, immunohistochemistry and Western blot analysis was used to label NPY, and Y1R, Y2R, and Y5R receptors in the heart tissue and intramural cardiac ganglia from rats of different ages (newborn, 10 days old, 20 days old, 30 days old, 60 days old, 1 year old, and 2 years old).The obtained data suggest age-dependent changes of NPY-mediated heart innervation. The density of NPY-immunoreactive (IR) fibers was the least in newborn animals and increased in the first 20 days of life. In the atria of newborn and 10-day-old rats, NPY-IR fibers were more abundant compared with the ventricles. The vast majority of NPY-IR fibers also contained tyrosine hydroxylase, a key enzyme in catecholamine synthesis.The expression of Y1R increased between 10 and 20 days of life. Faint Y2R immunoreactivity was observed in the atria and ventricles of 20-day-old and older rats. In contrast, the highest level of the expression of Y5R was found in newborn pups comparing with more adult rats. All intramural ganglionic neurons were also Y1R-IR and Y5R-IR and Y2R-negative in all studied animals.Thus, the increasing of density of NPY-containing nerve fibers accompanies changes in relation of different subtypes of NPY receptors in the heart during development.

  5. Neuropeptide Y (NPY) modulates oxidative burst and nitric oxide production in carrageenan-elicited granulocytes from rat air pouch.

    PubMed

    Dimitrijević, Mirjana; Stanojević, Stanislava; Mićić, Stana; Vujić, Vesna; Kovacević-Jovanović, Vesna; Mitić, Katarina; von Hörsten, Stephan; Kosec, Dusko

    2006-12-01

    We studied the effects of neuropeptide Y (NPY) and NPY-related receptor specific peptides on functions of carrageenan-elicited granulocytes in vitro and ability of NPY to modulate carrageenan-induced air pouch inflammation in rats in vivo. Anti-inflammatory effect of NPY comprises reduced granulocyte accumulation into the air pouch, to some extent attenuation of phagocytosis, attained via Y1 receptor, and considerable decrease in peroxide production, albeit mediated via Y2 and Y5 receptors activation. Conversely, NPY increases nitric oxide production and this potentiation is mediated via Y1 receptor. It is concluded that NPY Y1 and Y2/Y5 receptors' interaction participates in NPY-induced modulation of granulocyte functions related to inflammation.

  6. 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

  7. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine.

    PubMed

    Meyer-Lindenberg, Andreas; Domes, Gregor; Kirsch, Peter; Heinrichs, Markus

    2011-08-19

    The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are evolutionarily highly conserved mediators in the regulation of complex social cognition and behaviour. Recent studies have investigated the effects of OXT and AVP on human social interaction, the genetic mechanisms of inter-individual variation in social neuropeptide signalling and the actions of OXT and AVP in the human brain as revealed by neuroimaging. These data have advanced our understanding of the mechanisms by which these neuropeptides contribute to human social behaviour. OXT and AVP are emerging as targets for novel treatment approaches--particularly in synergistic combination with psychotherapy--for mental disorders characterized by social dysfunction, such as autism, social anxiety disorder, borderline personality disorder and schizophrenia.

  8. The interpersonal dimension of borderline personality disorder: toward a neuropeptide model.

    PubMed

    Stanley, Barbara; Siever, Larry J

    2010-01-01

    Borderline personality disorder is characterized by affective instability, impulsivity, identity diffusion, and interpersonal dysfunction. Perceived rejection and loss often serve as triggers to impulsive, suicidal, and self-injurious behavior, affective reactivity, and angry outbursts, suggesting that the attachment and affiliative system may be implicated in the disorder. Neuropeptides, including the opioids, oxytocin, and vasopressin, serve a crucial role in the regulation of affiliative behaviors and thus may be altered in borderline personality disorder. While clinical data are limited, the authors propose alternative neuropeptide models of borderline personality disorder and review relevant preclinical research supporting the role of altered neuropeptide function in this disorder in the hope of stimulating more basic research and the development of new treatment approaches.

  9. The Interpersonal Dimension of Borderline Personality Disorder: Toward a Neuropeptide Model

    PubMed Central

    Stanley, Barbara; Siever, Larry J.

    2014-01-01

    Borderline personality disorder is characterized by affective instability, impulsivity, identity diffusion, and interpersonal dysfunction. Perceived rejection and loss often serve as triggers to impulsive, suicidal, and self-injurious behavior, affective reactivity, and angry outbursts, suggesting that the attachment and affiliative system may be implicated in the disorder. Neuropeptides, including the opioids, oxytocin, and vasopressin, serve a crucial role in the regulation of affiliative behaviors and thus may be altered in borderline personality disorder. While clinical data are limited, the authors propose alternative neuropeptide models of borderline personality disorder and review relevant preclinical research supporting the role of altered neuropeptide function in this disorder in the hope of stimulating more basic research and the development of new treatment approaches. PMID:19952075

  10. 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…

  11. Changes in neuropeptide Y protein expression following photothrombotic brain infarction and epileptogenesis.

    PubMed

    Kharlamov, Elena A; Kharlamov, Alexander; Kelly, Kevin M

    2007-01-05

    This study characterized morphological changes in the cortex and hippocampus of Sprague-Dawley rats following photothrombotic infarction and epileptogenesis with emphasis on the distribution of neuropeptide Y (NPY) expression. Animals were lesioned in the left sensorimotor cortex and compared with age-matched naive and sham-operated controls by immunohistochemical techniques at 1, 3, 7, and 180 days post-lesioning (DPL). NPY immunostaining was assessed by light microscopy and quantified by the optical fractionator technique using unbiased stereological methods. At 1, 3, and 7 DPL, the number of NPY-positive somata in the lesioned cortex was increased significantly compared to controls and the contralateral cortex. At 180 DPL, lesioned epileptic animals with frequent seizure activity demonstrated significant increases of NPY expression in the cortex, CA1, CA3, hilar interneurons, and granule cells of the dentate gyrus. In addition to NPY immunostaining, neuronal degeneration, cell death/cell loss, and astroglial response were assessed with cell-specific markers. Nissl and NeuN staining showed reproducible infarctions at each investigated time point. FJB-positive somata were most abundant in the infarct core at 1 DPL, decreased markedly at 3 DPL, and virtually absent by 7 DPL. Activated astroglia were detected in the cortex and hippocampus following lesioning and the development of seizure activity. In summary, NPY protein expression and morphological changes following cortical photothrombosis were time-, region-, and pathologic state-dependent. Alterations in NPY expression may reflect reactive or compensatory responses of the rat brain to acute infarction and to the development and expression of epileptic seizures.

  12. The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour.

    PubMed

    Farzi, A; Reichmann, F; Holzer, P

    2015-03-01

    Neuropeptide Y (NPY), one of the most abundant peptides in the nervous system, exerts its effects via five receptor types, termed Y1, Y2, Y4, Y5 and Y6. NPY's pleiotropic functions comprise the regulation of brain activity, mood, stress coping, ingestion, digestion, metabolism, vascular and immune function. Nerve-derived NPY directly affects immune cells while NPY also acts as a paracrine and autocrine immune mediator, because immune cells themselves are capable of producing and releasing NPY. NPY is able to induce immune activation or suppression, depending on a myriad of factors such as the Y receptors activated and cell types involved. There is an intricate relationship between psychological stress, mood disorders and the immune system. While stress represents a risk factor for the development of mood disorders, it exhibits diverse actions on the immune system as well. Conversely, inflammation is regarded as an internal stressor and is increasingly recognized to contribute to the pathogenesis of mood and metabolic disorders. Intriguingly, the cerebral NPY system has been found to protect against distinct disturbances in response to immune challenge, attenuating the sickness response and preventing the development of depression. Thus, NPY plays an important homeostatic role in balancing disturbances of physiological systems caused by peripheral immune challenge. This implication is particularly evident in the brain in which NPY counteracts the negative impact of immune challenge on mood, emotional processing and stress resilience. NPY thus acts as a unique signalling molecule in the interaction of the immune system with the brain in health and disease.

  13. Changes in neuropeptide Y protein expression following photothrombotic brain infarction and epileptogenesis.

    PubMed Central

    Kharlamov, Elena A.; Kharlamov, Alexander; Kelly, Kevin M.

    2007-01-01

    This study characterized morphological changes in the cortex and hippocampus of Sprague-Dawley rats following photothrombotic infarction and epileptogenesis with emphasis on the distribution of neuropeptide Y (NPY) expression. Animals were lesioned in the left sensorimotor cortex and compared with age-matched naïve and sham-operated controls by immunohistochemical techniques at 1, 3, 7, and 180 days post-lesioning (DPL). NPY immunostaining was assessed by light microscopy and quantified by the optical fractionator technique using unbiased stereological methods. At 1, 3, and 7 DPL, the number of NPY-positive somata in the lesioned cortex was increased significantly compared to controls and the contralateral cortex. At 180 DPL, lesioned epileptic animals with frequent seizure activity demonstrated significant increases of NPY expression in the cortex, CA1, CA3, hilar interneurons, and granule cells of the dentate gyrus. In addition to NPY immunostaining, neuronal degeneration, cell death/cell loss, and astroglial response were assessed with cell-specific markers. Nissl and NeuN staining showed reproducible infarctions at each investigated time point. FJB-positive somata were most abundant in the infarct core at 1 DPL, decreased markedly at 3 DPL, and virtually absent by 7 DPL. Activated astroglia were detected in the cortex and hippocampus following lesioning and the development of seizure activity. In summary, NPY protein expression and morphological changes following cortical photothrombosis were time-, region- and pathologic state-dependent. Alterations in NPY expression may reflect reactive or compensatory responses of the rat brain to acute infarction and to the development and expression of epileptic seizures. PMID:17123484

  14. The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour

    PubMed Central

    Farzi, Aitak; Reichmann, Florian; Holzer, Peter

    2015-01-01

    Neuropeptide Y (NPY), one of the most abundant peptides in the nervous system, exerts its effects via 5 receptor types, termed Y1, Y2, Y4, Y5 and y6. NPY’s pleiotropic functions comprise the regulation of brain activity, mood, stress coping, ingestion, digestion, metabolism, vascular and immune function. Nerve-derived NPY directly affects immune cells while NPY also acts as a paracrine and autocrine immune mediator, since immune cells themselves are capable of producing and releasing NPY. NPY is able to induce immune activation or suppression, depending on a myriad of factors such as the Y receptors activated and cell types involved. There is an intricate relationship between psychological stress, mood disorders and the immune system. While stress represents a risk factor for the development of mood disorders, it exhibits diverse actions on the immune system as well. Conversely, inflammation is regarded as an internal stressor and is increasingly recognized to contribute to the pathogenesis of mood and metabolic disorders. Intriguingly, the cerebral NPY system has been found to protect against distinct disturbances in response to immune challenge, attenuating the sickness response and preventing the development of depression. Thus, NPY plays an important homeostatic role in balancing disturbances of physiological systems caused by peripheral immune challenge. This implication is particularly evident in the brain in which NPY counteracts the negative impact of immune challenge on mood, emotional processing and stress resilience. NPY thus acts as a unique signalling molecule in the interaction of the immune system with the brain in health and disease. PMID:25545642

  15. Neuropeptide W stimulates adrenocorticotrophic hormone release via corticotrophin-releasing factor but not via arginine vasopressin.

    PubMed

    Yogo, Kosuke; Oki, Yutaka; Iino, Kazumi; Yamashita, Miho; Shibata, Shoko; Hayashi, Chiga; Sasaki, Shigekazu; Suenaga, Toshiko; Nakahara, Daiichiro; Nakamura, Hirotoshi

    2012-01-01

    Neuropeptide W (NPW) was isolated as an endogenous ligand for NPBWR1, an orphan G protein-coupled receptor localized in the rat brain, including the paraventricular nucleus. It has been reported that central administration of NPW stimulates corticosterone secretion in rats. We hypothesized that NPW activates the hypothalamic-pituitary-adrenal (HPA) axis via corticotrophin-releasing factor (CRF) and/or arginine vasopressin (AVP). NPW at 1 pM to 10 nM did not affect basal or ACTH-induced corticosterone release from dispersed rat adrenocortical cells, or basal and CRF-induced ACTH release from dispersed rat anterior pituitary cells. In conscious and unrestrained male rats, intravenous administration of 2.5 and 25 nmol NPW did not affect plasma ACTH levels. However, intracerebroventricular (icv) administration of 2.5 and 5.0 nmol NPW increased plasma ACTH levels in a dose-dependent manner at 15 min after stimulation (5.0 vs. 2.5 nmol NPW vs. vehicle: 1802 ± 349 vs. 1170 ± 204 vs. 151 ± 28 pg/mL, respectively, mean ± SEM). Pretreatment with astressin, a CRF receptor antagonist, inhibited the increase in plasma ACTH levels induced by icv administration of 2.5 nmol NPW at 15 min (453 ± 176 vs. 1532 ± 343 pg/mL, p<0.05) and at 30 min (564 ± 147 vs. 1214 ± 139 pg/mL, p<0.05) versus pretreatment with vehicle alone. However, pretreatment with [1-(β-mercapto-β, β-cyclopentamethylenepropionic acid), 2-(Ο-methyl)tyrosine]-arg-vasopressin, a V1a/V1b receptor antagonist, did not affect icv NPW-induced ACTH release at any time (p>0.05). In conclusion, we suggest that central NPW activates the HPA axis by activating hypothalamic CRF but not AVP.

  16. Neuropeptide Y administration reverses tricyclic antidepressant treatment-resistant depression induced by ACTH in mice.

    PubMed

    Antunes, Michelle S; Ruff, Jossana Rodrigues; de Oliveira Espinosa, Dieniffer; Piegas, Manuela Bastos; de Brito, Maicon Lenon Otenio; Rocha, Kellen Athaíde; de Gomes, Marcelo Gomes; Goes, André Tiago Rossito; Souza, Leandro Cattelan; Donato, Franciele; Boeira, Silvana Peterini; Jesse, Cristiano R

    2015-07-01

    Depression is one of the most common mental disorders and a primary cause of disability. To better treat patients suffering this illness, elucidation of the underlying psychopathological and neurobiological mechanisms is urgently needed. Based on the above-mentioned evidence, we sought to investigate the effects of neuropeptide Y (NPY) treatment in tricyclic antidepressant treatment-resistant depression induced by adrenocorticotropic hormone (ACTH) administration. Mice were treated with NPY (5.84, 11.7 or 23.4mmol/μl) intracerebroventricularly (i.c.v.) for one or five days. The levels of serum corticosterone, tryptophan (TRP), kynurenine (KYN), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and indoleamine 2,3-dioxygenase (IDO) activity in the hippocampus were analyzed. The behavioral parameters (depressive-like and locomotor activity) were also verified. This study demonstrated that ACTH administration increased serum corticosterone levels, KYN, 5-HIAA levels, IDO activity (hippocampus), immobility in the forced swimming test (FST) and the latency to feed in the novelty suppressed feeding test (NSFT). In addition, ACTH administration decreased the BDNF and NGF levels in the hippocampus of mice. NPY treatment was effective in preventing these hormonal, neurochemical and behavioral alterations. It is suggested that the main target of NPY is the modulation of corticosterone and neuronal plasticity protein levels, which may be closely linked with pharmacological action in a model of tricyclic antidepressant treatment-resistant depression. Thus, this study demonstrated a protective effect of NPY on the alterations induced by ACTH administration in mice, indicating that it could be useful as a therapy for the treatment of tricyclic antidepressant treatment-resistant depression.

  17. Accurate Assignment of Significance to Neuropeptide Identifications Using Monte Carlo K-Permuted Decoy Databases

    PubMed Central

    Andrén, Per E.; Sweedler, Jonathan V.; Rodriguez-Zas, Sandra L.

    2014-01-01

    In support of accurate neuropeptide identification in mass spectrometry experiments, novel Monte Carlo permutation testing was used to compute significance values. Testing was based on k-permuted decoy databases, where k denotes the number of permutations. These databases were integrated with a range of peptide identification indicators from three popular open-source database search software (OMSSA, Crux, and X! Tandem) to assess the statistical significance of neuropeptide spectra matches. Significance p-values were computed as the fraction of the sequences in the database with match indicator value better than or equal to the true target spectra. When applied to a test-bed of all known manually annotated mouse neuropeptides, permutation tests with k-permuted decoy databases identified up to 100% of the neuropeptides at p-value < 10−5. The permutation test p-values using hyperscore (X! Tandem), E-value (OMSSA) and Sp score (Crux) match indicators outperformed all other match indicators. The robust performance to detect peptides of the intuitive indicator “number of matched ions between the experimental and theoretical spectra” highlights the importance of considering this indicator when the p-value was borderline significant. Our findings suggest permutation decoy databases of size 1×105 are adequate to accurately detect neuropeptides and this can be exploited to increase the speed of the search. The straightforward Monte Carlo permutation testing (comparable to a zero order Markov model) can be easily combined with existing peptide identification software to enable accurate and effective neuropeptide detection. The source code is available at http://stagbeetle.animal.uiuc.edu/pepshop/MSMSpermutationtesting. PMID:25329667

  18. Dexmedetomidine ameliorates muscle wasting and attenuates the alteration of hypothalamic neuropeptides and inflammation in endotoxemic rats

    PubMed Central

    Cheng, Minhua; Gao, Tao; Xi, Fengchan; Cao, Chun; Chen, Yan; Zhao, Chenyan; Li, Qiurong

    2017-01-01

    Dexmedetomidine is generally used for sedaton in critically ill, it could shorten duration of mechanical ventilation, ICU stay and lower basic metabolism. However, the exact mechanism of these positive effects remains unkown. Here we investigated the hypothesis that dexmedetomidine could ameliorate muscle wasting in endotoxemic rats and whether it was related to hypothalamic neuropeptides alteration and inflammation. Fourty-eight adult male Sprague–Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline, followed by 50 μg/kg dexmedetomidine or saline administration via the femoral vein catheter (infusion at 5 μg·kg-1·hr-1). Twenty-four hours after injection, hypothalamus tissues and skeletal muscle were obtained. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF-1) as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic inflammatory markers and neuropeptides expression were also detected in all four groups. Results showed that LPS administration led to significant increase in hypothalamic inflammation together with muscle wasting. Increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuropeptides Y (NPY) and decreased agouti-related protein (AgRP) were also observed. Meanwhile dexmedetomidine administration ameliorated muscle wasting, hypothalamic inflammation and modulated the alteration of neuropeptides, POMC, CART and AgRP, in endotoxemic rats. In conclusion, dexmedetomidine could alleviate muscle wasting in endotoxemic rats, and it could also attenuate the alteration of hypothalamic neuropeptides and reduce hypothalamic inflammation. PMID:28358856

  19. 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

  20. Identification of Neuropeptide Receptors Expressed by Melanin-Concentrating Hormone Neurons

    PubMed Central

    Parks, Gregory S.; Wang, Lien; Wang, Zhiwei; Civelli, Olivier

    2014-01-01

    Melanin-concentrating Hormone (MCH) is a 19 amino acid cyclic neuropeptide that acts in rodents via the MCH receptor 1 (MCHR1) to regulate a wide variety of physiological functions. MCH is produced by a distinct population of neurons located in the lateral hypothalamus (LH) and zona incerta (ZI) but MCHR1 mRNA is widely expressed throughout the brain. The physiological responses and behaviors regulated by the MCH system have been investigated, but less is known about how MCH neurons are regulated. The effects of most classical neurotransmitters on MCH neurons have been studied, but those of neuropeptides are poorly understood. In order to gain insight into how neuropeptides regulate the MCH system, we investigated which neuropeptide receptors are expressed by MCH neurons using double in situ hybridization. In all, twenty receptors, selected based upon either a suspected interaction with the MCH system or demonstrated high expression levels in the LH and ZI, were tested to determine whether they are expressed by MCH neurons. Overall, eleven neuropeptide receptors were found to exhibit significant colocalization with MCH neurons: Nociceptin / Orphanin FQ Opioid receptor (NOP), MCHR1, both Orexin receptors (ORX), Somatostatin receptor 1 and 2 (SSTR1, SSTR2), the Kisspeptin receotor (KissR1), Neurotensin receptor 1 (NTSR1), Neuropeptide S receptor (NPSR), Cholecystokinin receptor A (CCKAR) and the κ-opioid receptor (KOR). Of these receptors, six have never before been linked to the MCH system. Surprisingly, several receptors thought to regulate MCH neurons displayed minimal colocalization with MCH, suggesting that they may not directly regulate the MCH system. PMID:24978951

  1. 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.

  2. Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8

    PubMed Central

    Tanaka, Hirokazu; Yoshida, Tetsuo; Miyamoto, Norimasa; Motoike, Toshiyuki; Kurosu, Hiroshi; Shibata, Kenji; Yamanaka, Akihiro; Williams, S. Clay; Richardson, James A.; Tsujino, Natsuko; Garry, Mary G.; Lerner, Michael R.; King, David S.; O'Dowd, Brian F.; Sakurai, Takeshi; Yanagisawa, Masashi

    2003-01-01

    GPR7 and GPR8 are orphan G protein-coupled receptors that are highly similar to each other. These receptors are expressed predominantly in brain, suggesting roles in central nervous system function. We have purified an endogenous peptide ligand for GPR7 from bovine hypothalamus extracts. This peptide, termed neuropeptide B (NPB), has a C-6-brominated tryptophan residue at the N terminus. It binds and activates human GPR7 or GPR8 with median effective concentrations (EC50) of 0.23 nM and 15.8 nM, respectively. In situ hybridization shows distinct localizations of the prepro-NPB mRNA in mouse brain, i.e., in paraventricular hypothalamic nucleus, hippocampus, and several nuclei in midbrain and brainstem. Intracerebroventricular (i.c.v.) injection of NPB in mice induces hyperphagia during the first 2 h, followed by hypophagia. Intracerebroventricular injection of NPB produces analgesia to s.c. formalin injection in rats. Through EST database searches, we identified a putative paralogous peptide. This peptide, termed neuropeptide W (NPW), also has an N-terminal tryptophan residue. Synthetic human NPW binds and activates human GPR7 or GPR8 with EC50 values of 0.56 nM and 0.51 nM, respectively. The expression of NPW mRNA in mouse brain is confined to specific nuclei in midbrain and brainstem. These findings suggest diverse physiological functions of NPB and NPW in the central nervous system, acting as endogenous ligands on GPR7 and/or GPR8. PMID:12719537

  3. Nitric oxide synthase interneurons in the monkey cerebral cortex are subsets of the somatostatin, neuropeptide Y, and calbindin cells.

    PubMed

    Smiley, J F; McGinnis, J P; Javitt, D C

    2000-04-28

    99%) immunoreactive for somatostatin and neuropeptide Y, but did not express calbindin. The LNOS cells comprised about 30% of the somatostatin cells and about 60% of the neuropeptide Y cells. The SNOS cells were nearly always (87-98%) calbindin-immunoreactive, and were rarely or never labeled with antibodies to somatostatin or neuropeptide Y. The SNOS cells accounted for about 20% of all of the calbindin cells. The findings demonstrate that the two types of nNOS cells can be distinguished by antibodies to calbindin, somatostatin and neuropeptide Y, but none of these markers is found exclusively in nNOS cells. Nevertheless, neuropeptide Y-immunoreactivity provides a useful marker for LNOS cells, because it is very dense in these cells and only light in the interneurons that lack nNOS.

  4. 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.

  5. Lumbar cerebrospinal fluid concentrations of somatostatin and neuropeptide Y in multiple sclerosis

    SciTech Connect

    Vecsei, L.; Csala, B.; Widerloev, E.E.; Ekman, R.; Czopf, J.; Palffy, G. )

    1990-09-01

    The cerebrospinal fluid (CSF) concentrations of somatostatin and neuropeptide Y were investigated by use of radioimmunoassay in patients suffering from chronic progressive multiple sclerosis. The somatostatin level was significantly decreased in the CSF of patients with multiple sclerosis compared to the control group. The magnitude of this change was more pronounced in patients with severe clinical symptoms of the illness. The CSF neuropeptide Y concentration did not differ from the control values. These findings suggest a selective involvement of somatostatin neurotransmission in multiple sclerosis.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  7. Introduction of a neurohormone in the fire ants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  8. 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

  9. Neuropeptide Y and leptin sensitivity is dependent on diet composition.

    PubMed

    van den Heuvel, J K; Eggels, L; van Rozen, A J; Luijendijk, M C M; Fliers, E; Kalsbeek, A; Adan, R A H; la Fleur, S E

    2014-06-01

    Rats on different free-choice (fc) diets for 1 week of either chow, saturated fat and liquid sugar (fcHFHS), chow and saturated fat (fcHF), or chow and liquid sugar (fcHS) have differential levels of neuropeptide Y (NPY) mRNA in the arcuate nucleus. Because these differences were not explained by plasma leptin levels but did predict subsequent feeding behaviour, in the present study, we first examined whether leptin sensitivity could explain these differences. Second, we focused on the role of NPY on feeding behaviour, and measured NPY mRNA levels and sensitivity to NPY after 4 weeks on the different choice diets. To determine leptin sensitivity, we measured food intake after i.p. leptin or vehicle injections in male Wistar rats subjected to the fcHFHS, fcHS, fcHF or Chow diets for 7 days. Next, we measured levels of arcuate nucleus NPY mRNA with in situ hybridisation in rats subjected to the choice diets for 4 weeks. Finally, we studied NPY sensitivity in rats subjected to the fcHFHS, fcHS, fcHF or Chow diet for 4 weeks by measuring food intake after administration of NPY or vehicle in the lateral ventricle. Leptin decreased caloric intake in rats on Chow, fcHS and fcHF but not in rats on the fcHFHS diet. After 4 weeks, rats on the fcHFHS diet remained hyperphagic, whereas fcHS and fcHF rats decreased caloric intake to levels similar to rats on Chow. By contrast to 1 week, after 4 weeks, levels of NPY mRNA were not different between the diet groups. Lateral ventricle administration of NPY resulted in higher caloric intake in fcHFHS rats compared to rats on the other choice diets or rats on Chow. Our data show that consuming a combination of saturated fat and liquid sugar results in leptin resistance and increased NPY sensitivity that is associated with persistent hyperphagia.

  10. In vitro and in vivo pharmacological characterization of a neuropeptide S tetrabranched derivative

    PubMed Central

    Ruzza, Chiara; Rizzi, Anna; Malfacini, Davide; Pulga, Alice; Pacifico, Salvatore; Salvadori, Severo; Trapella, Claudio; Reinscheid, Rainer K; Calo, Girolamo; Guerrini, Remo

    2015-01-01

    The peptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity, and reproducibility. With this approach, a tetrabranched derivative of neuropeptide S (NPS) has been synthesized and pharmacologically characterized. The in vitro activity of PWT1-NPS has been studied in a calcium mobilization assay. In vivo, PWT1-NPS has been investigated in the locomotor activity (LA) and recovery of the righting reflex (RR) tests. In calcium mobilization studies, PWT1-NPS behaved as full agonist at the mouse NPS receptor (NPSR) being threefold more potent than NPS. The selective NPSR antagonists [tBu-D-Gly5]NPS and SHA 68 displayed similar potency values against NPS and PWT1-NPS. In vivo, both NPS (1–100 pmol, i.c.v.) and PWT1-NPS (0.1–100 pmol, i.c.v.) stimulated mouse LA, with PWT1-NPS showing higher potency than NPS. In the RR assay, NPS (100 pmol, i.c.v.) was able to reduce the percentage of mice losing the RR after diazepam administration and their sleep time 5 min after the i.c.v. injection, but it was totally inactive 2 h after the injection. On the contrary, PWT1-NPS (30 pmol, i.c.v.), injected 2 h before diazepam, displayed wake-promoting effects. This PWT1-NPS stimulant effect was no longer evident in mice lacking the NPSR receptor. The PWT1 technology can be successfully applied to the NPS sequence. PWT1-NPS displayed in vitro a pharmacological profile similar to NPS. In vivo PWT1-NPS mimicked NPS effects showing higher potency and long-lasting action. PMID:25692025

  11. Anxiogenic and Stressor Effects of the Hypothalamic Neuropeptide RFRP-3 Are Overcome by the NPFFR Antagonist GJ14.

    PubMed

    Kim, Joon S; Brownjohn, Phil W; Dyer, Blake S; Beltramo, Massimiliano; Walker, Christopher S; Hay, Debbie L; Painter, Gavin F; Tyndall, Joel D A; Anderson, Greg M

    2015-11-01

    RFamide-related peptide-3 (RFRP-3) is a recently discovered neuropeptide that has been proposed to play a role in the stress response. We aimed to elucidate the role of RFRP-3 and its receptor, neuropeptide FF (NPFF1R), in modulation of stress and anxiety responses. To achieve this, we characterized a new NPFF1R antagonist because our results showed that the only commercially available putative antagonist, RF9, is in fact an agonist at both NPFF1R and the kisspeptin receptor (KISS1R). We report here the identification and pharmacological characterization of GJ14, a true NPFFR antagonist. In in vivo tests of hypothalamic-pituitary-adrenal (HPA) axis function, GJ14 completely blocked RFRP-3-induced corticosterone release and neuronal activation in CRH neurons. Furthermore, chronic infusion of GJ14 led to anxiolytic-like behavior, whereas RFRP-3 infusion had anxiogenic effects. Mice receiving chronic RFRP-3 infusion also had higher basal circulating corticosterone levels. These results indicate a stimulatory action of RFRP-3 on the HPA axis, consistent with the dense expression of NPFF1R in the vicinity of CRH neurons. Importantly, coinfusion of RFRP-3 and GJ14 completely reversed the anxiogenic and HPA axis-stimulatory effects of RFRP-3. Here we have established the role of RFRP-3 as a regulator of stress and anxiety. We also show that GJ14 can reverse the effects of RFRP-3 both in vitro and in vivo. Infusion of GJ14 causes anxiolysis, revealing a novel potential target for treating anxiety disorders.

  12. Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction?

    PubMed

    Cifani, Carlo; Micioni Di Bonaventura, Maria V; Pucci, Mariangela; Giusepponi, Maria E; Romano, Adele; Di Francesco, Andrea; Maccarrone, Mauro; D'Addario, Claudio

    2015-01-01

    Several factors play a role in obesity (i.e., behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down-regulation of the orexigenic neuropeptide Y (NPY) and peroxisome proliferator-activated receptor gamma (PPAR-γ) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-γ, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opio-melanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism.

  13. Interaction of Cocaine- and Amphetamine-regulated Transcript and Neuropeptide Y on Behavior in the Central Nervous System

    PubMed Central

    MÜDÜROĞLU KIRMIZIBEKMEZ, Aynur; MENGİ, Murat; YURDAKOŞ, Ertan

    2016-01-01

    Introduction In the central nervous system, cocaine- and amphetamine-regulated transcript (CART) 55–102 peptide is localized in areas, such as the ventral tegmental area, amygdala, hypothalamus, and hippocampus, where emotional activity is regulated. Studies on the effects of the intracerebroventricular (ICV) administration of CART peptide on behavior remain limited. The findings from these studies suggest that this neuropeptide has anxiogenic-like effects. In the central nervous system, neuropeptide Y (NPY) has similar localization as CART. Previous behavioral studies have demonstrated that the ICV administration of NPY has anxiolytic-like effects. Methods In our study, we established five experimental groups of male Wistar rats to study the competitive effects of NPY and CART peptide. These groups were sham (n=10), CART (n=10), NPY (n=10), CART-NPY (n=10), and NPY-CART (n=10). The open field test, elevated plus maze test, and Porsolt swim test were performed for behavioral analyses. Moreover, the rats were decapitated after the behavioral tests, and the amount of these two peptide in their brains was quantified. Results Our study revealed that the ICV administration of CART peptide is anxiogenic and inhibits animals undergoing learned helplessness in the Porsolt swim test. When we evaluated the results of our study with respect to NPY, we observed its anxiolytic-like effects; in the Porsolt swim test, although it reduced the duration of immobilization, it did not affect the period of struggle. Conclusion Our results revealed that during the competitive interaction of these two peptides, anxiogenic CART peptide suppressed the anxiolytic effects of NPY. PMID:28360786

  14. Feed intake of gilts following intracerebroventicular injection of the novel hypothalamic RFamide (RFa) neuropeptide, 26RFa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  15. Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus.

    PubMed

    Ma, Shuangshuang; Ge, Yinlin; Gai, Xiaoying; Xue, Meilan; Li, Ning; Kang, Jingxuan; Wan, Jianbo; Zhang, Jinyu

    2016-01-12

    Body weight is related to fat mass, which is associated with obesity. Our study explored the effect of fat-1 gene on body weight in fat-1 transgenic mice. In present study, we observed that the weight/length ratio of fat-1 transgenic mice was lower than that of wild-type mice. The serum levels of triglycerides (TG), cholesterol (CT), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and blood glucose (BG) in fat-1 transgenic mice were all decreased. The weights of peri-bowels fat, perirenal fat and peri-testicular fat in fat-1 transgenic mice were reduced. We hypothesized that increase of n-3 PUFAs might alter the expression of hypothalamic neuropeptide genes and lead to loss of body weight in fat-1 transgenic mice. Therefore, we measured mRNA levels of appetite neuropeptides, Neuropeptide Y (NPY), Agouti-related peptides (AgRP), Proopiomelanocortin (POMC), Cocaine and amphetamine regulated transcript (CART), ghrelin and nesfatin-1 in hypothalamus by real-time PCR. Compared with wild-type mice, the mRNA levels of CART, POMC and ghrelin were higher, while the mRNA levels of NPY, AgRP and nesfatin-1 were lower in fat-1 transgenic mice. The results indicate that fat-1 gene or n-3 PUFAs participates in regulation of body weight, and the mechanism of this phenomenon involves the expression of appetite neuropeptides and lipoproteins in fat-1 transgenic mice.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    PubMed Central

    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. PMID:28373831

  18. Wounds increase activin in skin and a vasoactive neuropeptide in sensory ganglia.

    PubMed

    Cruise, Bethany A; Xu, Pin; Hall, Alison K

    2004-07-01

    Successful healing of skin wounds requires sensory innervation and the release of vasoactive neuropeptides that dilate blood vessels and deliver serum proteins to the wound, and that cause pain that protects from further injury. Activin has been proposed as a target-derived regulator of sensory neuropeptides during development, but its role in the mature nervous system is unknown. While adult skin contains a low level of activin, protein levels in skin adjacent to a wound increase rapidly after an excision. Neurons containing the neuropeptide calcitonin gene-related peptide (CGRP) increased in sensory ganglia that projected to the wounded skin, but not in ganglia that projected to unwounded skin, suggesting that neurons respond to a local skin signal. Indeed, many adult sensory neurons respond with increased CGRP expression to the application of activin in vitro and utilize a smad-mediated signal transduction pathway in this response. A second skin-derived factor nerve growth factor (NGF) also increased in wounded skin and increased CGRP in cultured adult dorsal root ganglia (DRG) neurons but with lower efficacy. Together, these data support the hypothesis that activin made by skin cells regulates changes in sensory neuropeptides following skin injury, thereby promoting vasodilation and wound healing.

  19. 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

  20. Neuropeptides as possible targets in sleep disorders: special emphasis on hypocretin-deficient narcolepsy.

    PubMed

    Fujiki, Nobuhiro; Nishino, Seiji

    2007-02-01

    Sleep disorders are disturbances of usual sleep patterns or behaviors caused by deregulation of neuronal synchronicity and of the balance of the neurotransmitter system involved in sleep regulation. Insomnia and hypersomnia are frequent sleep disorders, and these are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on gamma amino butyric acid (GABA)(A) receptors, and amphetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep, and thus, are possibly involved in the pathophysiology of some sleep disorders. Due to recent developments in molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. Recent discoveries also include the finding that the impairment of hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide and receptor system), is the major pathophysiology of narcolepsy with cataplexy. A hypocretin replacement therapy is anticipated to reverse the disease symptoms in humans. In this article, we will review the history of neuropeptide research, sleep modulatory effects of various neuropeptides, and the general strategies for the pharmacological therapeutics targeting the peptidergic systems by referring to hypocretin-deficient narcolepsy as an immediate example.

  1. Neuropeptide-like precursor 4 is uniquely expressed during pupal diapause in the flesh fly

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Suppression subtractive hybridization comparing brains from diapausing and nondiapausing pupae of the flesh fly, Sarcophaga crassipalpis, suggested that the gene encoding neuropeptide-like precursor 4 (Nplp4) was uniquely expressed during diapause. We have sequenced the full-length cDNA encoding Npl...

  2. Prevertebrate Local Gene Duplication Facilitated Expansion of the Neuropeptide GPCR Superfamily.

    PubMed

    Yun, Seongsik; Furlong, Michael; Sim, Mikang; Cho, Minah; Park, Sumi; Cho, Eun Bee; Reyes-Alcaraz, Arfaxad; Hwang, Jong-Ik; Kim, Jaebum; Seong, Jae Young

    2015-11-01

    In humans, numerous genes encode neuropeptides that comprise a superfamily of more than 70 genes in approximately 30 families and act mainly through rhodopsin-like G protein-coupled receptors (GPCRs). Two rounds of whole-genome duplication (2R WGD) during early vertebrate evolution greatly contributed to proliferation within gene families; however, the mechanisms underlying the initial emergence and diversification of these gene families before 2R WGD are largely unknown. In this study, we analyzed 25 vertebrate rhodopsin-like neuropeptide GPCR families and their cognate peptides using phylogeny, synteny, and localization of these genes on reconstructed vertebrate ancestral chromosomes (VACs). Based on phylogeny, these GPCR families can be divided into five distinct clades, and members of each clade tend to be located on the same VACs. Similarly, their neuropeptide gene families also tend to reside on distinct VACs. Comparison of these GPCR genes with those of invertebrates including Drosophila melanogaster, Caenorhabditis elegans, Branchiostoma floridae, and Ciona intestinalis indicates that these GPCR families emerged through tandem local duplication during metazoan evolution prior to 2R WGD. Our study describes a presumptive evolutionary mechanism and development pathway of the vertebrate rhodopsin-like GPCR and cognate neuropeptide families from the urbilaterian ancestor to modern vertebrates.

  3. Discovery and characterization of a conserved pigment dispersing factor-like neuropeptide pathway in Caenorhabditis elegans.

    PubMed

    Janssen, Tom; Husson, Steven J; Meelkop, Ellen; Temmerman, Liesbet; Lindemans, Marleen; Verstraelen, Karen; Rademakers, Suzanne; Mertens, Inge; Nitabach, Michael; Jansen, Gert; Schoofs, Liliane

    2009-10-01

    The neuropeptides pigment dispersing factor (PDF) and vasoactive intestinal peptide (VIP) are known as key players in the circadian clock system of insects and mammals, respectively. In this study, we report the discovery and characterization of a widely conserved PDF-like neuropeptide precursor pathway in nematodes. Using a combinatorial approach of biochemistry and peptidomics, we have biochemically isolated, identified and characterized three PDF-like neuropeptides in the free-living nematode Caenorhabditis elegans. The two PDF encoding genes, which were designated pdf-1 and pdf-2, display a very strong conservation within the phylum of nematodes. Many of the PDF expressing cells in C. elegans play a role in the control of locomotion and the integration of environmental stimuli, among which light. Our real-time PCR analysis indicates that both PDF genes are consistently expressed during the day and do not affect each other's expression. The transcription of both PDF genes seems to be regulated by atf-2 and ces-2, which encode bZIP transcription factors homologous to Drosophila vrille and par domain protein 1 (Pdp1epsilon), respectively. Together, our data suggest that the PDF neuropeptide pathway, which seems to be conserved throughout the protostomian evolutionary lineage, might be more complex than previously assumed.

  4. 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

    2015-11-02

    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.

  5. Neuropeptide gamma: a mammalian tachykinin endowed with potent antidipsogenic action in rats.

    PubMed

    Polidori, C; Staffinati, G; Perfumi, M C; de Caro, G; Massi, M

    1995-09-01

    Neuropeptide gamma (NP gamma) is a 21 aminoacid peptide belonging to the tachykinin (TK) family and including neurokinin A (NKA) in its C-terminal sequence. NP gamma possesses higher affinity than NKA for central NK-2 receptors; it shows lower affinity for NK-1 receptors, however, it potently stimulates salivary secretion, which is mediated by NK-1 receptor activation. Pulse intracerebroventricular (pICV) injection of TKs selectively inhibits water intake in rats. Our studies have suggested that NK-1 receptors may mediate the inhibition of angiotensin II-induced drinking, while NK-2 receptors that of drinking induced by cell dehydration. The present study evaluated the effect of pICV injections of NP gamma on water intake in rats. The injection of NP gamma, 8-250 ng/rat, markedly inhibited angiotensin II-induced drinking, and its effect was blocked by the NK-1 receptor antagonist WIN 62577. NP gamma potently inhibited also drinking induced by SC hypertonic NaCl load or water deprivation. The threshold dose for these effects was 31 ng/rat. Also carbachol-induced drinking was inhibited, but at higher doses. On the other hand, NP gamma did not modify food intake in food deprived rats or 0.1% saccharin intake in water and food sated rats, at the same doses effective on drinking. Present findings support the idea that TKs selectively inhibit water intake in rats and are in keeping with our hypothesis that NK-1 and NK-2 receptors mediate, respectively, inhibition of angiotensin II- and cell dehydration-induced drinking.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Investigations into neuropeptide Y-mediated presynaptic inhibition in cultured hippocampal neurones of the rat.

    PubMed Central

    Bleakman, D.; Harrison, N. L.; Colmers, W. F.; Miller, R. J.

    1992-01-01

    1. We have examined the effects of neuropeptide Y (NPY) on synaptic transmission and [Ca2+]i signals in rat hippocampal neurones grown in culture. [Ca2+]i in individual neurones displayed frequent spontaneous fluctuations often resulting in an elevated plateau [Ca2+]i. These fluctuations were reduced by tetrodotoxin (1 microM) or combinations of the excitatory amino acid antagonists 6-cyano-7-dinitro-quinoxaline (CNQX) (10 microM) and aminophosphonovalerate (APV) (50 microM), indicating that they were the result of glutamatergic transmission occurring between hippocampal neurones. 2. [Ca2+]i fluctuations were also prevented by Ni2+ (200 microM), by the GABAB receptor agonist, baclofen (10 microM) and by NPY (100 nM) or Y2 receptor-selective NPY agonists. Following treatment of cells with pertussis toxin, NPY produced only a brief decrease in [Ca2+]i fluctuations which rapidly recovered. 3. Perfusion of hippocampal neurones with 50 mM K+ produced a large rapid increase in [Ca2+]i. This increase was slightly reduced by NPY or by a combination of CNQX and APV. The effects of CNQX/APV occluded those of NPY. NPY had no effect on Ba2+ currents measured in hippocampal neurones under whole cell voltage-clamp even in the presence of intracellular GTP-gamma-S. On the other hand, Ba2+ currents were reduced by both Cd2+ (200 microM) and baclofen (10 microM). 4. Current clamp recordings from hippocampal neurones demonstrated the occurrence of spontaneous e.p.s.ps and action potential firing which were accompanied by increases in [Ca2+]i. This spontaneous activity and the accompanying [Ca2+]i signals were prevented by application of NPY (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1358389

  7. Anxiolytic-like effect of neuropeptide S in the rat defensive burying.

    PubMed

    Vitale, Giovanni; Filaferro, Monica; Ruggieri, Valentina; Pennella, Sonia; Frigeri, Claudio; Rizzi, Anna; Guerrini, Remo; Calò, Girolamo

    2008-12-01

    Neuropeptide S (NPS) has been recently identified as the endogenous ligand of a previously orphan G-protein-coupled receptor now named NPSR. Both NPS and its receptor are expressed in the brain, where they modulate different functions. In particular, it has been demonstrated that intracerebroventricular (i.c.v.) injection of NPS in rodents increases wakefulness and promotes anxiolytic-like effects. In the present study we used the defensive burying (DB) test in rats to further investigate the action of human NPS (0.1-10 nmol, i.c.v.) on anxiety-related behaviors. Diazepam (1.5mg/kg, i.p.) and caffeine (20mg/kg, i.p.) were used in parallel experiments as standard anxiolytic and anxiogenic drugs, respectively. None of the tested drugs produced statistical differences in the latency to contact the probe, burying behavior latency, number of shocks received or immobility/freezing duration. Caffeine increased cumulative burying behavior and the buried bedding height in a statistically significant manner thus promoting anxiogenic like effects. Opposite results were obtained with diazepam that significantly reduced these behavioral parameters. The anxiolytic-like action of diazepam was mimicked by NPS that reduced cumulative burying behavior in a dose dependent manner. Collectively, robust anxiolytic-like effects were recorded in response to NPS in the DB test. These results are of particular interest since the outcome of this assay is marginally influenced by drug effects on locomotor activity. In conclusion, we provide further evidence that NPS evokes genuine anxiolytic-like effects in the rat; therefore NPSR selective agonists are worthy of development as innovative drugs for the treatment of anxiety disorders.

  8. Regulation of feeding by Neuropeptide F in the desert locust, Schistocerca gregaria.

    PubMed

    Van Wielendaele, Pieter; Dillen, Senne; Zels, Sven; Badisco, Liesbeth; Vanden Broeck, Jozef

    2013-01-01

    Our knowledge on the physiological function of the insect Neuropeptide F (NPF) mostly comes from studies in the fruit fly, Drosophila melanogaster, where NPF was shown to regulate diverse processes, such as feeding, learning and responding to stress. In the desert locust, Schistocerca gregaria, only a truncated form of the "full-length" NPF (the biologically active "trNPF") has been isolated. In this study, we investigated whether this peptide is involved in the regulation of feeding in this orthopteran species. In the S. gregaria EST-database, an NPF-precursor encoding transcript was found. Alignment with other insect NPF-precursors showed relatively highest sequence conservation within the trNPF region (and the flanking dibasic cleavage site), as compared to other regions of the NPF-precursor. Quantitative real-time RT-PCR revealed that the Schgr-NPF-precursor encoding transcript occurs throughout the central nervous system with relatively high transcript levels in the brain, optic lobes and suboesophageal ganglion. It was also detected at relatively high levels in the midgut, which suggests that the encoded peptide also functions in the digestive system. Moreover, Schgr-NPF-transcript levels were notably higher in starved animals than in animals fed ad libitum, while transcript levels were also shown to be regulated after the consumption of a meal. Injection of locust trNPF in adults stimulated food intake, while RNAi knockdown reduced food intake. Furthermore, injection of trNPF in adults stimulated weight increase, while RNAi knockdown reduced weight gain. This effect of trNPF on body weight gain may result from its stimulatory effect on food intake. Taken together, we provide clear evidence for an important role of trNPF in the regulation of feeding in the desert locust, S. gregaria.

  9. Mass Spectrometric Detection of Neuropeptides Using Affinity-Enhanced Microdialysis with Antibody-Coated Magnetic Nanoparticles

    PubMed Central

    Schmerberg, Claire M.; Li, Lingjun

    2012-01-01

    Microdialysis (MD) is a useful sampling tool for many applications due to its ability to permit sampling from an animal concurrent with normal activity. MD is of particular importance in the field of neuroscience, in which it is used to sample neurotransmitters (NTs) while the animal is behaving in order to correlate dynamic changes in NTs with behavior. One important class of signaling molecules, the neuropeptides (NPs), however, presented significant challenges when studied with MD, due to the low relative recovery (RR) of NPs by this technique. Affinity-enhanced microdialysis (AE-MD) has previously been used to improve recovery of NPs and similar molecules. For AE-MD, an affinity agent (AA), such as an antibody-coated particle or free antibody, is added to the liquid perfusing the MD probe. This AA provides an additional mass transport driving force for analyte to pass through the dialysis membrane, and thus increases the RR. In this work, a variety of AAs have been investigated for AE-MD of NPs in vitro and in vivo, including particles with C18 surface functionality and antibody-coated particles. Antibody-coated magnetic nanoparticles (AbMnP) provided the best RR enhancement in vitro, with statistically significant (p<0.05) enhancements for 4 out of 6 NP standards tested, and RR increases up to 41-fold. These particles were then used for in vivo MD in the Jonah crab, Cancer borealis, during a feeding study, with mass spectrometric (MS) detection. 31 NPs were detected in a 30 min collection sample, compared to 17 when no AA was used. The use of AbMnP also increased the temporal resolution from 4–18 hrs in previous studies to just 30 min in this study. The levels of NPs detected were also sufficient for reliable quantitation with the MS system in use, permitting quantitative analysis of the concentration changes for 7 identified NPs on a 30 min time course during feeding. PMID:23249250

  10. Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1)

    PubMed Central

    Anedda, Francesca; Zucchelli, Marco; Schepis, Danika; Hellquist, Anna; Corrado, Lucia; D'Alfonso, Sandra; Achour, Adnane; McInerney, Gerald; Bertorello, Alejandro; Lördal, Mikael; Befrits, Ragnar; Björk, Jan; Bresso, Francesca; Törkvist, Leif; Halfvarson, Jonas

    2011-01-01

    Background neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02). Principal Findings we identified one promoter SNP (rs2530547 [−103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk. Significance these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance. PMID:22216302

  11. Behavioural phenotypic characterization of CD-1 mice lacking the neuropeptide S receptor.

    PubMed

    Ruzza, C; Pulga, A; Rizzi, A; Marzola, G; Guerrini, R; Calo', G

    2012-04-01

    Neuropeptide S (NPS) is the endogenous ligand of a previously orphan receptor now named NPSR. In the brain NPS regulates several biological functions including anxiety, arousal, locomotion, food intake, learning and memory, pain and drug abuse. Mice lacking the NPSR gene (NPSR(-/-)) represent an useful tool to investigate the neurobiology of the NPS/NPSR system. NPSR(-/-) mice have been generated in a 129S6/SvEv genetic background. In the present study we generated CD-1 congenic NPSR(+/+) and NPSR(-/-) mice and investigated their phenotype and sensitivity to NPS in various behavioural assays. The phenotype analysis revealed no locomotor differences between NPSR(+/+) and NPSR(-/-) mice. The behaviour of NPSR(+/+) and NPSR(-/-) mice in the righting reflex test was superimposable. No differences were recorded between the two genotypes in the elevated plus maze, open field and stress-induced hyperthermia tests, with the exception of rearing behaviour that was reduced in knockout animals. Moreover the behaviour of NPSR(+/+) and NPSR(-/-) mice in the forced swimming, novel object recognition and formalin assays was similar. The stimulatory effects of NPS in the locomotor activity test and its anxiolytic-like actions in the elevated plus maze and open field assays were evident in NPSR(+/+) but not NPSR(-/-) animals. In conclusion, the present study indicates that the NPS/NPSR system does not tonically control locomotion, sensitivity to diazepam, anxiety, depressive-like behaviours, memory and pain transmission in mice. Furthermore our results clearly show that the product of the NPSR gene represents the mandatory protein for all the NPS biological effects so far described.

  12. Structural and functional characterization of neuropeptide Y in a primitive teleost, the Japanese eel (Anguilla japonica).

    PubMed

    Li, Shuisheng; Zhao, Liping; Xiao, Ling; Liu, Qiongyu; Zhou, Wenyi; Qi, Xin; Chen, Huapu; Yang, Huirong; Liu, Xiaochun; Zhang, Yong; Lin, Haoran

    2012-10-01

    In the present study, the first full-length cDNA encoding Neuropeptide Y (NPY) was cloned from the brain of Japanese eel (Anguilla japonica). The open reading frame of Japanese eel NPY gene is 294 bp in length, encoding a precursor protein of 97 amino acids, which contains a 36-amino-acid mature peptide. Sequence analysis showed that the Japanese eel NPY peptide is similar to that of other species. Real-time PCR revealed that NPY in Japanese eel is mainly expressed in the brain, especially in the hypothalamus and the optic tectum thalamus. The effect of a negative energy balance on NPY gene expression was examined subsequently. The mRNA level of NPY in the hypothalamus and the optic tectum thalamus showed a pronounced increase after 4 days of food deprivation. The biological activities of Japanese eel NPY were further investigated in vivo and in vitro. Intraperitoneal injection of the NPY peptide into Japanese eel could potently elevate the expression of the mammalian gonadotropin-releasing hormone (mGnRH) in hypothalamus and the follicle-stimulating hormone beta (FSHβ), the luteinizing hormone beta (LHβ) and growth hormone (GH) in pituitary. In static incubation studies, the stimulatory effects of NPY on mGnRH expression in hypothalamic fragments and on FSHβ, LHβ and GH expression in pituitary cells were also observed. However, in vivo and in vitro studies showed that NPY exhibits an inhibitory action on the expression of thyroid-stimulating hormone beta (TSHβ) in pituitary. The results indicate that NPY is involved in the regulation of multiple physiological processes in Japanese eel.

  13. Neuropeptides encoded within a neural transcriptome of the giant triton snail Charonia tritonis, a Crown-of-Thorns Starfish predator.

    PubMed

    Bose, U; Suwansa-Ard, S; Maikaeo, L; Motti, C A; Hall, M R; Cummins, S F

    2017-01-10

    Neuropeptides represent a diverse class of signaling molecules originating from neural tissues. These chemical modulators orchestrate complex physiological events including those associated with growth and reproduction. De novo transcriptome sequencing of a cerebral ganglion library of the endangered giant triton snail (Charonia tritonis) was undertaken in an effort to identify key neuropeptides that control or influence its physiology. The giant triton snail is considered a primary predator of the corallivore Acanthaster planci (Crown-of-Thorns Starfish) that is responsible for a significant loss in coral cover on reefs in the Indo-Pacific. The transcriptome library was assembled into contigs, and then bioinformatic analysis was used to identify a repertoire of 38 giant triton snail neuropeptide precursor genes, and various isoforms, that encode conserved molluscan neuropeptides. C. tritonis neuropeptides show overall precursor organisation consistent with those of other molluscs. These include those neuropeptides associated with mollusc reproduction such as the APGWamide, buccalin, conopressin, gonadotropin-releasing hormone (GnRH), NKY and egg-laying hormone. These data provide a foundation for further studies targeted towards the functional characterisation of neuropeptides to further understand aspects of the biology of the giant triton snail, such as elucidating its reproductive neuroendocrine pathway to allow the development of knowledge based captive breeding programs.

  14. Role of neuropeptides in appetite regulation and obesity--a review.

    PubMed

    Arora, Sarika; Anubhuti

    2006-12-01

    Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.

  15. High-definition De Novo Sequencing of Crustacean Hyperglycemic Hormone (CHH)-family Neuropeptides*

    PubMed Central

    Jia, Chenxi; Hui, Limei; Cao, Weifeng; Lietz, Christopher B.; Jiang, Xiaoyue; Chen, Ruibing; Catherman, Adam D.; Thomas, Paul M.; Ge, Ying; Kelleher, Neil L.; Li, Lingjun

    2012-01-01

    A complete understanding of the biological functions of large signaling peptides (>4 kDa) requires comprehensive characterization of their amino acid sequences and post-translational modifications, which presents significant analytical challenges. In the past decade, there has been great success with mass spectrometry-based de novo sequencing of small neuropeptides. However, these approaches are less applicable to larger neuropeptides because of the inefficient fragmentation of peptides larger than 4 kDa and their lower endogenous abundance. The conventional proteomics approach focuses on large-scale determination of protein identities via database searching, lacking the ability for in-depth elucidation of individual amino acid residues. Here, we present a multifaceted MS approach for identification and characterization of large crustacean hyperglycemic hormone (CHH)-family neuropeptides, a class of peptide hormones that play central roles in the regulation of many important physiological processes of crustaceans. Six crustacean CHH-family neuropeptides (8–9.5 kDa), including two novel peptides with extensive disulfide linkages and PTMs, were fully sequenced without reference to genomic databases. High-definition de novo sequencing was achieved by a combination of bottom-up, off-line top-down, and on-line top-down tandem MS methods. Statistical evaluation indicated that these methods provided complementary information for sequence interpretation and increased the local identification confidence of each amino acid. Further investigations by MALDI imaging MS mapped the spatial distribution and colocalization patterns of various CHH-family neuropeptides in the neuroendocrine organs, revealing that two CHH-subfamilies are involved in distinct signaling pathways. PMID:23028060

  16. Neuropeptide release from airways of young and fully-grown rabbits.

    PubMed

    Larsen, Gary L; Fratelli, Cori; Loader, Joan; Kang, June-Ku Brian; Dakhama, Azzeddine

    2006-12-01

    Nerve growth factor (NGF), a neurotrophin that regulates neuronal development, enhances production of neuropeptides that control airway caliber including substance P (SP). Little is known about the developmental interplay between neurotrophins and neuropeptides. Our goal was to assess release of NGF, SP, and vasoactive intestinal peptide (VIP) from tracheal segments of young (2-week-old) and fully-grown (13-week-old) rabbits, and ascertain location of neuropeptides in airways with mechanical denudation of epithelium and immunohistochemistry. After electrical field stimulation of nerves, bath solutions were collected and immunoassays performed to quantify NGF, SP, and VIP release. There were significant decreases in NGF, SP, and VIP release from airways in 13- versus 2-week-old rabbits. There were also significant decreases in SP and VIP release from denuded versus normal tissues at 2 weeks of age. A similar pattern for SP was seen in 13-week-old rabbits. Immunohistochemistry demonstrated increased neuropeptides in airways from younger rabbits. Although SP was seen in the epithelium and submucosal nerves in the younger group, it was localized to the latter location in fully-grown rabbits. VIP was seen in only submucosal nerves at both ages. Thus, release of NGF, SP, and VIP with neural stimulation decreases in rabbit tracheal segments with age. Decreases in SP with maturation and epithelial denudation appear related in part to decreases in epithelial SP with growth. However, decreases in VIP that occur normally and with epithelial denudation are not explained by location of VIP within the epithelium. The epithelium may be a source of factors that inhibit release of neuropeptides.

  17. Local neuropeptide signaling modulates serotonergic transmission to shape the temporal organization of C. elegans egg-laying behavior.

    PubMed

    Banerjee, Navonil; Bhattacharya, Raja; Gorczyca, Michael; Collins, Kevin M; Francis, Michael M

    2017-04-06

    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.

  18. Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans.

    PubMed

    Ezcurra, Marina; Walker, Denise S; Beets, Isabel; Swoboda, Peter; Schafer, William R

    2016-03-16

    Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways.

  19. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  1. Classical neurotransmitters and neuropeptides involved in major depression in a multi-neurotransmitter system: a focus on antidepressant drugs.

    PubMed

    Werner, Felix-Martin; Coveñas, R

    2013-01-01

    We summarize the alterations of classical neurotransmitters and neuropeptides and the corresponding subreceptors involved in major depression. Neuronal circuits in the brainstem, hippocampus and hypothalamus are developed, since they can be used to derive a multimodal pharmacotherapy. In this sense, serotonin hypoactivity could occur through a strong presynaptic inhibition of glutaminergic neurons via the subtype 5 of metabotropic glutaminergic receptors, and noradrenaline hypoactivity could be due to an enhanced presynaptic inhibition of GABAergic neurons via GABAB receptors. In the hippocampus, dopamine hypoactivity leads to a decreased positive effect. In clinical trials, the antidepressant effect of drugs interfering with the mentioned subreceptors, for example the triple reuptake inhibitor amitifadine, is being investigated. Moreover, the alterations of neuropeptides, such as corticotropin-releasing hormone, neuropeptide Y and galanin are pointed out. The additional antidepressant effect of analogs, agonists and antagonists of the mentioned neuropeptides should be examined.

  2. 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

  3. Effects of Intracerebroventricular Administration of Neuropeptide Y on Metabolic Gene Expression and Energy Metabolism in Male Rats.

    PubMed

    Su, Yan; Foppen, Ewout; Fliers, Eric; Kalsbeek, Andries

    2016-08-01

    Neuropeptide Y (NPY) is an important neurotransmitter in the control of energy metabolism. Several studies have shown that obesity is associated with increased levels of NPY in the hypothalamus. We hypothesized that the central release of NPY has coordinated and integrated effects on energy metabolism in different tissues, resulting in increased energy storage and decreased energy expenditure (EE). We first investigated the acute effects of an intracerebroventricular (ICV) infusion of NPY on gene expression in liver, brown adipose tissue, soleus muscle, and sc and epididymal white adipose tissue (WAT). We found increased expression of genes involved in gluconeogenesis and triglyceride secretion in the liver already 2-hour after the start of the NPY administration. In brown adipose tissue, the expression of thermogenic genes was decreased. In sc WAT, the expression of genes involved in lipogenesis was increased, whereas in soleus muscle, the expression of lipolytic genes was decreased after ICV NPY. These findings indicate that the ICV infusion of NPY acutely and simultaneously increases lipogenesis and decreases lipolysis in different tissues. Subsequently, we investigated the acute effects of ICV NPY on locomotor activity, respiratory exchange ratio, EE, and body temperature. The ICV infusion of NPY increased locomotor activity, body temperature, and EE as well as respiratory exchange ratio. Together, these results show that an acutely increased central availability of NPY results in a shift of metabolism towards lipid storage and an increased use of carbohydrates, while at the same time increasing activity, EE, and body temperature.

  4. Towards understanding the free and receptor bound conformation of neuropeptide Y by fluorescence resonance energy transfer studies.

    PubMed

    Haack, Michael; Beck-Sickinger, Annette G

    2009-06-01

    Despite a considerable sequence identity of the three mammalian hormones of the neuropeptide Y family, namely neuropeptide Y, peptide YY and pancreatic polypeptide, their structure in solution is described to be different. A so-called pancreatic polypeptide-fold has been identified for pancreatic polypeptide, whereas the structure of the N-terminal segment of neuropeptide Y is unknown. This element is important for the binding of neuropeptide Y to two of its relevant receptors, Y(1) and Y(5), but not to the Y(2) receptor subtype. In this study now, three doubly fluorescent-labeled analogs of neuropeptide Y have been synthesized that still bind to the Y(5) receptor with high affinity to investigate the conformation in solution and, for the first time, to probe the conformational changes upon binding of the ligand to its receptor in cell membrane preparations. The results obtained from the fluorescence resonance energy transfer investigations clearly show considerable differences in transfer efficiency that depend both on the solvent as well as on the peptide concentration. However, the studies do not support a pancreatic polypeptide-like folding of neuropeptide Y in the presence of membranes that express the human Y(5) receptor subtype.

  5. Neuropeptides in the cerebral ganglia of the mud crab, Scylla paramamosain: transcriptomic analysis and expression profiles during vitellogenesis

    PubMed Central

    Bao, Chenchang; Yang, Yanan; Huang, Huiyang; Ye, Haihui

    2015-01-01

    Neuropeptides play a critical role in regulating animal reproduction. In vertebrates, GnRH, GnIH and kisspeptin are the key neuropeptide hormones of the reproductive axis, however, the reproductive axis for invertebrates is vague. Knowledge on ovarian development of the mud crab, Scylla paramamosain, is critical for aquaculture and resources management of the commercially important species. This study employed Illumina sequencing, reverse transcription-polymerase chain reaction and quantitative real-time PCR techniques to identify neuropeptides that may be involved in ovarian development of S. paramamosain. A total of 32 neuropeptide transcripts from two dozen neuropeptide families, 100 distinct mature peptides were predicted from the transcriptome data of female S. paramamosain cerebral ganglia. Among them, two families, i.e. GSEFLamide and WXXXRamide, were first identified from the cerebral ganglia of crustaceans. Of these neuropeptides, 21 transcripts of interest were selected for further confirmation and all of them were detected in the cerebral ganglia, as well as in other nervous tissues and the ovary. Most of them also had differential expression in the cerebral ganglia during various vitellogenic stages, suggesting their likely involvement in regulating vitellogenesis and ovarian maturation. Overall, these findings provide an important basis for subsequent studies on peptide function in reproduction of S. paramamosain. PMID:26592767

  6. Neuropeptide Y in normal eating and in genetic and dietary-induced obesity

    PubMed Central

    Beck, B

    2006-01-01

    Neuropeptide Y (NPY) is one the most potent orexigenic peptides found in the brain. It stimulates food intake with a preferential effect on carbohydrate intake. It decreases latency to eat, increases motivation to eat and delays satiety by augmenting meal size. The effects on feeding are mediated through at least two receptors, the Y1 and Y5 receptors. The NPY system for feeding regulation is mostly located in the hypothalamus. It is formed of the arcuate nucleus (ARC), where the peptide is synthesized, and the paraventricular (PVN), dorsomedial (DMN) and ventromedial (VMN) nuclei and perifornical area where it is active. This activity is modulated by the hindbrain and limbic structures. It is dependent on energy availability, e.g. upregulation with food deprivation or restriction, and return to baseline with refeeding. It is also sensitive to diet composition with variable effects of carbohydrates and fats. Leptin signalling and glucose sensing which are directly linked to diet type are the most important factors involved in its regulation. Absence of leptin signalling in obesity models due to gene mutation either at the receptor level, as in the Zucker rat, the Koletsky rat or the db/db mouse, or at the peptide level, as in ob/ob mouse, is associated with increased mRNA abundance, peptide content and/or release in the ARC or PVN. Other genetic obesity models, such as the Otsuka–Long–Evans–Tokushima Fatty rat, the agouti mouse or the tubby mouse, are characterized by a diminution in NPY expression in the ARC nucleus and by a significant increase in the DMN. Further studies are necessary to determine the exact role of NPY in these latter models. Long-term exposure to high-fat or high-energy palatable diets leads to the development of adiposity and is associated with a decrease in hypothalamic NPY content or expression, consistent with the existence of a counter-regulatory mechanism to diminish energy intake and limit obesity development. On the other hand, an

  7. [Membrane-bound proteases involved in neuropeptide degradation in the brain].

    PubMed

    Yokosawa, H

    1993-07-01

    The action of neuropeptides at the synapse is terminated through enzymatic degradation by membrane-bound proteases. We defined and purified membrane-bound proteases functioning at the initial stage of degradation of four neuropeptides. 1. Substance P-degrading endopeptidases isolated from the rat brain and pig striatum showed similar properties to those of endopeptidase-24.16 (neurolysin) except for cleavage sites of substance P. 2. LHRH fragment (1-5)-generating endopeptidases isolated from the neuroblastoma cells and rat brain showed similar properties to those of endopeptidase-24.15 (thimet oligopeptidase). 3. One of two dynorphin-degrading cysteine proteases isolated from neuroblastoma cells showed strict specificity toward the Arg-Arg residues. 4. Endopeptidase-24.11 (neprilysin) isolated from the rat brain was identified as a somatostatin-degrading enzyme.

  8. Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow.

    PubMed

    Park, Min Hee; Jin, Hee Kyung; Min, Woo-Kie; Lee, Won Woo; Lee, Jeong Eun; Akiyama, Haruhiko; Herzog, Herbert; Enikolopov, Grigori N; Schuchman, Edward H; Bae, Jae-sung

    2015-06-12

    Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide.

  9. Studies on the possible central effects in man of a neuropeptide (ACTH 4-9 analogue).

    PubMed

    Nicholson, A N; Stone, B M; Jones, S J

    1984-01-01

    The central effects of a neuropeptide, ACTH 4-9 analogue (Organon 2766), were studied in man using digit symbol substitution (DSS), symbol copying, digit span, electroencephalography and auditory evoked potentials, critical flicker fusion (CFF) and pupillary response to light. Performance was measured overnight, and each of 6 subjects ingested 300 mg caffeine, 40 mg ACTH 4-9 analogue and matching placebo. With placebo there was a marked deterioration in performance overnight. The number of substitutions on DSS and the numbers of symbols copied fell, and the threshold for CFF and number of errors on the vigilance task increased. These effects were not seen after ingestion of caffeine (300 mg), though caffeine may have led to some deterioration in the ability to remember digits. The neuropeptide did not attenuate the decrements in performance overnight.

  10. Stress-related neuropeptides and addictive behaviors: beyond the usual suspects.

    PubMed

    Schank, Jesse R; Ryabinin, Andrey E; Giardino, William J; Ciccocioppo, Roberto; Heilig, Markus

    2012-10-04

    Addictive disorders are chronic, relapsing conditions that cause extensive disease burden. Genetic factors partly account for susceptibility to addiction, but environmental factors such as stressful experiences and prolonged exposure of the brain to addictive drugs promote its development. Progression to addiction involves neuroadaptations within neurocircuitry that mediates stress responses and is influenced by several peptidergic neuromodulators. While corticotrophin releasing factor is the prototypic member of this class, recent work has identified several additional stress-related neuropeptides that play an important role in regulation of drug intake and relapse, including the urocortins, nociceptin, substance P, and neuropeptide S. Here, we review this emerging literature, discussing to what extent the properties of these neuromodulators are shared or distinct and considering their potential as drug targets.

  11. Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow

    PubMed Central

    Park, Min Hee; Jin, Hee Kyung; Min, Woo-Kie; Lee, Won Woo; Lee, Jeong Eun; Akiyama, Haruhiko; Herzog, Herbert; Enikolopov, Grigori N; Schuchman, Edward H; Bae, Jae-sung

    2015-01-01

    Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide. PMID:25916827

  12. Lipid-Conjugation of Endogenous Neuropeptides: Improved Biotherapy against Human Pancreatic Cancer

    PubMed Central

    Gopalakrishnan, Gopakumar; Lepetre, Sinda; Maksimenko, Andrei; Mura, Simona; Desmaële, Didier; Couvreur, Patrick

    2015-01-01

    Neuropeptides are small neuronal signaling molecules that act as neuromodulators for a variety of neural functions including analgesia, reproduction, social behavior, learning, and memory. One of the endogenous neuropeptides—Met-Enkephalin (Met-Enk), has been shown to display an inhibitory effect on cell proliferation and differentiation. Here, a novel lipid-modification approach is shown to create a small library of neuropeptides that will allow increased bioavailability and plasma stability after systemic administration. It is demonstrated, on an experimental model of human pancreatic adenocarcinoma, that lipid conjugation of Met-Enk enhances its tumor suppression efficacy compared to its nonlipidated counterparts, both in vitro and in vivo. More strikingly, the in vivo studies show that a combination therapy with a reduced concentration of Gemcitabine has suppressed the tumor growth considerably even three weeks after the last treatment. PMID:25694262

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

    PubMed Central

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

    2008-01-01

    Summary The neuropeptide PDF is released by sixteen clock neurons in Drosophila and helps maintain circadian activity rhythms by coordinating a network of ~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, DH 31, stimulates large cAMP increases in all PDF-expressing clock neurons. Thus the network of ~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 sub-cellular resolution. Specifically, it experimentally confirms the longstanding hypothesis that PDF is a direct modulator of most neurons in the Drosophila clock network. PMID:18439407

  14. Unique accumulation of neuropeptides in an insect: FMRFamide-related peptides in the cockroach, Periplaneta americana.

    PubMed

    Predel, R; Neupert, S; Wicher, D; Gundel, M; Roth, S; Derst, C

    2004-09-01

    FMRFamides belong to the most extensively studied neuropeptides in invertebrates and exhibit diverse physiological effects on different target organs, such as muscles, intestine and the nervous system. This study on the American cockroach confirms for the first time that extended FMRFamides occur in non-dipteran insects. By means of tandem mass spectrometry, these neuropeptides were structurally elucidated, and sequence information was used for subsequent cloning of the cockroach FMRFamide gene. This precursor gene encodes for 24 putative peptides and shows sufficient similarity with the Drosophila FMRFamide gene. Of the 24 peptides, 23 were detected by mass spectrometric methods; it is the highest number of neuropeptide forms shown to be expressed from a single precursor in any insect. The expression was traced back to single neurons in the thoracic ganglia. The unique accumulation of these FMRFamide-related peptides in thoracic perisympathetic organs provides the definite evidence for a tagma-specific distribution of peptidergic neurohormones in neurohaemal release sites of the insect CNS. Excitatory effects of the cockroach FMRFamides were observed on antenna-heart preparations. In addition, the newly described FMRFamides reduce the spike frequency of dorsal-unpaired median neurons and reduce the intracellular calcium concentration, which may affect the peripheral release of the biogenic amine octopamine.

  15. Radiosynthesis and in Vivo Evaluation of Neuropeptide Y5 Receptor (NPY5R) PET Tracers.

    PubMed

    Kumar, J S Dileep; Walker, Mary; Packiarajan, Mathivanan; Jubian, Vrej; Prabhakaran, Jaya; Chandrasena, Gamini; Pratap, Mali; Parsey, Ramin V; Mann, J John

    2016-05-18

    Neuropeptide Y receptor type 5 (NPY5R) is a G-protein coupled receptor (GPCR) that belongs to the subfamily of neuropeptide receptors (NPYR) that mediate the action of endogenous neuropeptide Y (NPY). Animal models and preclinical studies indicate a role for NPY5R in the pathophysiology of depression, anxiety, and obesity and as a target of potential therapeutic drugs. To better understand the pathophysiological involvement of NPY5R, and to measure target occupancy by potential therapeutic drugs, it would be advantageous to measure NPY5R binding in vivo by positron emission tomography (PET). Four potent and selective NPY5R antagonists were radiolabeled via nucleophilic aromatic substitution reactions with [(18)F]fluoride. Of the four radioligands investigated, PET studies in anesthetized baboons showed that [(18)F]LuAE00654 ([(18)F]N-[trans-4-({[4-(2-fluoropyridin-3-yl)thiazol-2-yl]amino}methyl)cyclohexyl]propane-2-sulfonamide) penetrates blood brain barrier (BBB) and a small amount is retained in the brain. Slow metabolism of [(18)F]LuAE00654 was observed in baboon plasma. Blocking studies with a specific NPY5R antagonist demonstrated up to 60% displacement of radioactivity in striatum, the brain region with highest NPY5R binding. Our studies suggest that [(18)F]LuAE00654 can be a potential PET radiotracer for the quantification and occupancy studies of NPY5R drug candidates.

  16. Mitogenic effects of vasoactive neuropeptides on cultured smooth muscle cell lines

    SciTech Connect

    Mitsuhashi, M.; Payan, D.G.

    1987-03-02

    In order to investigate the relationship between the biochemical pathways that characterize contraction and cell growth, the authors have studied both contraction, mitogenesis and protein synthesis induced by the vasoactive neuropeptides, substance P (SP), calcitonin gene related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) on four different established vascular and non-vascular smooth muscle cell lines. Contraction in vitro was evaluated by light microscopy and recorded photographically. Mitogenesis and protein synthesis were evaluated by (/sup 3/H)-thymidine incorporation into cells and (/sup 3/H)-amino acid incorporation into trichloroacetic acid precipitated materials, respectively. SP stimulated mitogenesis of A7r5 cells (embryonic rat aorta), but failed to induce significant contraction of these cells, whereas, SP induced contraction of cultured adult rat vascular smooth muscle cells (VSMC), but failed to stimulate mitogenesis. CGRP and VIP stimulated mitogenesis and protein synthesis, respectively, of DDT/sub 1/MF-2 cells (hamster vas deferens), but neither induced contraction of this cell line. All three neuropeptides showed no effect on BC/sub 3/H1 (mouse smooth muscle-like) cells. These results suggest that neuropeptides with vasoactive properties modulate different stages of cellular mitogenic responses which may be regulated by the degree of maturation of smooth muscle cell. 22 references, 5 figures.

  17. Appetite regulatory neuropeptides are expressed in the sheep hypothalamus before birth.

    PubMed

    Mühlhäusler, B S; McMillen, I C; Rouzaud, G; Findlay, P A; Marrocco, E M; Rhind, S M; Adam, C L

    2004-06-01

    In the adult, a hypothalamic neural network acts to maintain energy balance in response to nutritional feedback from the periphery. Although there is an immediate requirement for this system to be functional at birth, it is unknown whether the components of this central neural network are expressed in the developing brain before birth. We therefore examined in the fetal sheep hypothalamus during late gestation gene expression for leptin receptor (OB-Rb) and neuropeptides that regulate energy balance in the adult. Brains were collected from fetal sheep at 110 days (n = 12) and 140 days of gestation (n = 5) (term = 150 days) and gene expression was detected in all hypothalami using in situ hybridization with radiolabelled riboprobes for OB-Rb, neuropeptide Y (NPY), agouti-related peptide, pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript (CART). All mRNAs were expressed in the arcuate nucleus of fetuses at both time points. Additional sites of mRNA expression were the dorsomedial hypothalamus (DMH) for NPY, the paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and lateral hypothalamic area for CART, and the DMH, PVN and VMH for OB-Rb. We have therefore demonstrated that adult-like localization of gene expression for OB-Rb and key appetite regulatory neuropeptides is established in the ovine hypothalamus before birth. Thus, the fetus possesses a central appetite regulatory neural network with the potential to respond to changes in nutrient supply, which could impact on energy balance regulation both before and after birth.

  18. Postprandial effects on appetite-related neuropeptide expression in the brain of Atlantic salmon, Salmo salar.

    PubMed

    Valen, R; Jordal, A-E O; Murashita, K; Rønnestad, I

    2011-05-01

    Following feeding of a single meal to Atlantic salmon, the temporal changes in the brain mRNA expression of neuropeptide y (npy), cocaine-amphetamine regulated transcript (cart), peptide yy (pyy), two isoforms of agouti-related protein (agrp), two isoforms of cholecystokinin (cck), and four isoforms of proopiomelanocortin (pomc) were assessed by q-PCR. In the course of 24h post-feeding (hpf), several of the brain neuropeptides displayed changes in mRNA expression compared to an unfed control group, indicating that food intake and processing affect the regulation of expression of these genes in Atlantic salmon. Expression of cart, cck-l, pomc-a1 and pomc-b all increased within 3h of feeding, while most of the feed was still in the stomach, suggesting that these neuropeptides play central anorexigenic roles similar to those described in higher vertebrates, including determining meal intervals. On the other hand, the npy and agrp isoforms which have been described as playing orexigenic roles in mammals, showed an opposite response in salmon and both were elevated in the first 3h after feeding. The different isoforms of cck, agrp and pomc had different mRNA expression patterns, which indicate specific roles related to feeding regulation. The minimal effect of feeding and digestion on pyy expression in the brain indicates that PYY plays a minor role in the central control of short-term food intake in Atlantic salmon.

  19. Forebrain neuropeptide regulation of pair association and behavior in cooperating cleaner fish.

    PubMed

    Cardoso, Sónia C; Grutter, Alexandra S; Paula, José R; André, Gonçalo I; Messias, João P; Gozdowska, Magdalena; Kulczykowska, Ewa; Soares, Marta C

    2015-06-01

    Animals establish privileged relationships with specific partners, which are treated differently from other conspecifics, and contribute to behavioral variation. However, there is limited information on the underlying physiological mechanisms involved in the establishment of these privileged ties and their relationship to individual cooperation levels. The Indo-Pacific bluestreak cleaner wrasse Labroides dimidiatus often forages in mixed-sex pairs when cleaning fish clients. Intra-couple conflicts often arise during a joint client inspection, which may alter the overall quality of cleaning service provided. Here we tested two hypotheses: a) whether intra-pair association (i.e. association index), measured with joint interspecific cleaning and intraspecific behavior, is correlated with neuroendocrine mechanisms involving forebrain neuropeptides arginine vasotocin (AVT) and isotocin (IT) and b) whether these neuropeptide level shifts relate to an individual's interspecific service quality. We found that partner support (number of cleaning interactions and tactile stimulation) received by male cleaners increased with association index. When cleaners inspected clients alone, cleaners' cheating decreased with association index for females but not males. AVT levels did not differ according to sex or association level. Forebrain IT levels increased with association index for males, whereas no relationship was found for females. Finally, cleaner cheating varied between sex and forebrain IT levels. Findings indicate that variation in pairs' relationships influences male and female cleaner fish differently and contributes to the variation of brain neuropeptide levels, which is linked to distinct cooperative outcomes.

  20. Neuropeptide Modulation of Central Amygdala Neuroplasticity is a Key Mediator of Alcohol Dependence

    PubMed Central

    Gilpin, Nicholas W.; Roberto, Marisa

    2011-01-01

    Alcohol use disorders are characterized by compulsive drug-seeking and drug-taking, loss of control in limiting intake, and withdrawal syndrome in the absence of drug. The central amygdala (CeA) and neighboring regions (extended amygdala) mediate alcohol-related behaviors and chronic alcohol-induced plasticity. Acute alcohol suppresses excitatory (glutamatergic) transmission whereas chronic alcohol enhances glutamatergic transmission in CeA. Acute alcohol facilitates inhibitory (GABAergic) transmission in CeA, and chronic alcohol increases GABAergic transmission. Electrophysiology techniques are used to explore the effects of neuropeptides/neuromodulators (CRF, NPY, nociceptin, dynorphin, endocannabinoids, galanin) on inhibitory transmission in CeA. In general, pro-anxiety peptides increase, and anti-anxiety peptides decrease CeA GABAergic transmission. These neuropeptides facilitate or block the action of acute alcohol in CeA, and chronic alcohol produces plasticity in neuropeptide systems, possibly reflecting recruitment of negative reinforcement mechanisms during the transition to alcohol dependence. A disinhibition model of CeA output is discussed in the context of alcohol dependence- and anxiety-related behaviors. PMID:22101113

  1. Neuropeptide W: a key player in the homeostatic regulation of feeding and energy metabolism?

    PubMed

    Takenoya, Fumiko; Kageyama, Haruaki; Shiba, Kanako; Date, Yukari; Nakazato, Masamitsu; Shioda, Seiji

    2010-07-01

    Neuropeptide W (NPW), recently isolated from porcine hypothalamus, has been identified as the endogenous ligand for both NPBWR1 (GPR7) and NPBWR2 (GPR8), which belong to the orphan G protein-coupled receptor family. NPW is thought to play an important role in the regulation of feeding and drinking behavior, and to be related to the stress response. NPW-containing neurons are localized in several regions of the brain, including the hypothalamus, hippocampus, limbic system, midbrain, and brain stem. Accumulated evidence suggests that hypothalamic neuropeptides, such as neuropeptide Y (NPY), orexin, melanin-concentrating hormone (MCH), and proopiomelanocortin (POMC), are involved in the regulation of feeding behavior and energy homeostasis via neuronal circuits in the hypothalamus. NPW also forms part of the feeding-regulating neuronal circuitry in conjunction with other feeding-regulating peptide-containing neurons within the hypothalamus. We summarize our current understanding of the distribution of NPW and of the neuronal interactions between NPW and the different feeding-regulating peptide-containing neurons. This review also discusses evidence for the dichotomous actions of NPW on energy balance and the potential mechanisms involved.

  2. Crustose coralline algae and a cnidarian neuropeptide trigger larval settlement in two coral reef sponges.

    PubMed

    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.

  3. Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence.

    PubMed

    Gilpin, Nicholas W; Roberto, Marisa

    2012-02-01

    Alcohol use disorders are characterized by compulsive drug-seeking and drug-taking, loss of control in limiting intake, and withdrawal syndrome in the absence of drug. The central amygdala (CeA) and neighboring regions (extended amygdala) mediate alcohol-related behaviors and chronic alcohol-induced plasticity. Acute alcohol suppresses excitatory (glutamatergic) transmission whereas chronic alcohol enhances glutamatergic transmission in CeA. Acute alcohol facilitates inhibitory (GABAergic) transmission in CeA, and chronic alcohol increases GABAergic transmission. Electrophysiology techniques are used to explore the effects of neuropeptides/neuromodulators (CRF, NPY, nociceptin, dynorphin, endocannabinoids, galanin) on inhibitory transmission in CeA. In general, pro-anxiety peptides increase, and anti-anxiety peptides decrease CeA GABAergic transmission. These neuropeptides facilitate or block the action of acute alcohol in CeA, and chronic alcohol produces plasticity in neuropeptide systems, possibly reflecting recruitment of negative reinforcement mechanisms during the transition to alcohol dependence. A disinhibition model of CeA output is discussed in the context of alcohol dependence- and anxiety-related behaviors.

  4. Effects of starvation on the expression of feeding related neuropeptides in the larval zebrafish hypothalamus.

    PubMed

    Shanshan, Liu; Cuizhen, Zhang; Gang, Peng

    2016-09-01

    Vertebrate feeding behavior is regulated by neuropeptide Y (NPY), GALANIN and GMAP prepropeptide (GAL), agouti related neuropeptide (AGRP) and proopiomelanocortin (POMC) in the hypothalamus. However, there are few studies on the relationship between these neuropeptides and feeding in zebrafish larvae. In the present study, real-time quantitative PCR and in situ hybridization were applied to examine the expression levels of npy, galanin, agrp and pomca in the hypothalamus of zebrafish larvae after starvation and re-feeding. The results showed the expression of agrp and galanin increased significantly after starvation compared to the control group, whilst the expression of pomca decreased significantly compared to control. If the animals were re-fed for two days after starvation, the expression of pomca, agrp and galanin showed no significant difference from the control. Expression of npy did not alter in either condition. These results indicate that starvation increases expression levels of agrp and galanin, and reduces the pomca expression. In addition, these starvation-induced changes can be reversed by re-feeding.

  5. Receptors for the Neuropeptides, Myoinhibitory Peptide and SIFamide, in Control of the Salivary Glands of the Blacklegged Tick Ixodes scapularis

    PubMed Central

    Šimo, Ladislav; Koči, Juraj; Park, Yoonseong

    2013-01-01

    Tick salivary glands are important organs that enable the hematophagous feeding of the tick. We previously described the innervation of the salivary gland acini types II and III by a pair of protocerebral salivary gland neurons that produce both myoinhibitory peptide (MIP) and SIFamide (Šimo et al., 2009b). In this study we identified authentic receptors expressed in the salivary glands for these neuropeptides. Homology-based searches for these receptors in the Ixodes scapularis genome sequence were followed by gene cloning and functional expression of the receptors. Both receptors were activated by low nanomolar concentrations of their respective ligands. The temporal expression patterns of the two ligands and their respective receptors suggest that the SIFamide signaling system pre-exists in unfed salivary glands, while the MIP system is activated upon initiation of feeding. Immunoreactivity for the SIFamide receptor in the salivary gland was detected in acini types II and III, surrounding the acinar valve and extending to the basal region of the acinar lumen. The location of the SIFamide receptor in the salivary glands suggests three potential target cell types and their probable functions: myoepithelial cells that may function in the contraction of the acini and/or the control of the valve; large, basally located dopaminergic granular cells for regulation of paracrine dopamine; and neck cells that may be involved in the control of the acinar duct and its valve. PMID:23357681

  6. Challenges in mass spectrometry-based quantification of bioactive peptides: a case study exploring the neuropeptide Y family.

    PubMed

    Xi, Li; Jin, Yaping; Parker, Edward A; Josh, Peter; Jones, Alun; Wijffels, Gene; Colgrave, Michelle L

    2012-01-01

    The study of biologically active peptides is critical to the understanding of physiological pathways, especially those involved in the development of disease. Historically, the measurement of biologically active endogenous peptides has been undertaken by radioimmunoassay, a highly sensitive and robust technique that permits the detection of physiological concentrations in different biofluid and tissue extracts. Over recent years, a range of mass spectrometric approaches have been applied to peptide quantification with limited degrees of success. Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) belong to the NPY family exhibiting regulatory effects on appetite and feeding behavior. The physiological significance of these peptides depends on their molecular forms and in vivo concentrations systemically and at local sites within tissues. In this report, we describe an approach for quantification of individual peptides within mixtures using high-performance liquid chromatography electrospray ionization tandem mass spectrometry analysis of the NPY family peptides. Aspects of quantification including sample preparation, the use of matrix-matched calibration curves, and internal standards will be discussed. This method for the simultaneous determination of NPY, PYY, and PP was accurate and reproducible but lacks the sensitivity required for measurement of their endogenous concentration in plasma. The advantages of mass spectrometric quantification will be discussed alongside the current obstacles and challenges.

  7. Association of neuropeptide Y promoter polymorphism (rs16147) with perceived stress and cardiac vagal outflow in humans

    PubMed Central

    Chang, Hsin-An; Fang, Wen-Hui; Chang, Tieh-Ching; Huang, San-Yuan; Chang, Chuan-Chia

    2016-01-01

    Neuropeptide Y (NPY) is involved in resilience to stress, and higher vagal (parasympathetic) activity has been associated with greater stress resilience. Thus, we examined whether rs16147, a functional promoter polymorphism (C>T) of the NPY gene, could influence vagal tone during chronic high stress levels. NPY genotyping, chronic psychological stress level measurement (using the Perceived Stress Scale [PSS]), cardiac autonomic function assessment (using short-term heart rate variability [HRV]) were performed in 1123 healthy, drug-free Han Chinese participants who were divided into low- and high-PSS groups. In the high-PSS group (n = 522), the root mean square of successive heartbeat interval differences and high frequency power (both HRV indices of parasympathetic activity) were significantly increased in T/T homozygotes compared to C/C homozygotes. However, no significant between-genotype difference was found in any HRV variable in the low-PSS group (n = 601). Our results are the first to demonstrate that functional NPY variation alters chronic stress-related vagal control, suggesting a potential parasympathetic role for NPY gene in stress regulation. PMID:27527739

  8. A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala.

    PubMed

    Streit, Fabian; Haddad, Leila; Paul, Torsten; Frank, Josef; Schäfer, Axel; Nikitopoulos, Jörg; Akdeniz, Ceren; Lederbogen, Florian; Treutlein, Jens; Witt, Stephanie; Meyer-Lindenberg, Andreas; Rietschel, Marcella; Kirsch, Peter; Wüst, Stefan

    2014-07-01

    We have previously shown that urban upbringing and city living were associated with stress-induced activity in the amygdala and the perigenual anterior cingulate cortex (pACC). This finding might link the epidemiological risk factor "urbanicity" to neurobiological mechanisms of psychiatric disorders. However, given the heritability of stress-related phenotypes, it appears likely that genetic factors can modulate the effect of urbanicity on social stress processing. In the present exploratory study, we investigated if a functional sequence variation in the neuropeptide S receptor gene (NPSR1 rs324981) is associated with brain activation patterns under acute psychosocial stress and if it modulates the link between urbanicity and central stress processing. In animals, neuropeptide S has strong anxiolytic effects and it induces hypothalamus-pituitary-adrenal (HPA) axis activation. In humans, rs324981 was found to be associated with anxiety and stress-related phenotypes. Forty-two subjects were exposed to a psychosocial stress task for scanner environments (ScanSTRESS). While no main effect of rs324981 on amygdala and pACC activity was detected, we found a distinct interaction between rs324981 and urban upbringing modulating right amygdala responses. Moreover, right amygdala responses were significantly higher in subjects who also showed a salivary cortisol response to the stress exposure. The present finding of a gene × environment interaction further supports the view that the brain NPS system is involved in central stress regulation. This study provides first evidence for the assumption that a NPSR1 variant modulates brain activation under stress, interacting with the environmental risk factor urban upbringing.

  9. Neuropeptide FF-sensitive confinement of mu opioid receptor does not involve lipid rafts in SH-SY5Y cells

    SciTech Connect

    Mouledous, Lionel

    2008-08-15

    *: Mu opioid (MOP) receptor activation can be functionally modulated by stimulation of Neuropeptide FF 2 (NPFF{sub 2}) G protein-coupled receptors. Fluorescence recovery after photobleaching experiments have shown that activation of the NPFF{sub 2} receptor dramatically reduces the fraction of MOP receptors confined in microdomains of the plasma membrane of SH-SY5Y neuroblastoma cells. The aim of the present work was to assess if the direct observation of receptor compartmentation by fluorescence techniques in living cells could be related to indirect estimation of receptor partitioning in lipid rafts after biochemical fractionation of the cell. Our results show that MOP receptor distribution in lipid rafts is highly dependent upon the method of purification, questioning the interpretation of previous data regarding MOP receptor compartmentation. Moreover, the NPFF analogue 1DMe does not modify the distribution profile of MOP receptors, clearly demonstrating that membrane fractionation data do not correlate with direct measurement of receptor compartmentation in living cells.

  10. 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.

  11. Aplysia Locomotion: Network and Behavioral Actions of GdFFD, a D-Amino Acid-Containing Neuropeptide.

    PubMed

    Yang, Chao-Yu; Yu, Ke; Wang, Ye; Chen, Song-An; Liu, Dan-Dan; Wang, Zheng-Yang; Su, Yan-Nan; Yang, Shao-Zhong; Chen, Ting-Ting; Livnat, Itamar; Vilim, Ferdinand S; Cropper, Elizabeth C; Weiss, Klaudiusz R; Sweedler, Jonathan V; Jing, Jian

    2016-01-01

    One emerging principle is that neuromodulators, such as neuropeptides, regulate multiple behaviors, particularly motivated behaviors, e.g., feeding and locomotion. However, how neuromodulators act on multiple neural networks to exert their actions remains poorly understood. These actions depend on the chemical form of the peptide, e.g., an alternation of L- to D-form of an amino acid can endow the peptide with bioactivity, as is the case for the Aplysia peptide GdFFD (where dF indicates D-phenylalanine). GdFFD has been shown to act as an extrinsic neuromodulator in the feeding network, while the all L-amino acid form, GFFD, was not bioactive. Given that both GdFFD/GFFD are also present in pedal neurons that mediate locomotion, we sought to determine whether they impact locomotion. We first examined effects of both peptides on isolated ganglia, and monitored fictive programs using the parapedal commissural nerve (PPCN). Indeed, GdFFD was bioactive and GFFD was not. GdFFD increased the frequency with which neural activity was observed in the PPCN. In part, there was an increase in bursting spiking activity that resembled fictive locomotion. Additionally, there was significant activity between bursts. To determine how the peptide-induced activity in the isolated CNS is translated into behavior, we recorded animal movements, and developed a computer program to automatically track the animal and calculate the path of movement and velocity of locomotion. We found that GdFFD significantly reduced locomotion and induced a foot curl. These data suggest that the increase in PPCN activity observed in the isolated CNS during GdFFD application corresponds to a reduction, rather than an increase, in locomotion. In contrast, GFFD had no effect. Thus, our study suggests that GdFFD may act as an intrinsic neuromodulator in the Aplysia locomotor network. More generally, our study indicates that physiological and behavioral analyses should be combined to evaluate peptide actions.

  12. Study of air pollution: Effects of ozone on neuropeptide-mediated responses in human subjects. Final report

    SciTech Connect

    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 nerves 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.

  13. Neuropeptide Y promotes neurogenesis and protection against methamphetamine-induced toxicity in mouse dentate gyrus-derived neurosphere cultures.

    PubMed

    Baptista, Sofia; Bento, Ana Rita; Gonçalves, Joana; Bernardino, Liliana; Summavielle, Teresa; Lobo, Andrea; Fontes-Ribeiro, Carlos; Malva, João O; Agasse, Fabienne; Silva, Ana P

    2012-06-01

    Methamphetamine (METH) is a psychostimulant drug of abuse that causes severe brain damage. However, the mechanisms responsible for these effects are poorly understood, particularly regarding the impact of METH on hippocampal neurogenesis. Moreover, neuropeptide Y (NPY) is known to be neuroprotective under several pathological conditions. Here, we investigated the effect of METH on dentate gyrus (DG) neurogenesis, regarding cell death, proliferation and differentiation, as well as the role of NPY by itself and against METH-induced toxicity. DG-derived neurosphere cultures were used to evaluate the effect of METH or NPY on cell death, proliferation or neuronal differentiation. Moreover, the role of NPY and its receptors (Y(1), Y(2) and Y(5)) was investigated under conditions of METH-induced DG cell death. METH-induced cell death by both apoptosis and necrosis at concentrations above 10 nM, without affecting cell proliferation. Furthermore, at a non-toxic concentration (1 nM), METH decreased neuronal differentiation. NPY's protective effect was mainly due to the reduction of glutamate release, and it also increased DG cell proliferation and neuronal differentiation via Y(1) receptors. In addition, while the activation of Y(1) or Y(2) receptors was able to prevent METH-induced cell death, the Y(1) subtype alone was responsible for blocking the decrease in neuronal differentiation induced by the drug. Taken together, METH negatively affects DG cell viability and neurogenesis, and NPY is revealed to be a promising protective tool against the deleterious effects of METH on hippocampal neurogenesis.

  14. High neuropeptide Y release associates with Ewing sarcoma bone dissemination - in vivo model of site-specific metastases.

    PubMed

    Hong, Sung-Hyeok; Tilan, Jason U; Galli, Susana; Izycka-Swieszewska, Ewa; Polk, Taylor; Horton, Meredith; Mahajan, Akanksha; Christian, David; Jenkins, Shari; Acree, Rachel; Connors, Katherine; Ledo, Phuong; Lu, Congyi; Lee, Yi-Chien; Rodriguez, Olga; Toretsky, Jeffrey A; Albanese, Chris; Kitlinska, Joanna

    2015-03-30

    Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.

  15. Effects of neuropeptide Y and ethanol on arousal and anxiety-like behavior in alcohol-preferring rats.

    PubMed

    Gilpin, Nicholas W; Henderson, Angela N; Badia-Elder, Nancy E; Stewart, Robert B

    2011-03-01

    Neuropeptide Y (NPY) is abundant in the mammalian brain and plays a prominent role in behaviors related to negative affect and alcohol. NPY suppresses anxiety-like behavior and alcohol-drinking behaviors in a wide array of rodent models and also affects changes in these behaviors produced by fearful and stressful stimuli. Rats selectively bred for high alcohol preference (P rats) appear to be particularly sensitive to the behavioral effects of NPY. The dual purpose of the present investigation was to determine the effects of intraventricular NPY on (1) the acoustic startle response (ASR) of P rats in a high-anxiety setting and (2) social interaction behavior of P rats. In experiment 1, P rats were either cycled through periods of long-term ethanol access and abstinence or they remained ethanol naive. Rats were injected with one of four NPY doses and tested for ASR before and after footshock stress. NPY suppressed ASR in all P rats regardless of shock condition or drinking history. In experiment 2, rats received intraventricular infusion of one of four NPY doses and were then injected with either ethanol (0.75 g/kg) or saline and tested for social interaction. NPY increased social interaction in P rats even at doses that suppressed locomotor activity, regardless of ethanol dose. Suppression of anxiety-like and arousal behaviors by NPY in the present study confirm a role for NPY in alcohol-related behaviors in alcohol-preferring P rats.

  16. Neuropeptide Y suppresses ethanol drinking in ethanol-abstinent, but not non-ethanol-abstinent, Wistar rats.

    PubMed

    Gilpin, Nicholas W; Stewart, Robert B; Badia-Elder, Nancy E

    2008-11-01

    In outbred rats, increases in brain neuropeptide Y (NPY) activity suppress ethanol consumption in a variety of access conditions, but only following a history of ethanol dependence. NPY reliably suppresses ethanol drinking in alcohol-preferring rats, and this effect is augmented following a period of ethanol abstinence. The purpose of this experiment was to examine the effects of NPY on two-bottle choice ethanol drinking and feeding in Wistar rats that had undergone chronic ethanol vapor exposure, cycles of ethanol abstinence, or both. Ethanol-drinking Wistar rats were given 6 weeks of access to 15% (vol/vol) ethanol and water followed by either: two cycles of 1 week ethanol vapor exposure and 2 weeks with no ethanol; two cycles of 1 week ethanol bottle availability and 2 weeks with no ethanol; or 2 weeks of ethanol vapor exposure. Rats were infused intracerebroventricularly with one of four NPY doses (0.0, 2.5, 5.0, or 10.0 microg) following the ethanol exposure patterns described above, and tested for ethanol drinking and feeding in a two-bottle choice situation. NPY dose dependently increased food intake regardless of ethanol exposure history, but suppressed ethanol drinking only in rats that underwent cycles of ethanol access and ethanol abstinence. These results support the notion that dysregulation of brain NPY systems during chronic intermittent ethanol exposure is important in the motivational drive for subsequent relapse to ethanol drinking.

  17. Transcriptomic characterization and curation of candidate neuropeptides regulating reproduction in the eyestalk ganglia of the Australian crayfish, Cherax quadricarinatus

    PubMed Central

    Nguyen, Tuan Viet; Cummins, Scott F.; Elizur, Abigail; Ventura, Tomer

    2016-01-01

    The Australian redclaw crayfish (Cherax quadricarinatus) has recently received attention as an emerging candidate for sustainable aquaculture production in Australia and worldwide. More importantly, C. quadricarinatus serves as a good model organism for the commercially important group of decapod crustaceans as it is distributed worldwide, easy to maintain in the laboratory and its reproductive cycle has been well documented. In order to better understand the key reproduction and development regulating mechanisms in decapod crustaceans, the molecular toolkit available for model organisms such as C. quadricarinatus must be expanded. However, there has been no study undertaken to establish the C. quadricarinatus neuropeptidome. Here we report a comprehensive study of the neuropeptide genes expressed in the eyestalk in the Australian crayfish C. quadricarinatus. We characterised 53 putative neuropeptide-encoding transcripts based on key features of neuropeptides as characterised in other species. Of those, 14 neuropeptides implicated in reproduction regulation were chosen for assessment of their tissue distribution using RT-PCR. Further insights are discussed in relation to current knowledge of neuropeptides in other species and potential follow up studies. Overall, the resulting data lays the foundation for future gene-based neuroendocrinology studies in C. quadricarinatus. PMID:27924858

  18. Neuropeptide Y reduces the expression of PLCB2, PLCD1 and selected PLC genes in cultured human endothelial cells.

    PubMed

    Lo Vasco, V R; Leopizzi, M; Puggioni, C; Della Rocca, C; Businaro, R

    2014-09-01

    Endothelial cells (EC) are the first elements exposed to mediators circulating in the bloodstream, and react to stimulation with finely tuned responses mediated by different signal transduction pathways, leading the endothelium to adapt. Neuropeptide Y (NPY), the most abundant peptide in heart and brain, is mainly involved in the neuroendocrine regulation of the stress response. The regulatory roles of NPY depend on many factors, including its enzymatic processing, receptor subtypes and related signal transduction systems, including the phosphoinositide (PI) pathway and related phospholipase C (PI-PLC) family of enzymes. The panel of expression of PI-PLC enzymes differs comparing quiescent versus differently stimulated human EC. Growing evidences indicate that the regulation of the expression of PLC genes, which codify for PI-PLC enzymes, might act as an additional mechanism of control of the PI signal transduction pathway. NPY was described to potentiate the activation of PI-PLC enzymes in different cell types, including EC. In the present experiments, we stimulated human umbilical vein EC using different doses of NPY in order to investigate a possible role upon the expression PLC genes. NPY reduced the overall transcription of PLC genes, excepting for PLCE. The most significant effects were observed for PLCB2 and PLCD1, both isoforms recruited by means of G-proteins and G-protein-coupled receptors. NPY behavior was comparable with other PI-PLC interacting molecules that, beside the stimulation of phospholipase activity, also affect the upcoming enzymes' production acting upon gene expression. That might represent a mode to regulate the activity of PI-PLC enzymes after activation.

  19. Regulation of pheromone inhibition in mated females of Choristoneura fumiferana and C. rosaceana.

    PubMed

    Delisle; Picimbon; Simard

    2000-06-01

    In the spruce budworm, Choristoneura fumiferana, and the obliquebanded leafroller, C. rosaceana, mating significantly depressed pheromone production after 24 h. On subsequent days, the pheromone titre increased slightly in C. fumiferana, but not in C. rosaceana. No pheromonostatic activity was associated with male accessory sex gland (ASG) extracts, 20-hydroxy-ecdysone or hemolymph taken from mated females. However, pheromone production in mated females was not suppressed when the ventral nerve cord (VNC) was transected prior to mating, indicating that an intact VNC is required to permanently switch off pheromone production after mating. As suggested for other moth species, the presence of sperm in the spermatheca probably triggers the release of a signal, via the VNC, to inhibit pheromone production. The fact that in both species the brain-suboesophageal ganglion (Br-SEG) of mated females contains pheromonotropic activity and that their pheromone glands may be stimulated by the synthetic pheromone-biosynthesis-activating-neuropeptide (PBAN) or a brain extract supports the hypothesis that the neural signal prevents the release of PBAN into the hemolymph rather than inhibiting its biosynthesis. Therefore, we speculate that following the depletion of sperm in the spermatheca, the neural signal declines and is less effective in preventing the release of PBAN, thereby stimulating the resumption of pheromone production, as seen in mated C. fumiferana females. In a previous study, mating was shown to induce a significant rise in the juvenile hormone (JH) titre of both Choristoneura female moths, suggesting that post-mating pheromone inhibition may be under hormonal regulation. However, following topical applications or injections of the juvenile hormone analogue (JHA) and JH II into virgins, the pheromone only declined significantly 48 h after treatment in C. rosaceana. This suggests that the significant rise in the hemolymph JH titre after mating in C. rosaceana females

  20. Semisynthesis and characterization of the first analogues of pro-neuropeptide y.

    PubMed

    von Eggelkraut-Gottanka, Regula; Machova, Zuzana; Grouzmann, Eric; Beck-Sickinger, Annette G

    2003-05-09

    Enzymatic cleavage of prohormone neuropeptide Y (proNPY) leads to mature neuropeptide Y (NPY), a widely distributed neuropeptide with multiple functions both peripherally and centrally. A single dibasic pair of amino acids, Lys38-Arg39, represents the recognition motif for a class of hormone-processing enzymes known as prohormone convertases (PCs). Two members of this PC family, PC1/3 and PC2, are involved in proNPY cleavage. The aim of this work was to establish an effective method for the generation of full-length 69-amino acid proNPY analogues for further studies of prohormone convertase interaction. We have chosen two ligation sites in order to perform the semisynthesis of proNPY analogues by expressed protein ligation (EPL). By using the intein-mediated purification system (IMPACT) with improved conditions for intein splicing, we were able to isolate proNPY 1-40 and proNPY 1-54 fragments as Cterminal thioesters. Peptides bearing Nterminal cysteine instead of the naturally occurring Ser41 and Thr55 residues, respectively, were generated by solid-phase peptide synthesis. Moreover, labels (carboxyfluorescein and biotin) were inserted into the peptide sequences. The synthesis of the [C41]proNPY 41-69 fragment, which proved to be a difficult peptide sequence, could be achieved by the incorporation of two pseudo-proline derivatives. Western blot analysis revealed that all five proNPY analogues are recognized by monoclonal antibodies directed against NPY as well as against the Cflanking peptide of NPY (CPON).

  1. 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

  2. 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.

  3. Smoking Habits and Neuropeptides: Adiponectin, Brain-derived Neurotrophic Factor, and Leptin Levels

    PubMed Central

    Won, Yong Lim; Ko, Kyung Sun; Roh, Ji won

    2014-01-01

    This study aimed to identify changes in the level of neuropeptides among current smokers, former smokers, and individuals who had never smoked, and how smoking habits affect obesity and metabolic syndrome (MetS). Neuropeptide levels, anthropometric parameters, and metabolic syndrome diagnostic indices were determined among male workers; 117 of these had never smoked, whereas 58 and 198 were former and current smokers, respectively. The total sample comprised 373 male workers. The results obtained from anthropometric measurements showed that current smokers attained significantly lower body weight, body mass index, waist circumference, and abdominal fat thickness values than former smokers and those who had never smoked. Current smokers’ eating habits proved worse than those of non-smokers and individuals who had never smoked. The level of brain-derived neurotrophic factor (BDNF) in the neuropeptides in the case of former smokers was 23.6 ± 9.2 pg/ml, higher than that of current smokers (20.4 ± 6.1) and individuals who had never smoked (22.4 ± 5.8) (F = 6.520, p = 0.002). The level of adiponectin among former smokers was somewhat lower than that of current smokers, whereas leptin levels were higher among former smokers than current smokers; these results were not statistically significant. A relationship was found between adiponectin and triglyceride among non-smokers (odds ratio = 0.660, β value = −0.416, p < 0.01) and smokers (odds ratio = 0.827, β value = −0.190, p < 0.05). Further, waist circumference among non-smokers (odds ratio = 1.622, β value = 0.483, p < 0.001) and smokers (odds ratio = 1.895, β value = 0.639, p < 0.001) was associated with leptin. It was concluded that cigarette smoking leads to an imbalance of energy expenditure and appetite by changing the concentration of neuropeptides such as adiponectin, BDNF, leptin, and hsCRP, and influences food intake, body weight, the body mass index, blood pressure, and abdominal fat, which are

  4. Neuropeptide Y (NPY) Y2 receptors of rabbit kidney cortex are largely dimeric.

    PubMed

    Estes, A M; Wong, Y Y; Parker, M S; Sallee, F R; Balasubramaniam, A; Parker, S L

    2008-10-09

    The neuropeptide Y (NPY) Y2 receptors and the pancreatic polypeptide Y4 receptors from rabbit kidney cortex are isolated largely as approximately 180 kDa complexes constituted of one receptor dimer and one G-protein heterotrimer, similar to NPY receptors expressed in the Chinese hamster ovary (CHO) cells. As expected, kidney and CHO cell Y2 dimers are converted into monomers by increasing concentrations of a selective agonist. Prevalence of dimeric Y2 receptors in the kidney could be related to low plasma levels of Y2 agonists, and possibly also to a relatively low concentration of Gi alpha subunits.

  5. 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

  6. Role of neuropeptide Y and its receptors in the progression of endocrine-related cancer.

    PubMed

    Ruscica, Massimiliano; Dozio, Elena; Motta, Marcella; Magni, Paolo

    2007-02-01

    The neuropeptide Y (NPY) family of peptides, in addition to its many physiological actions, has also been involved in the modulation of tumor progression, with specific reference to endocrine-related cancers such as neuroendocrine tumors, breast and prostate cancers. These have been found either to express NPY receptors, or to secrete NPY-related peptides, or both. The study of the role of the NPY family of peptides in the biology of endocrine-related tumors, specifically concerning cell proliferation, angiogenesis, invasion and metastatization, may help to clarify some aspects of tumor pathophysiology, as well as to indicate novel diagnostic markers and therapeutical approaches.

  7. Impact of prosocial neuropeptides on human brain function.

    PubMed

    Meyer-Lindenberg, Andreas

    2008-01-01

    Oxytocin and vasopressin are key effectors of social behaviour (Insel, T. R. and Fernald, R. D. (2004). Annu. Rev. Neurosci., 27: 697-722). Oxytocin effects in humans were recently demonstrated by a behavioural study showing selectively increased trust after hormone administration (Kosfeld, M., et al. (2005). Nature, 435: 673-676). Since this suggested involvement of the amygdala, which is linked to trust (Winston, J. S., et al. (2002). Nat. Neurosci., 5: 277-283) - presumably because of its role in danger monitoring - and highly expresses oxytocin receptors (Huber, D., et al. (2005). Science, 308: 245-248), we studied amygdala circuitry after double-blind crossover intranasal application of placebo or oxytocin (Kirsch, P., et al. (2005). J. Neurosci., 25: 11489-11493). Oxytocin potently reduced amygdala activation and decreased coupling to brainstem regions implicated in autonomic and behavioural manifestations of fear, indicating a neural mechanism for the effects of oxytocin in social cognition in humans and providing a potential therapeutic approach to social anxiety currently being tested in social phobia and autism. Furthermore, these data suggested a translational genetic approach. Preliminary findings (data not presented) from our laboratory using imaging genetics indeed implicate genetic variants for both AVPR1A, encoding the primary receptor of vasopressin in brain, and the oxytocin receptor, OXTR, in amygdala regulation and activation. Taken together, our results indicate neural mechanisms for human social behaviour mediating genetic risk for autism through an impact on amygdala signalling and provide a rationale for exploring therapeutic strategies aimed at abnormal amygdala function in this disorder and in social dysfunction in general.

  8. 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.

  9. RNA-seq analysis of Drosophila clock and non-clock neurons reveals neuron-specific cycling and novel candidate neuropeptides

    PubMed Central

    Luo, Weifei; Wiyanto, Evelyn; Rahman, Reazur; Guo, Fang; Shafer, Orie

    2017-01-01

    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. PMID:28182648

  10. Neuropeptide Y modulation of interleukin-1{beta} (IL-1{beta})-induced nitric oxide production in microglia.

    PubMed

    Ferreira, Raquel; Xapelli, Sara; Santos, Tiago; Silva, Ana Paula; Cristóvão, Armando; Cortes, Luísa; Malva, João O

    2010-12-31

    Given the modulatory role of neuropeptide Y (NPY) in the immune system, we investigated the effect of NPY on the production of NO and IL-1β in microglia. Upon LPS stimulation, NPY treatment inhibited NO production as well as the expression of inducible nitric-oxide synthase (iNOS). Pharmacological studies with a selective Y(1) receptor agonist and selective antagonists for Y(1), Y(2), and Y(5) receptors demonstrated that inhibition of NO production and iNOS expression was mediated exclusively through Y(1) receptor activation. Microglial cells stimulated with LPS and ATP responded with a massive release of IL-1β, as measured by ELISA. NPY inhibited this effect, suggesting that it can strongly impair the release of IL-1β. Furthermore, we observed that IL-1β stimulation induced NO production and that the use of a selective IL-1 receptor antagonist prevented NO production upon LPS stimulation. Moreover, NPY acting through Y(1) receptor inhibited LPS-stimulated release of IL-1β, inhibiting NO synthesis. IL-1β activation of NF-κB was inhibited by NPY treatment, as observed by confocal microscopy and Western blotting analysis of nuclear translocation of NF-κB p65 subunit, leading to the decrease of NO synthesis. Our results showed that upon LPS challenge, microglial cells release IL-1β, promoting the production of NO through a NF-κB-dependent pathway. Also, NPY was able to strongly inhibit NO synthesis through Y(1) receptor activation, which prevents IL-1β release and thus inhibits nuclear translocation of NF-κB. The role of NPY in key inflammatory events may contribute to unravel novel gateways to modulate inflammation associated with brain pathology.

  11. Role of the autonomic nervous system and neuropeptides in the development of obesity in humans: targets for therapy?

    PubMed

    Greenfield, Jerry R; Campbell, Lesley V

    2008-01-01

    Obesity and type 2 diabetes have reached epidemic proportions worldwide. These metabolic disorders, particularly obesity, are characterised by increased basal sympathetic nervous system (SNS) activity but an impaired sympathetic response to certain stimuli, such as insulin. Although targeting the SNS may seem an attractive avenue for the pharmacological prevention and treatment of obesity and related metabolic disorders, it remains unknown whether changes in SNS tone are primary and contribute to the development of these metabolic conditions or whether they develop secondary to the obese state. This question can be answered by the study of insulin-resistant individuals prior to the development of obesity and type 2 diabetes. Using this model, it has been shown that early insulin resistance is associated with increased SNS activity in genetically-predisposed humans. It has been suggested that in insulin-resistant states, hyperinsulinaemia is the initiating factor that increases sympathetic neural activity. Over time, adrenoreceptor down-regulation and/or reduced sensitivity are likely to develop, resulting in reduced sympathetic responsiveness. In the postprandial state, this will lead to impaired diet-induced thermogenesis and post-prandial fat oxidation, promoting the accumulation of body fat. More recent evidence demonstrates that stress-induced SNS overactivity up-regulates Neuropeptide Y, an orexigenic hormone, and its Y2 receptor, in visceral adipose tissue, the fat depot most strongly linked to insulin resistance and type 2 diabetes. There is evidence that SNS overactivity specifically contributes to the development of abdominal obesity via this pathway, which could represent a novel target for the prevention and treatment of abdominal obesity and related metabolic consequences.

  12. Cloning and expression of long neuropeptide F and the role of FMRFamide-like peptides in regulating egg production in the Chagas vector, Rhodnius prolixus.

    PubMed

    Sedra, Laura; Lange, Angela B

    2016-08-01

    Long neuropeptide F (NPF) is a neuropeptide implicated in the control of feeding, digestion and reproduction in various insect species. Here we have isolated the cDNA sequence encoding NPF in Rhodnius prolixus (RhoprNPF). The RhoprNPF gene is composed of 3 exons and 2 introns, one of which is present in the peptide coding region. RhoprNPF is 42 amino acids long and has the characteristic RFamide C-terminus, which is common of FMRFamide-like peptides (FLPs). Quantitative PCR (qPCR) shows that RhoprNPF mRNA is present in higher amounts in fifth instars than in adults, implying that it may play a role in growth and development. In situ hybridization shows that the RhoprNPF transcript is present in median neurosecretory cells (MNSCs) in the brain, cells in the fifth instar hindgut and cells along the longitudinal muscle fibers of the adult female lateral oviducts. Injection of the last 8 amino acids of RhoprNPF (truncated RhoprNPF, AVAGRPRFa), which is considered to be the active core sequence for biological activity, into mated, fed, female adult R. prolixus decreased the number of eggs found in the ovaries as well as increased the number of eggs laid. This suggests that RhoprNPF may play a role in accelerating the process of ovulation from the ovary of the female R. prolixus. An increase in oogenesis was observed following the injection of other FLPs such as RhoprShortNPF, GNDNFMRFamide and AKDNFIRFamide, whereas the FLP, RhoprMS, and the allatostatin, RhoprAST-2, inhibited egg production.

  13. Expression of neuropeptides and anoctamin 1 in the embryonic and adult zebrafish intestine, revealing neuronal subpopulations and ICC-like cells.

    PubMed

    Uyttebroek, Leen; Shepherd, Iain T; Hubens, Guy; Timmermans, Jean-Pierre; Van Nassauw, Luc

    2013-11-01

    This immunohistochemical study in zebrafish aims to extend the neurochemical characterization of enteric neuronal subpopulations and to validate a marker for identification of interstitial cells of Cajal (ICC). The expression of neuropeptides and anoctamin 1 (Ano1), a selective ICC marker in mammals, was analyzed in both embryonic and adult intestine. Neuropeptides were present from 3 days postfertilization (dpf). At 3 dpf, galanin-positive nerve fibers were found in the proximal intestine, while calcitonin gene-related peptide (CGRP)- and substance P-expressing fibers appeared in the distal intestine. At 5 dpf, immunoreactive fibers were present along the entire intestinal length, indicating a well-developed peptidergic innervation at the onset of feeding. In the adult intestine, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP), galanin, CGRP and substance P were detected in nerve fibers. Colchicine pretreatment enhanced only VIP and PACAP immunoreactivity. VIP and PACAP were coexpressed in enteric neurons. Colocalization stainings revealed three neuronal subpopulations expressing VIP and PACAP: a nitrergic noncholinergic subpopulation, a serotonergic subpopulation and a subpopulation expressing no other markers. Ano1-immunostaining revealed a 3-dimensional network in the adult intestine containing multipolar cells at the myenteric plexus and bipolar cells interspersed between circular smooth muscle cells. Ano1 immunoreactivity first appeared at 3 dpf, indicative of the onset of proliferation of ICC-like cells. It is shown that the Ano1 antiserum is a selective marker of ICC-like cells in the zebrafish intestine. Finally, it is hypothesized that ICC-like cells mediate the spontaneous regular activity of the embryonic intestine.

  14. 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

  15. The neuropeptide SIFamide in the brain of three cockroach species.

    PubMed

    Arendt, Andreas; Neupert, Susanne; Schendzielorz, Julia; Predel, Reinhard; Stengl, Monika

    2016-05-01

    The sequence as well as the distribution pattern of SIFamide in the brain of different insects is highly conserved. As a general rule, at least four prominent SIFamide-immunoreactive somata occur in the pars intercerebralis. They arborize throughout the brain and the ventral nerve cord. Whereas SIFamide is implicated in mating and sleep regulation in Drosophila, other functions of this peptide remain largely unknown. To determine whether SIFamide plays a role in the circadian system of cockroaches, we studied SIFamide in Rhyparobia (= Leucophaea) maderae (Blaberidae), Periplaneta americana (Blattidae), and Therea petiveriana (Polyphagidae). Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry revealed identical SIFamide sequences (TYRKPPFNGSIFamide) in the three species. In addition to four large immunoreactive cells in the pars intercerebralis (group 1), smaller SIFamide-immunoreactive somata were detected in the pars intercerebralis (group 2), in the superior median protocerebrum (group 3), and in the lateral protocerebrum (group 4). Additional cells in the optic lobe (group 5) and posterior protocerebrum (group 6) were stained only in P. americana. Almost the entire protocerebrum was filled with a beaded network of SIFamide-immunoreactive processes that especially strongly invaded the upper unit of the central body. Double-label experiments did not confirm colocalizations with γ-aminobutyric acid (GABA) or the circadian coupling peptide pigment-dispersing factor (PDF). In contrast to locusts, colocalization of SIFamide and histamine immunoreactivity occurred not in group 1, but in group 4 cells. Because the accessory medulla displayed SIFamide immunoreactivity and injections of SIFamide delayed locomotor activity rhythms circadian time-dependently, SIFamide plays a role in the circadian system of cockroaches. J. Comp. Neurol. 524:1337-1360, 2016. © 2015 Wiley Periodicals, Inc.

  16. Effects of selected neuropeptides, mating status and castration on male reproductive tract movements and immunolocalization of neuropeptides in earwigs.

    PubMed

    Rankin, Susan M; TeBrugge, Victoria A; Murray, Jill A; Schuler, Ashley M; Tobe, Stephen S

    2009-01-01

    In earwigs, the male reproductive system is complex, comprising accessory glands and long dual intromittent organs for transfer of materials to the female and for removal of rival sperm. We investigated potential factors altering contractions of the male reproductive tracts in vitro. Tracts from 0-day (newly emerged) males displayed relatively little motility in vitro; however, those from 5-day (intermediate stage of sexual maturity) and 8-day (fully mature) males pulsed vigorously. Both 1 and 100 nM proctolin (RYLPT-OH) stimulated the rate of contraction of reproductive tracts from both 5-day and 8-day males. In contrast, 1 nM and 100 nM FGLa AST (cockroach allatostatin) did not affect pulsations. However, 10 microM FGLa AST decreased activity of reproductive tracts. Mating decreased motility of tracts from 5-day old males, but did not alter motility of tracts from 8-day old males. Castration of larvae significantly suppressed reproductive tract motility in subsequent 8-day old adults compared with those of intact or sham-operated adults. Castration also suppressed seminal vesicle size. Lastly, we assessed the presence and distribution of proctolin-like and allatostatin-like immunoreactivity in tissues. Immunoreactivity to FGLa AST and proctolin was widespread, occurring in the brain and ventral ganglia. Surprisingly, we did not detect immunoreactivity to either FGLa AST or proctolin within the reproductive system; however, proctolin immunoreactivity was evident in nerves extending from the terminal ganglion of 8-day, but not 0-day, males. Collectively, these experiments demonstrate that the male earwig reproductive system is an appropriate model for use in addressing sexual maturation and activities in male insects.

  17. Maternal nicotine exposure during lactation alters hypothalamic neuropeptides expression in the adult rat progeny.

    PubMed

    Younes-Rapozo, Viviane; Moura, Egberto G; Manhães, Alex C; Pinheiro, Cintia R; Santos-Silva, Ana Paula; de Oliveira, Elaine; Lisboa, Patricia C

    2013-08-01

    Maternal exposure to nicotine during lactation causes hyperleptinemia in the pups and, at adulthood, these animals are overweight and hyperleptinemic, while, in their hypothalamus, the leptin signaling pathway is reduced, evidencing a central leptin resistance. Then, we evaluated the expression of pro-opiomelanocortin (POMC), alpha-melanocyte stimulating hormone (α-MSH), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY), agouti-related peptide (AgRP) and others in different hypothalamic nuclei in order to better understand the mechanisms underlying the obese phenotype observed in these animals at adulthood. On the 2nd postnatal day (P2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6 mg/kg/day) or saline for 14 days. Offspring were killed in P180 and immunohistochemistry and Western blot analysis were carried out. Significance data had p<0.05. Adult NIC offspring showed more intense NPY staining in the paraventricular nucleus (PVN) (+21%) and increased number of POMC-positive cells in the: arcuate nucleus (+33%), as an increase in fiber density of α-MSH in PVN (+85%). However, the number of CART-positive cells was reduced in the PVN (-25%). CRH staining was more intense in NIC offspring (+136%). Orexins and AgRP were not altered. Thus, maternal nicotine exposure changes hypothalamic neuropeptides in the adult progeny that is partially compatible with leptin resistance.

  18. 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.

  19. Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome.

    PubMed

    Kim, S I; Grum-Tokars, V; Swanson, T A; Cotter, E J; Cahill, P A; Roberts, J L; Cummins, P M; Glucksman, M J

    2003-11-01

    Neuropeptide processing metalloenzymes, such as angiotensin converting enzyme, neprilysin, endothelin converting enzyme, neurolysin, and EC3.4.24.15 (EP24.15), are central to the formation and degradation of bioactive peptides. We present EP24.15 as a paradigm for novel functions ascribed to these enzymes in the neurome. Although the neurome typically encompasses proteomes of the brain and central nervous system, exciting new roles of these neuropeptidases have been demonstrated in other organ systems. We discuss the involvement of EP24.15 with clinical sequelae involving the use of gonadotropin-releasing hormone (GnRH; LHRH) analogs that act as enzyme inhibitors, in vascular physiology (blood pressure regulation), and in the hematologic system (immune surveillance). Hemodynamic forces, such as cyclic strain and shear stress, on vascular cells, induce an increase in EP24.15 transcription, suggesting that neuropeptidase-mediated hydrolysis of pressor/depressor peptides is likely regulated by changes in hemodynamic force and blood pressure. Lastly, EP24.15 regulates surface expression of major histocompatibility complex Class I proteins in vivo, suggesting that EP24.15 may play an important role in maintenance of immune privilege in sites of increased endogenous expression. In these extraneural systems, regulation of both neuropeptide and other peptide substrates by neuropeptidases indicates that the influence of these enzymes may be more global than was anticipated previously, and suggests that their attributed role as neuropeptidases underestimates their physiologic actions in the neural system.

  20. Role of neuropeptide Y in the bone marrow hematopoietic stem cell microenvironment.

    PubMed

    Park, Min Hee; Min, Woo-Kie; Jin, Hee Kyung; Bae, Jae-Sung

    2015-12-01

    The sympathetic nervous system (SNS) or neurotransmitters in the bone marrow microenvironment has been known to regulate hematopoietic stem cell (HSC) functions such as self-renewal, proliferation and differentiation. However, the specific role of neuropeptide Y (NPY) in this process remains relatively unexplored. In this study, we demonstrated that NPY deficient mice have significantly reduced HSC numbers and impaired bone marrow regeneration due to apoptotic destruction of SNS fibers and/or endothelial cells. Moreover, NPY treatment prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while conditional knockout mice lacking the Y1 receptor in macrophages did not restore bone marrow dysfunction in spite of NPY injection. Transforming growth factor-beta (TGF-β) secreted by NPY-mediated Y1 receptor stimulation in macrophages plays a key role in neuroprotection and HSC survival in the bone marrow. Therefore, this study reveals a new role of NPY in bone marrow HSC microenvironment, and provides an insight into the therapeutic application of this neuropeptide.

  1. Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats.

    PubMed

    Kursungoz, Canan; Ak, Mehmet; Yanik, Tulin

    2015-01-30

    Although the use of atypical antipsychotic drugs has been successful in the treatment of schizophrenia, they can cause some complications in the long-term use, including weight gain. Patients using these drugs tend to disrupt treatment primarily due to side effects. The atypical antipsychotic mechanism of action regulates a number of highly disrupted neurotransmitter pathways in the brains of psychotic patients but may also cause impairment of neurohormonal pathways in different brain areas. In this study, we investigated the circulating levels of hypothalamic neurohormones, which are related to appetite regulation; neuropeptide Y (NPY); alpha melanocyte stimulating hormone (α-MSH); cocaine and amphetamine regulated transcript (CART); agouti-related peptide (AgRP); and leptin in male Wistar rats, which were treated with risperidone, a serotonin antagonist, for four weeks. Alterations in the mRNA expression levels of these candidate genes in the hypothalamus were also analyzed. We hypothesized that risperidone treatment might alter both hypothalamic and circulating levels of neuropeptides through serotonergic antagonism, resulting in weight gain. Gene expression studies revealed that the mRNA expression levels of proopiomelanocortin (POMC), AgRP, and NPY decreased as well as their plasma levels, except for NPY. Unexpectedly, CART mRNA levels increased when their plasma levels decreased. Because POMC neurons express the serotonin receptor (5HT2C), the serotonergic antagonism of risperidone on POMC neurons may cause an increase in appetite and thus increase food consumption even in a short-term trial in rats.

  2. Expression of neuropeptide W in rat stomach mucosa: regulation by nutritional status, glucocorticoids and thyroid hormones.

    PubMed

    Caminos, Jorge E; Bravo, Susana B; García-Rendueles, María E R; Ruth González, C; Garcés, Maria F; Cepeda, Libia A; Lage, Ricardo; Suárez, Miguel A; López, Miguel; Diéguez, Carlos

    2008-02-07

    Neuropeptide W (NPW) is a recently identified neuropeptide that binds to G-protein-coupled receptor 7 (GPR7) and 8 (GPR8). In rodent brain, NPW mRNA is confined to specific nuclei in hypothalamus, midbrain and brainstem. Expression of NPW mRNA has also been confirmed in peripheral organs such as stomach. Several reports suggested that brain NPW is implicated in the regulation of energy and hormonal homeostasis, namely the adrenal and thyroid axes; however the precise physiological role and regulation of peripheral NPW remains unclear. In this study, we examined the effects of nutritional status on the regulation of NPW in stomach mucosa. Our results show that in this tissue, NPW mRNA and protein expression is negatively regulated by fasting and food restriction, in all the models we studied: males, females and pregnant females. Next, we examined the effect of glucocorticoids and thyroid hormones on NPW mRNA expression in the stomach mucosa. Our data showed that NPW expression is decreased in this tissue after glucocorticoid treatment or hyperthyroidism. Conversely, hypothyroidism induces a marked increase in the expression of NPW in rat stomach. Overall, these data indicate that stomach NPW is regulated by nutritional and hormonal status.

  3. The pleiotropic allatoregulatory neuropeptides and their receptors: A mini-review.

    PubMed

    Verlinden, Heleen; Gijbels, Marijke; Lismont, Els; Lenaerts, Cynthia; Vanden Broeck, Jozef; Marchal, Elisabeth

    2015-09-01

    Juvenile hormones (JH) are highly pleiotropic insect hormones essential for post-embryonic development. The circulating JH titer in the hemolymph of insects is influenced by enzymatic degradation, binding to JH carrier proteins, uptake and storage in target organs, but evidently also by rates of production at its site of synthesis, the corpora allata (CA). The multiple processes in which JH is involved alongside the critical significance of JH in insect development emphasize the importance for elucidating the control of JH production. Production of JH in CA cells is regulated by different factors: by neurotransmitters, such as dopamine and glutamate, but also by allatoregulatory neuropeptides originating from the brain and axonally transported to the CA where they bind to their G protein-coupled receptors (GPCRs). Different classes of allatoregulatory peptides exist which have other functions aside from acting as influencers of JH production. These pleiotropic neuropeptides regulate different processes in different insect orders. In this mini-review, we will give an overview of allatotropins and allatostatins, and their recently characterized GPCRs with a view to better understand their modes of action and different action sites.

  4. C-terminal motif of human neuropeptide Y4 receptor determines internalization and arrestin recruitment.

    PubMed

    Wanka, Lizzy; Babilon, Stefanie; Burkert, Kerstin; Mörl, Karin; Gurevich, Vsevolod V; Beck-Sickinger, Annette G

    2017-01-01

    The human neuropeptide Y4 receptor is a rhodopsin-like G protein-coupled receptor (GPCR), which contributes to anorexigenic signals. Thus, this receptor is a highly interesting target for metabolic diseases. As GPCR internalization and trafficking affect receptor signaling and vice versa, we aimed to investigate the molecular mechanism of hY4R desensitization and endocytosis. The role of distinct segments of the hY4R carboxyl terminus was investigated by fluorescence microscopy, binding assays, inositol turnover experiments and bioluminescence resonance energy transfer assays to examine the internalization behavior of hY4R and its interaction with arrestin-3. Based on results of C-terminal deletion mutants and substitution of single amino acids, the motif (7.78)EESEHLPLSTVHTEVSKGS(7.96) was identified, with glutamate, threonine and serine residues playing key roles, based on site-directed mutagenesis. Thus, we identified the internalization motif for the human neuropeptide Y4 receptor, which regulates arrestin-3 recruitment and receptor endocytosis.

  5. Mass Spectrometric Measurement of Neuropeptide Secretion in the Crab, Cancer borealis, by In Vivo Microdialysis

    PubMed Central

    Liang, Zhidan; Schmerberg, Claire M.; Li, Lingjun

    2015-01-01

    Neuropeptides (NPs), a unique and highly important class of signaling molecules across the animal kingdom, have been extensively characterized in the neuronal tissues of various crustaceans. Because many NPs are released into circulating fluid (hemolymph) and travel to distant sites in order to exhibit physiological effects, it is important to measure the secretion of these NPs from living animals. In this study, we report on extensive characterization of NPs released in the crab Cancer borealis by utilizing in vivo microdialysis to sample NPs from the hemolymph. We determined the necessary duration for collection of microdialysis samples, enabling more comprehensive identification of NP content while maintaining the temporal resolution of sampling. Analysis of in vivo microdialysates using a hybrid quadrupole-Orbitrap™ Q-Exactive mass spectrometer revealed that more than 50 neuropeptides from 9 peptide families—including the allatostatin, RFamide, orcokinin, tachykinin-related peptide and RYamide families–were released into the circulatory system. The presence of these peptides both in neuronal tissues as well as in hemolymph indicates their putative hormonal roles, a finding that merits further investigation. Preliminary quantitative measurement of these identified NPs suggested several potential candidates that may be associated with the circadian rhythm in Cancer borealis. PMID:25537886

  6. Combined light and electron microscopic visualization of neuropeptides and their receptors in central neurons.

    PubMed

    Salio, Chiara; Lossi, Laura; Merighi, Adalberto

    2011-01-01

    The study of neuronal connections and neuron to neuron (or neuron to glia) communication is of fundamental importance in understanding brain structure and function. Therefore, ultrastructural investigation by the use of immunocytochemical techniques is a really precious tool to obtain an exact map of the localization of neurotransmitters (neuropeptides) and their receptors at different types of synapses. However, in immunocytochemical procedures one has always to search for the optimal compromise between structural preservation and retention of antigenicity. This is often made difficult by the need to localize not only small transmitter molecules, as in the case of transmitter amino acids and neuropeptides, but also their specific receptors that are usually large proteins very sensitive to fixation procedures. We describe here a preembedding procedure employing the Fluoronanogold™ reagent, a probe consisting of fluorescein-tagged antibodies conjugated with ultrasmall gold particles that can be made visible under the electron microscope by a gold intensification procedure. This technique permits correlative fluorescence and electron microscopy observations, providing a very useful tool for the study of neuronal connectivity. Moreover, the Fluoronanogold™ procedure can be combined with conventional postembedding immunogold techniques in multiple labeling studies.

  7. Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.

    PubMed

    Toneff, Thomas; Funkelstein, Lydiane; Mosier, Charles; Abagyan, Armen; Ziegler, Michael; Hook, Vivian

    2013-08-01

    Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.

  8. Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron distribution.

    PubMed Central

    Hill, J M; Ruff, M R; Weber, R J; Pert, C B

    1985-01-01

    We have characterized and visualized the binding of 125I-labeled transferrin to sections of rat brain. This saturable, reversible, high-affinity (Kd = 1 X 10(-9) M) binding site appears indistinguishable from transferrin receptors previously characterized in other tissues. Moreover, a monoclonal antibody raised to rat lymphocyte transferrin receptors could immunoprecipitate recovered intact transferrin solubilized from labeled brain slices, indicating that labeling was to the same molecular entity previously characterized as the transferrin receptor. The pattern of transferrin receptor distribution visualized in brain with both 125I-labeled transferrin and an anti-transferrin receptor monoclonal antibody are almost indistinguishable but differ from the pattern of iron distribution. Iron-rich brain areas generally receive neuronal projections from areas with abundant transferrin receptors, suggesting that iron may be transported neuronally. However, many brain areas with a high density of transferrin receptors appear unrelated to iron uptake and neuronal transport and form a receptor distribution pattern similar to that of other known neuropeptides. This "neuropeptide-like" distribution pattern suggests that transferrin may have neuromodulatory, perhaps behavioral, function in brain. Images PMID:2989832

  9. Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin.

    PubMed

    Zwanzger, P; Domschke, K; Bradwejn, J

    2012-09-01

    Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

  10. Discovery by proteogenomics and characterization of an RF-amide neuropeptide from cone snail venom

    PubMed Central

    Robinson, Samuel D.; Safavi-Hemami, Helena; Raghuraman, Shrinivasan; Imperial, Julita S.; Papenfuss, Anthony T.; Teichert, Russell W.; Purcell, Anthony W.; Olivera, Baldomero M.; Norton, Raymond S.

    2015-01-01

    In this study, a proteogenomic annotation strategy was used to identify a novel bioactive peptide from the venom of the predatory marine snail Conus victoriae. The peptide, conorfamide-Vc1 (CNF-Vc1), defines a new gene family. The encoded mature peptide was unusual for conotoxins in that it was cysteine-free and, despite low overall sequence similarity, contained two short motifs common to known neuropeptides/hormones. One of these was the C-terminal RF-amide motif, commonly observed in neuropeptides from a range of organisms, including humans. The mature venom peptide was synthesized and characterized structurally and functionally. The peptide was bioactive upon injection into mice, and calcium imaging of mouse dorsal root ganglion (DRG) cells revealed that the peptide elicits an increase in intracellular calcium levels in a subset of DRG neurons. Unusually for most Conus venom peptides, it also elicited an increase in intracellular calcium levels in a subset of non-neuronal cells. PMID:25464369

  11. Discovery of defense- and neuropeptides in social ants by genome-mining.

    PubMed

    Gruber, Christian W; Muttenthaler, Markus

    2012-01-01

    Natural peptides of great number and diversity occur in all organisms, but analyzing their peptidome is often difficult. With natural product drug discovery in mind, we devised a genome-mining approach to identify defense- and neuropeptides in the genomes of social ants from Atta cephalotes (leaf-cutter ant), Camponotus floridanus (carpenter ant) and Harpegnathos saltator (basal genus). Numerous peptide-encoding genes of defense peptides, in particular defensins, and neuropeptides or regulatory peptide hormones, such as allatostatins and tachykinins, were identified and analyzed. Most interestingly we annotated genes that encode oxytocin/vasopressin-related peptides (inotocins) and their putative receptors. This is the first piece of evidence for the existence of this nonapeptide hormone system in ants (Formicidae) and supports recent findings in Tribolium castaneum (red flour beetle) and Nasonia vitripennis (parasitoid wasp), and therefore its confinement to some basal holometabolous insects. By contrast, the absence of the inotocin hormone system in Apis mellifera (honeybee), another closely-related member of the eusocial Hymenoptera clade, establishes the basis for future studies on the molecular evolution and physiological function of oxytocin/vasopressin-related peptides (vasotocin nonapeptide family) and their receptors in social insects. Particularly the identification of ant inotocin and defensin peptide sequences will provide a basis for future pharmacological characterization in the quest for potent and selective lead compounds of therapeutic value.

  12. fDWI Evaluation of Hypothalamic Appetite Regulation Pathways in Mice Genetically Deficient in Leptin or Neuropeptide Y.

    PubMed

    Lizarbe, Blanca; López-Larrubia, Pilar; Cerdán, Sebastián

    2015-12-01

    We evaluate the contribution of leptin-dependent anorexigenic pathways and neuropeptide Y (NPY)-dependent orexigenic pathways to the changes in hypothalamic water diffusion parameters observed in vivo by functional diffusion weighted MRI (fDWI). Mice genetically deficient in leptin (B6.V-Lep (ob) /J) or NPY (129S-Npy (tm1Rpa) /J) and the corresponding wild-type controls, were subjected to sequential isocaloric feeding, fasting and recovery regimes. Non-invasive fDWI measurements were performed under these conditions, and complemented with parallel determinations of food and water consumption, respiratory exchange ratio (RER), locomotor activity and endocrine profiles. Control mice showed significant increases in hypothalamic water diffusion parameters upon fasting, returning to normal values in the recovery period. Leptin deficient mice depicted permanently increased water diffusion parameters under all feeding conditions as compared to wild type controls, without important changes upon fasting or recovery. These results paralleled sustained increases in food and water intake, significantly augmented body weight, and decreased RER values or locomotor activity, thus configuring an obese phenotype. NPY-deficient mice showed significantly reduced increases (or even slight decreases) in the water diffusion parameters upon fasting as compared to wild type controls, paralleled by decreased food and water intake during the recovery period. In conclusion, leptin deficiency results in sustained orexigenic stimulation, leading to increased water diffusion parameters, while NPY deficiency lead to reduced orexigenic stimulation and water diffusion parameters. Diffusion changes are proposed to reflect net astrocytic volume changes induced by the balance between the orexigenic and anorexigenic firings of AgRP/NPY and POMC/CART neurons, respectively. Together, our results suggest that fDWI provides an adequate tool to investigate hypothalamic appetite disorders.

  13. Effects of early and late neonatal bromocriptine treatment on hypothalamic neuropeptides, dopaminergic reward system and behavior of adult rats.

    PubMed

    Carvalho, Janaine C; Lisboa, Patricia C; de Oliveira, Elaine; Peixoto-Silva, Nayara; Pinheiro, Cintia R; Fraga, Mabel C; Claudio-Neto, Sylvio; Franci, Celso R; Manhães, Alex C; Moura, Egberto G

    2016-06-14

    In humans, bromocriptine (BRO) is used as a treatment for many disorders, such as prolactinomas, even during pregnancy and lactation. Previously we demonstrated that maternal BRO treatment at the end of lactation programs offspring for obesity and several endocrine dysfunctions. Here, we studied the long-term effects of direct BRO injection in neonatal Wistar rats on their dopaminergic pathway, anxiety-like behavior and locomotor activity at adulthood. Male pups were either s.c. injected with BRO (0.1μg/once daily) from postnatal day (PN) 1 to 10 or from PN11 to 20. Controls were injected with methanol-saline. Body mass, food intake, neuropeptides, dopamine pathway parameters, anxiety-like behavior and locomotor activity were analyzed. The dopamine pathway was analyzed in the ventral tegmental area (VTA), nucleus accumbens (NAc) and dorsal striatum (DS) at PN180. PN1-10 BRO-treated animals had normal body mass and adiposity but lower food intake and plasma prolactin (PRL). This group had higher POMC in the arcuate nucleus (ARC), higher tyrosine hydroxylase (TH) in the VTA, higher dopa decarboxylase (DDc), higher D2R and μu-opioid receptor in the NAc. Concerning behavior in elevated plus maze (EPM), BRO-treated animals displayed more anxiety-like behaviors. PN11-20 BRO-treated showed normal body mass and adiposity but higher food intake and plasma PRL. This group had lower POMC in the ARC, lower TH in the VTA and lower DAT in the NAc. BRO-treated animals showed less anxiety-like behaviors in the EPM. Thus, neonatal BRO injection, depending on the time of treatment, leads to different long-term dysfunctions in the dopaminergic reward system, food intake behavior and anxiety levels, findings that could be partially due to PRL and POMC changes.

  14. Feedforward Compensation Mediated by the Central and Peripheral Actions of a Single Neuropeptide Discovered Using Representational Difference Analysis

    PubMed Central

    Jing, Jian; Sweedler, Jonathan V; Cropper, Elizabeth C; Alexeeva, Vera; Park, Ji-Ho; Romanova, Elena V.; Xie, Fang; Dembrow, Nikolai C.; Ludwar, Bjoern C.; Weiss, Klaudiusz R; Vilim, Ferdinand S

    2010-01-01

    Compensatory mechanisms are often used to achieve stability by reducing variance, which can be accomplished via negative feedback during homeostatic regulation. In principle, compensation can also be implemented through feedforward mechanisms where a regulator acts to offset the anticipated output variation; however, few such neural mechanisms have been demonstrated. We provide evidence that an Aplysia neuropeptide, identified using an enhanced representational difference analysis procedure, implements feedforward compensation within the feeding network. We named the novel peptide allatotropin-related peptide (ATRP) because of its similarity to insect allatotropin. Mass spectrometry confirmed the peptide's identity, and in situ hybridization and immunostaining mapped its distribution in the Aplysia CNS. ATRP is present in the higher-order cerebral-buccal interneuron (CBI), CBI-4, but not in CBI-2. Previous work showed that CBI-4-elicited motor programs have a shorter protraction duration than those elicited by CBI-2. Here we show that ATRP shortens protraction duration of CBI-2-elicited ingestive programs, suggesting a contribution of ATRP to the parametric differences between CBI-4- and CBI-2-evoked programs. Importantly, because Aplysia muscle contractions are a graded function of motoneuronal activity, one consequence of the shortening of protraction is that it can weaken protraction movements. However, this potential weakening is offset by feedforward compensatory actions exerted by ATRP. Centrally, ATRP increases the activity of protraction motoneurons. Moreover, ATRP is present in peripheral varicosities of protraction motoneurons and enhances peripheral motoneuron-elicited protraction muscle contractions. Therefore, feedforward compensatory mechanisms mediated by ATRP make it possible to generate a faster movement with an amplitude that is not greatly reduced, thereby producing stability. PMID:21147994

  15. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.

    PubMed

    Kamegai, J; Tamura, H; Shimizu, T; Ishii, S; Sugihara, H; Wakabayashi, I

    2001-11-01

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic growth hormone secretagogues (GHSs), ghrelin specifically releases growth hormone (GH) after intravenous administration. Also consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypothalamic arcuate nucleus as well as the stomach. Recently, we showed that a single central administration of ghrelin increased food intake and hypothalamic agouti-related protein (AGRP) gene expression in rodents, and the orexigenic effect of this peptide seems to be independent of its GH-releasing activity. However, the effect of chronic infusion of ghrelin on food consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracerebroventricular treatment with ghrelin on metabolic factors and on neuropeptide genes that are expressed in hypothalamic neurons that have been previously shown to express the GHS-R and to regulate food consumption. Chronic central administration of rat ghrelin (1 microg/rat every 12 h for 72 h) significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that chronic central administration of ghrelin increased both neuropeptide Y (NPY) mRNA levels (151.0 +/- 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 +/- 22.5% of saline-treated controls; P < 0.05) in the arcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/AGRP-containing neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach.

  16. TRPV1 receptor in the human trigeminal ganglion and spinal nucleus: immunohistochemical localization and comparison with the neuropeptides CGRP and SP.

    PubMed

    Quartu, Marina; Serra, Maria Pina; Boi, Marianna; Poddighe, Laura; Picci, Cristina; Demontis, Roberto; Del Fiacco, Marina

    2016-12-01

    This work presents new data concerning the immunohistochemical occurrence of the transient receptor potential vanilloid type-1 (TRPV1) receptor in the human trigeminal ganglion (TG) and spinal nucleus of subjects at different ontogenetic stages, from prenatal life to postnatal old age. Comparisons are made with the sensory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). TRPV1-like immunoreactive (LI) material was detected by western blot in homogenates of TG and medulla oblongata of subjects at prenatal and adult stages of life. Immunohistochemistry showed that expression of the TRPV1 receptor is mostly restricted to the small- and medium-sized TG neurons and to the caudal subdivision of the spinal trigeminal nucleus (Sp5C). The extent of the TRPV1-LI TG neuronal subpopulation was greater in subjects at early perinatal age than at late perinatal age and in postnatal life. Centrally, the TRPV1 receptor localized to fibre tracts and punctate elements, which were mainly distributed in the spinal tract, lamina I and inner lamina II of the Sp5C, whereas stained cells were rare. The TRPV1 receptor colocalized partially with CGRP and SP in the TG, and was incompletely codistributed with both neuropeptides in the spinal tract and in the superficial laminae of the Sp5C. Substantial differences were noted with respect to the distribution of the TRPV1-LI structures described in the rat Sp5C and with respect to the temporal expression of the receptor during the development of the rat spinal dorsal horn. The distinctive localization of TRPV1-LI material supports the concept of the involvement of TRPV1 receptor in the functional activity of the protopathic compartment of the human trigeminal sensory system, i.e. the processing and neurotransmission of thermal and pain stimuli.

  17. Somatostatin and Neuropeptide Y Neurons Undergo Different Plasticity in Parahippocampal Regions in Kainic Acid–Induced Epilepsy

    PubMed Central

    Drexel, Meinrad; Kirchmair, Elke; Wieselthaler-Hölzl, Anna; Preidt, Adrian Patrick; Sperk, Günther

    2012-01-01

    Parahippocampal brain areas including the subiculum, presubiculum and parasubiculum, and entorhinal cortex give rise to major input and output neurons of the hippocampus and exert increased excitability in animal models and human temporal lobe epilepsy. Using immunohistochemistry and in situ hybridization for somatostatin and neuropeptide Y, we investigated plastic morphologic and neurochemical changes in parahippocampal neurons in the kainic acid (KA) model of temporal lobe epilepsy. Although constitutively contained in similar subclasses of γ-aminobutyric acid (GABA)-ergic neurons, both neuropeptide systems undergo distinctly different changes in their expression. Somatostatin messenger RNA (mRNA) is rapidly but transiently expressed de novo in pyramidal neurons of the subiculum and entorhinal cortex 24 hours after KA. Surviving somatostatin interneurons display increased mRNA levels at late intervals (3 months) after KA and increased labeling of their terminals in the outer molecular layer of the subiculum; the labeling correlates with the number of spontaneous seizures, suggesting that the seizures may trigger somatostatin expression. In contrast, neuropeptide Y mRNA is consistently expressed in principal neurons of the proximal subiculum and the lateral entorhinal cortex and labeling for the peptide persistently increased in virtually all major excitatory pathways of the hippocampal formation. The pronounced plastic changes differentially involving both neuropeptide systems indicate marked rearrangement of parahippocampal areas, presumably aiming at endogenous seizure protection. Their receptors may be targets for anticonvulsive drug therapy. PMID:22437342

  18. 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

  19. A selective CAP2b neuropeptide antagonist for an expressed receptor from the red flour beetle, Tribolium castaneum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diapause hormone (DH) is an insect neuropeptide that is highly effective in terminating the overwintering pupal diapause in members of the Helicoverpa/Heliothis complex of agricultural pests, thus DH and related compounds have promise as tools for pest management. To augment our development of effec...

  20. Beta-Amino Acid Analogs of an Insect Neuropeptide Feature Potent Bioactivity and Resistance to Peptidase Hydrolysis

    DTIC Science & Technology

    2006-01-01

    AND METHODS Peptide Synthesis Insect kinin analogs were synthesized via Fmoc methodology on Rink Amide resin (Novabiochem, San Diego, CA) using Fmoc ...500–1,900) 100 a 95% confidence limit ( CL ) values in parentheses.10 b-Amino Acid Analogs of an Insect Neuropeptide 79 Biopolymers (Peptide Science) DOI

  1. Peptidomics of neurohemal organs from species of the cockroach family Blattidae: how do neuropeptides of closely related species differ?

    PubMed

    Predel, Reinhard; Gäde, Gerd

    2005-01-01

    The primary structures and molecular mass data of neuropeptides that are released from major neuroendocrine sites of the American cockroach, Periplaneta americana, are well known. In the current study we extensively surveyed neuropeptides of the corpora cardiaca, the corpora allata and the abdominal perisympathetic organs, from 14 related cockroach species belonging to the family Blattidae. Mainly, this survey was executed by using mass spectrometric methods (MALDI-TOF MS). Peptides which appeared to be modified, as judged from their mass data and comparison with known data from P. americana, were fragmented by means of the post-source decay technique to determine their amino acid sequence. Single organ preparations sufficed to reveal the peptide pattern in neurohemal organs and to identify species-specific modifications, making it possible to glean information also from tissues of less abundant species that were caught during field trips. The peptide inventory described in this study is very typical of cockroaches of the family Blattidae and clearly separates this taxon from other taxa of cockroaches. The majority of neuropeptides was identical in all investigated species. Some peptides, however, displayed remarkable variations in their sequence which hint to a differential rate of modification among peptides of the same neuropeptide family. These modifications serve to distinguish further relatedness of taxa within the Blattidae.

  2. Hypothalamic neuropeptide Y (NPY) gene expression is not affected by central serotonin in the rainbow trout (Oncorhynchus mykiss).

    PubMed

    Mancebo, María J; Ceballos, Francisco C; Pérez-Maceira, Jorge; Aldegunde, Manuel

    2013-09-01

    Mammalian studies have shown a link between serotonin (5-HT) and neuropeptide Y (NPY) in the acute regulation of feeding and energy homeostasis. Taking into account that the actions of 5-HT and NPY on food intake in fish are similar to those observed in mammals, the objective of this study was to characterize a possible short-term interaction between hypothalamic 5-HT and NPY, by examining whether 5-HT regulates NPY gene expression, to help clarify the mechanism underlying the observed anorexigenic action of central 5-HT in the rainbow trout. We used qRT-PCR to determine the levels of NPY mRNA in the hypothalamus-preoptic area (HPA) of rainbow trout after intraperitoneal (i.p.) injection of a single dose of dexfenfluramine (dFF, 3mgkg(-1); 24h-fasted and fed fish) or intracerebroventricular (i.c.v.) administration of 5-HT (100μgkg(-1); 24h-fasted fish). Significant suppression of food intake was observed after administration of 5-HT and dFF. No significant changes in NPY gene expression were obtained 150min after administration of 5-HT or dFF. However, administration of the 5HT1B receptor agonist anpirtoline did not have any significant effect on food intake in rainbow trout. The results suggest that in fish, unlike in mammals, neither the NPY neurons of the HPA nor the 5-HT1B receptor subtype participate in the neural circuitry involved in the inhibition of food intake induced by central serotoninergic activation.

  3. Neuropeptide Y as a presynaptic modulator of norepinephrine release from the sympathetic nerve fibers in the pig pineal gland.

    PubMed

    Ziółkowska, N; Lewczuk, B; Przybylska-Gornowicz, B

    2015-01-01

    Norepinephrine (NE) released from the sympathetic nerve endings is the main neurotransmitter controlling melatonin synthesis in the mammalian pineal gland. Although neuropeptide Y (NPY) co-exists with NE in the pineal sympathetic nerve fibers it also occurs in a population of non-adrenergic nerve fibers located in this gland. The role of NPY in pineal physiology is still enigmatic. The present study characterizes the effect of NPY on the depolarization-evoked 3H-NE release from the pig pineal explants. The explants of the pig pineal gland were loaded with 3H-NE in the presence of pargyline and superfused with Tyrode medium. They were exposed twice to the modified Tyrode medium containing 60 mM of K+ to evoke the 3H-NE release via depolarization. NPY, specific agonists of Y1- and Y2- receptors and pharmacologically active ligands of α2-adrenoceptors were added to the medium before and during the second depolarization. The radioactivity was measured in medium fractions collected every 2 minutes during the superfusion. NPY (0.1-10 μM) significantly decreased the depolarization-induced 3H-NE release. Similar effect was observed after the treatment with Y2-agonist: NPY13-36, but not with Y1-agonist: [Leu31,Pro34]-NPY. The tritium overflow was lower in the explants exposed to the 5 μM NPY and 1 μM rauwolscine than to rauwolscine only. The effects of 5 μM NPY and 0.05 μM UK 14,304 on the depolarization-evoked 3H-NE release were additive. The results show that NPY is involved in the regulation of NE release from the sympathetic terminals in the pig pineal gland, inhibiting this process via Y2-receptors.

  4. Plasticity of Y1 and Y2 receptors and neuropeptide Y fibers in patients with temporal lobe epilepsy.

    PubMed

    Furtinger, S; Pirker, S; Czech, T; Baumgartner, C; Ransmayr, G; Sperk, G

    2001-08-01

    Marked expression of neuropeptide Y (NPY) and its Y2 receptors in hippocampal mossy fibers has been reported in animal models of epilepsy. Because NPY can suppress glutamate release by activating presynaptic Y2 receptors, these changes have been proposed as an endogenous protective mechanism. Therefore, we investigated whether similar changes in the NPY system may also take place in human epilepsy. We investigated Y1 and Y2 receptor binding and NPY immunoreactivity in hippocampal specimens that were obtained at surgery from patients with temporal lobe epilepsy and in autopsy controls. Significant increases in Y2 receptor binding (by 43-48%) were observed in the dentate hilus, sectors CA1 to CA3, and subiculum of specimens with, but not in those without, hippocampal sclerosis. On the other hand, Y1 receptor binding was significantly reduced (by 62%) in the dentate molecular layer of sclerotic specimens. In the same patients, the total lengths of NPY immunoreactive (NPY-IR) fibers was markedly increased (by 115-958%) in the dentate molecular layer and hilus, in the stratum lucidum of CA3, and throughout sectors CA1 to CA3 and the subiculum, as compared with autopsies. In nonsclerotic specimens, increases in lengths of NPY-IR fibers were more moderate and statistically not significant. NPY mRNA was increased threefold in hilar interneurons of sclerotic and nonsclerotic specimens. It is suggested that abundant sprouting of NPY fibers, concomitant upregulation of Y2 receptors, and downregulation of Y1 receptors in the hippocampus of patients with Ammon's horn sclerosis may be endogenous anticonvulsant mechanisms.

  5. Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness

    PubMed Central

    Megahed, Tarick; Hattiangady, Bharathi; Shuai, Bing; Shetty, Ashok K.

    2015-01-01

    Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI. PMID:25620912

  6. Co-expression of neuropeptide Y Y1 and Y5 receptors results in heterodimerization and altered functional properties.

    PubMed

    Gehlert, Donald R; Schober, Douglas A; Morin, Michelle; Berglund, Magnus M

    2007-12-03

    Centrally administered neuropeptide Y (NPY) produces anxiolytic and orexigenic effects by interacting with Y1 and Y5 receptors that are colocalized in many brain regions. Therefore, we tested the hypothesis that co-expression of Y1 and Y5 receptors results in heterodimerization, altered pharmacological properties and altered desensitization. To accomplish this, the carboxyl-termini of Y1 and Y5 receptors were fused with Renilla luciferase and green fluorescent protein and the proximity of the tagged receptors assessed using bioluminescent resonance energy transfer. Under basal conditions, cotransfection of tagged Y1 receptor and Y5 produced a substantial dimerization signal that was unaffected by the endogenous, nonselective agonists, NPY and peptide YY (PYY). Selective Y5 agonists produced an increase in the dimerization signal while Y5 antagonists also produced a slight but significant increase. In the absence of agonists, selective antagonists decreased dimerization. In functional studies, Y5 agonists produced a greater inhibition of adenylyl cyclase activity in Y1/Y5 cells than cells expressing Y5 alone while NPY and PYY exhibited no difference. With PYY stimulation, the Y1 antagonist became inactive and the Y5 antagonist exhibited uncompetitive kinetics in the Y1/Y5 cell line. In confocal microscopy studies, Y1/Y5 co-expression resulted in increased Y5 signaling following PYY stimulation. Addition of both Y1 and Y5 receptor antagonists was required to significantly decrease PYY-induced internalization. Therefore, Y1/Y5 co-expression results in heterodimerization, altered agonist and antagonist responses and reduced internalization rate. These results may account for the complex pharmacology observed when assessing the responses to NPY and analogs in vivo.

  7. A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P.

    PubMed

    Davidson, S; Miller, K A; Dowell, A; Gildea, A; Mackenzie, A

    2006-04-01

    The neuropeptide substance P (SP), encoded by the preprotachykinin-A (PPTA) gene, is expressed in the central and medial amygdaloid nucleus, where it plays a critical role in modulating fear and anxiety related behaviour. Determining the regulatory systems that support PPTA expression in the amygdala may provide important insights into the causes of depression and anxiety related disorders and will provide avenues for the development of novel therapies. In order to identify the tissue specific regulatory element responsible for supporting expression of the PPTA gene in the amygdala, we used long-range comparative genomics in combination with transgenic analysis and immunohistochemistry. By comparing human and chicken genomes, it was possible to detect and characterise a highly conserved long-range enhancer that supported tissue specific expression in SP expressing cells of the medial and central amygdaloid bodies (ECR1; 158.5 kb 5' of human PPTA ORF). Further bioinformatic analysis using the TRANSFAC database indicated that the ECR1 element contained multiple and highly conserved consensus binding sequences of transcription factors (TFs) such as MEIS1. The results of immunohistochemical analysis of transgenic lines were consistent with the hypothesis that the MEIS1 TF interacts with and maintains ECR1 activity in the central amygdala in vivo. The discovery of ECR1 and the in vivo functional relationship with MEIS1 inferred by our studies suggests a mechanism to the regulatory systems that control PPTA expression in the amygdala. Uncovering these mechanisms may play an important role in the future development of tissue specific therapies for the treatment of anxiety and depression.

  8. Tumor necrosis factor (TNF)-neuropeptide Y (NPY) crosstalk regulates inflammation, epithelial barrier functions and colonic motility

    PubMed Central

    Chandrasekharan, Bindu; Jeppsson, Sabrina; Pienkowski, Stefan; Belsham, Denise D; Sitaraman, Shanthi V.; Merlin, Didier; Kokkotou, Efi; Nusrat, Asma; Tansey, Malu G.; Srinivasan, Shanthi

    2014-01-01

    Background Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is up regulated in the enteric nervous system (ENS) during murine colitis, and that NPY knockout mice exhibit reduced inflammation. Here we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main pro-inflammatory cytokine. Methods Utilizing primary enteric neurons and colon explant cultures from WT and NPY knockout (NPY−/−) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, utilizing the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). Results We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY−/− mice produced less TNF compared to WT. Further, TNF activated NPY promoter in enteric neurons via phospho-c-jun. NPY−/− mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability via phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF-inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared to etanercept. Conclusions We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF maybe a better therapeutic option than using anti-TNF antibodies. PMID:24108115

  9. Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness.

    PubMed

    Megahed, Tarick; Hattiangady, Bharathi; Shuai, Bing; Shetty, Ashok K

    2014-01-01

    Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.

  10. A differential role for neuropeptides in acute and chronic adaptive responses to alcohol: behavioural and genetic analysis in Caenorhabditis elegans.

    PubMed

    Mitchell, Philippa; Mould, Richard; Dillon, James; Glautier, Steven; Andrianakis, Ioannis; James, Christopher; Pugh, Amanda; Holden-Dye, Lindy; O'Connor, Vincent

    2010-05-03

    Prolonged alcohol consumption in humans followed by abstinence precipitates a withdrawal syndrome consisting of anxiety, agitation and in severe cases, seizures. Withdrawal is relieved by a low dose of alcohol, a negative reinforcement that contributes to alcohol dependency. This phenomenon of 'withdrawal relief' provides evidence of an ethanol-induced adaptation which resets the balance of signalling in neural circuits. We have used this as a criterion to distinguish between direct and indirect ethanol-induced adaptive behavioural responses in C. elegans with the goal of investigating the genetic basis of ethanol-induced neural plasticity. The paradigm employs a 'food race assay' which tests sensorimotor performance of animals acutely and chronically treated with ethanol. We describe a multifaceted C. elegans 'withdrawal syndrome'. One feature, decrease reversal frequency is not relieved by a low dose of ethanol and most likely results from an indirect adaptation to ethanol caused by inhibition of feeding and a food-deprived behavioural state. However another aspect, an aberrant behaviour consisting of spontaneous deep body bends, did show withdrawal relief and therefore we suggest this is the expression of ethanol-induced plasticity. The potassium channel, slo-1, which is a candidate ethanol effector in C. elegans, is not required for the responses described here. However a mutant deficient in neuropeptides, egl-3, is resistant to withdrawal (although it still exhibits acute responses to ethanol). This dependence on neuropeptides does not involve the NPY-like receptor npr-1, previously implicated in C. elegans ethanol withdrawal. Therefore other neuropeptide pathways mediate this effect. These data resonate with mammalian studies which report involvement of a number of neuropeptides in chronic responses to alcohol including corticotrophin-releasing-factor (CRF), opioids, tachykinins as well as NPY. This suggests an evolutionarily conserved role for neuropeptides

  11. Structure and dynamics of micelle-bound neuropeptide Y: comparison with unligated NPY and implications for receptor selection.

    PubMed

    Bader, R; Bettio, A; Beck-Sickinger, A G; Zerbe, O

    2001-01-12

    the micelle is promoted by the amphiphilic alpha-helical segment of residues Tyr21-Thr32. NPY is located at the lipid-water interface with its C-terminal helix parallel to the membrane surface and penetrates the hydrophobic interior only via insertions of a few long aliphatic or aromatic side-chains. From these data we can demonstrate that the dimer interface of neuropeptide Y is similar to the interface of the monomer binding to DPC-micelles. We speculate that binding of the NPY monomer to the membrane is an essential key step preceeding receptor binding, thereby pre-orientating the C-terminal tetrapeptide and possibly inducing the bio-active conformation.

  12. Monoclonal Antibody to an Endogenous Neuropeptide with Putative Morphine-Modulating Activity

    DTIC Science & Technology

    1988-12-01

    the Naval Medical Research Institute. Additional copies may be purchased from: National Technical Information Service 5285 Port Royal Road Springfield...well); plates were incubated at 40C for 1 hr and washed 3 times with 100 pjI of PBS-Triton. Goat-anti mouse lgG conjugated to alkaline phosphatase...X13M1 is 50-100 fmol/sample which is 10-20 times lower than the sensitivity obtainable in the RIA with polyclonal antiserum raised in rabbits (Majane

  13. Singing modulates mood, stress, cortisol, cytokine and neuropeptide activity in cancer patients and carers.

    PubMed

    Fancourt, Daisy; Williamon, Aaron; Carvalho, Livia A; Steptoe, Andrew; Dow, Rosie; Lewis, Ian

    2016-01-01

    There is growing evidence that psychosocial interventions can have psychological benefits for people affected by cancer, including improved symptoms of mental health and wellbeing and optimised immune responses. However, despite growing numbers of music interventions, particularly singing, in cancer care, there is less research into their impact. We carried out a multicentre single-arm preliminary study to assess the impact of singing on mood, stress and immune response in three populations affected by cancer: carers (n = 72), bereaved carers (n = 66) and patients (n = 55). Participants were excluded if pregnant or if they were currently being treated with chemotherapy, radiotherapy or oral immunosuppressive drugs. Participants were regular participants in five choirs across South Wales and took part in one hour of group singing. Before and after singing, visual analogue mood scales, stress scales and saliva samples testing for cortisol, beta-endorphin, oxytocin and ten cytokines were taken. Across all five centres and in all four participant groups, singing was associated with significant reductions in negative affect and increases in positive affect (p < .01) alongside significant increases in cytokines including GM-CSF, IL17, IL2, IL4 and sIL-2rα (all p < .01). In addition, singing was associated with reductions in cortisol, beta-endorphin and oxytocin levels. This study provides preliminary evidence that singing improves mood state and modulates components of the immune system. Further work is needed to ascertain how this differs for more specific patient groups and whether repeat exposure could lead to meaningful, longitudinal effects.

  14. Singing modulates mood, stress, cortisol, cytokine and neuropeptide activity in cancer patients and carers

    PubMed Central

    Fancourt, Daisy; Williamon, Aaron; Carvalho, Livia A; Steptoe, Andrew; Dow, Rosie; Lewis, Ian

    2016-01-01

    There is growing evidence that psychosocial interventions can have psychological benefits for people affected by cancer, including improved symptoms of mental health and wellbeing and optimised immune responses. However, despite growing numbers of music interventions, particularly singing, in cancer care, there is less research into their impact. We carried out a multicentre single-arm preliminary study to assess the impact of singing on mood, stress and immune response in three populations affected by cancer: carers (n = 72), bereaved carers (n = 66) and patients (n = 55). Participants were excluded if pregnant or if they were currently being treated with chemotherapy, radiotherapy or oral immunosuppressive drugs. Participants were regular participants in five choirs across South Wales and took part in one hour of group singing. Before and after singing, visual analogue mood scales, stress scales and saliva samples testing for cortisol, beta-endorphin, oxytocin and ten cytokines were taken. Across all five centres and in all four participant groups, singing was associated with significant reductions in negative affect and increases in positive affect (p < .01) alongside significant increases in cytokines including GM-CSF, IL17, IL2, IL4 and sIL-2rα (all p < .01). In addition, singing was associated with reductions in cortisol, beta-endorphin and oxytocin levels. This study provides preliminary evidence that singing improves mood state and modulates components of the immune system. Further work is needed to ascertain how this differs for more specific patient groups and whether repeat exposure could lead to meaningful, longitudinal effects. PMID:27170831

  15. Duck cerebellum participates in regulation of food intake via the neurotransmitters serotonin and neuropeptide Y.

    PubMed

    Liu, Hua Z; Li, Xin Y; Tong, Jing J; Qiu, Zheng Y; Zhan, Han C; Sha, Jun N; Peng, Ke M

    2008-10-01

    Two important neurotransmitters, serotonin (5-hydroxytryptamine, 5-HT) and neuropeptide Y (NPY), have been confirmed to be involved in food intake regulation. To clarify whether the cerebellum participates in modulation of food intake through these two neurotransmitters, we investigated the distribution and expression levels of 5-HT and NPY in cerebellum of the duck. Our results showed that 5-HT and NPY were distributed only at the Purkinje cell layer of the duck cerebellum. Moreover, the expression level of 5-HT in fasted (4 h) and tryptophan (100-200 mg/kg)-treated ducks was significantly higher than that in control animals (P<0.01), whereas the expression of NPY was significantly decreased (P<0.01). Therefore, our results indicated that inhibitory regulation of food intake respectively increased and decreased cerebellar 5-HT and NPY in the duck.

  16. 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.

  17. [Calcitonin gene-related peptide: a key player neuropeptide in migraine].

    PubMed

    Ramos-Romero, M L; Sobrino-Mejia, F E

    2016-11-16

    Calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP is widely distributed in the nervous system, particularly at anatomical areas thought to be involved with migraine pathophysiology, including the trigeminovascular nociceptive system. Over the past two decades, a convergence of basic and clinical evidence has established the CGRP as a key player in migraine. CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Within the brain, the wide distribution of CGRP and CGRP receptors provides numerous possible targets for CGRP to act as a neuromodulator. Now, CGRP has emerged as a promising therapeutic target for a number of novel treatments for migraine. This review discusses the evidence behind the role of CGRP in migraine and the state of CGRP-based mechanism treatment development.

  18. Neuropeptide Release Is Impaired in a Mouse Model of Fragile X Mental Retardation Syndrome

    PubMed Central

    2010-01-01

    Fragile X syndrome (FXS), an inherited disorder characterized by mental retardation and autism-like behaviors, is caused by the failure to transcribe the gene for fragile X mental retardation protein (FMRP), a translational regulator and transporter of select mRNAs. FXS model mice (Fmr1 KO mice) exhibit impaired neuropeptide release. Release of biogenic amines does not differ between wild-type (WT) and Fmr1 KO mice. Rab3A, an mRNA cargo of FMRP involved in the recruitment of vesicles, is decreased by ∼50% in synaptoneurosomes of Fmr1 KO mice; however, the number of dense-core vesicles (DCVs) does not differ between WT and Fmr1 KO mice. Therefore, deficits associated with FXS may reflect this aberrant vesicle release, specifically involving docking and fusion of peptidergic DCVs, and may lead to defective maturation and maintenance of synaptic connections. PMID:20495672

  19. Targeting the neuropeptide Y system in stress-related psychiatric disorders

    PubMed Central

    Enman, Nicole M.; Sabban, Esther L.; McGonigle, Paul; Van Bockstaele, Elisabeth J.

    2014-01-01

    Repeated, extreme, or traumatic stressors can elicit pathological effects leading to many negative physical and psychological outcomes. Stressors can precipitate the onset of psychiatric diseases, or exacerbate pre-existing disorders including various anxiety and mood disorders. As stressors can negatively impact human psychiatric health, it is essential to identify neurochemicals that may confer protection from the negative sequelae of repeated or extreme stress exposure. Elucidating the neurobiological underpinnings of stress resilience will enhance our ability to promote resilience to, or recovery from, stress-related psychiatric disease. Herein, we will review the evidence for neuropeptide Y as an endogenous mediator of resilience and its potential relevance for the treatment of stress-related psychiatric diseases. PMID:25506604

  20. Neuropeptide Y protects kidney against cisplatin-induced nephrotoxicity by regulating p53-dependent apoptosis pathway.

    PubMed

    Kim, Namoh; Min, Woo-Kie; Park, Min Hee; Lee, Jong Kil; Jin, Hee Kyung; Bae, Jae-Sung

    2016-05-01

    Cisplatin is a platinum-based chemotherapeutic drug for treating various types of cancers. However, the use of cisplatin is limited by its negative effect on normal tissues, particularly nephrotoxicity. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and apoptosis are involved in the adverse effect induced by cisplatin treatment. Several studies have suggested that neuropeptide Y (NPY) is involved in neuroprotection as well as restoration of bone marrow dysfunction from chemotherapy induced nerve injury. However, the role of NPY in chemotherapy- induced nephrotoxicity has not been studied. Here, we show that NPY rescues renal dysfunction by reducing the expression of pro-apoptotic proteins in cisplatin induced nephrotoxicity through Y1 receptor, suggesting that NPY can protect kidney against cisplatin nephrotoxicity as a possible useful agent to prevent and treat cisplatin-induced nephrotoxicity. [BMB Reports 2016; 49(5): 288-292].

  1. Amphetamine, an appetite suppressant, decreases neuropeptide Y immunoreactivity in rat hypothalamic paraventriculum.

    PubMed

    Hsieh, Yih-Shou; Yang, Shun-Fa; Kuo, Dong-Yih

    2005-04-15

    Amphetamine (AMPH) is a well-known anorectic agent. The mechanism underlying the anorectic response of AMPH has been attributed to its inhibitory effect on hypothalamic neuropeptide Y (NPY), an orexigenic peptide in the brain. However, there is still lack of genomic or in situ immunohistochemical evidence to prove it. The present study was aimed to assess the molecular mechanism of AMPH anorexia by immunostaining of hypothalamic NPY protein in the area of paraventricular nucleus (PVN) and by detecting the change of hypothalamic NPY mRNA level using RT-PCR. Results revealed that an AMPH treatment might reduce the expression of NPY at both transcriptional and posttranslational levels. Comparatively, a treatment of clomipramine, a serotonin transporter inhibitor, was unable to reduce NPY mRNA level, revealing the noninvolvement of hypothalamic NPY gene in serotonin anorexia. Our results provided genomic and in situ immunohistochemical evidence to confirm the mediation of hypothalamic NPY neurons in the anorectic action of AMPH.

  2. Neuropeptides and enzymes are targets for the action of endocrine disrupting chemicals in the vertebrate brain.

    PubMed

    Panzica, G C; Bo, E; Martini, M A; Miceli, D; Mura, E; Viglietti-Panzica, C; Gotti, S

    2011-01-01

    Endocrine-disrupting chemicals (EDC) are molecules that interfere with endocrine signaling pathways and produce adverse consequences on animal and human physiology, such as infertility or behavioral alterations. Some EDC act through binding to androgen or/and estrogen receptors primarily operating through a genomic mechanism regulating gene expression. This mechanism of action may induce profound developmental adverse effects, and the major targets of the EDC action are the gene products, i.e., mRNAs inducing the synthesis of various peptidic molecules, which include neuropeptides and enzymes related to neurotransmitters syntheses. Available immunohistochemical data on some of the systems that are affected by EDC in lower and higher vertebrates are detailed in this review.

  3. Plasma membrane poration by opioid neuropeptides: a possible mechanism of pathological signal transduction.

    PubMed

    Maximyuk, O; Khmyz, V; Lindskog, C-J; Vukojević, V; Ivanova, T; Bazov, I; Hauser, K F; Bakalkin, G; Krishtal, O

    2015-03-12

    Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (~2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.

  4. Disentangling the molecular genetic basis of personality: from monoamines to neuropeptides.

    PubMed

    Montag, Christian; Reuter, Martin

    2014-06-01

    The present review/perspectives article provides a short overview of our current understanding of the molecular genetics of personality. In the first part, the most important gene candidates such as COMT or SLC6A4 gene are presented. Since several seminal review st