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Sample records for amino-butyric acid gaba

  1. Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): modifying serotonin's downstream effects on glutamate and GABA (gamma amino butyric acid) release.

    PubMed

    Stahl, Stephen M

    2015-08-01

    Vortioxetine is an antidepressant with multiple pharmacologic modes of action at targets where serotonin neurons connect with other neurons. These actions modify the release of both glutamate and GABA (gamma amino butyric acid) within various brain circuits. PMID:26062900

  2. EFFECT OF LEAD ON GAMMA AMINO BUTYRIC ACID SYNTHESIS

    EPA Science Inventory

    The project studies the inhibitory effect of lead on the enzymatic activity of brain glutamic amino acid decarboxylase (GADC). The enzyme is responsible for the catalytic formation of gamma amino butyric acid (GABA) inhibitory neurons which is believed to be involved with the tra...

  3. γ-Amino-butyric acid (GABA) receptor subunit and transporter expression in the gonad and liver of the fathead minnow (Pimephales promelas).

    PubMed

    Biggs, Katie; Seidel, Jason S; Wilson, Alex; Martyniuk, Christopher J

    2013-09-01

    γ-Amino-butyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate central nervous system. GABA receptors and synthesizing enzymes have also been localized to peripheral tissues including the liver, oviduct, uterus and ovary of mammals but the distribution and role of GABA in peripheral tissues of fish has not been fully investigated. The objectives of this study were to (1) determine if mRNA encoding GABA synthesizing enzymes (glutamic acid decarboxylase 65 and 67; gad65 and gad67), GABA transporters, and GABAA receptor subunits are localized to liver and gonad of fathead minnow (Pimephales promelas) (FHM) (2) investigate the effects of GABA on ovarian 17β-estradiol (E2) production, and (3) measure transcript responses in the ovary after in vitro incubation to GABA. Real-time PCR assays were developed for gad65, gad67, vesicular GABA transporter (vgat) and GABA transporter 1 (gat1), and select GABAA receptor subunits (gabra1, gabra5, gabrb1, gabrb2, gabrg1, gabrg2). All transcripts were localized to the brain as expected; however transcripts were also detected in the liver, ovary, and testis of FHMs. In the female liver, gad65 mRNA was significantly higher in expression compared to the male liver. Transcripts for gad67 were the highest in the brain>gonad>liver and in the gonads, gad67 was significantly higher in expression than gad65 mRNA. In the liver and gonad, the relative abundance of the subunits followed a general trend of gabrb1>gabrb2=gabrg1=gabrg2>gabra1=gabra5. To explore the effects of GABA in the ovary, tissue explants from reproductive female FHMs were treated with GABA (10(-10), 10(-8) and 10(-6)M) for 12h. GABA had no significant effect on 17β-estradiol production or on mRNA abundance for genes involved in ovarian steroidogenesis (e.g., 11βhsd, cyp17, cyp19a). There was a significant decrease in estrogen receptor 2a (esr2a) mRNA with 10(-10)M GABA. This study begins to investigate the GABA system in non-neural tissues of

  4. Gamma amino butyric acid accumulation in medicinal plants without stress

    PubMed Central

    Anju, P.; Moothedath, Ismail; Rema Shree, Azhimala Bhaskaranpillai

    2014-01-01

    Introduction: Gamma amino butyric acid (GABA) is an important ubiquitous four carbon nonprotein amino acid with an amino group attached to gamma carbon instead of beta carbon. It exists in different organisms including bacteria, plants, and animals and plays a crucial role in humans by regulating neuronal excitability throughout the nervous system. It is directly responsible for the regulation of muscle tone and also effective in lowering stress, blood pressure, and hypertension. Aim and Objective: The aim of the study was to develop the fingerprint profile of selected medicinally and economically important plants having central nervous system (CNS) activity and to determine the quantity of GABA in the selected plants grown under natural conditions without any added stress. Materials and Methods: The high-performance thin layer chromatography analysis was performed on precoated silica gel plate 60F–254 plate (20 cm × 10 cm) in the form of bands with width 8 mm using Hamilton syringe (100 μl) using n-butanol, acetic acid, and water in the proportion 5:2:2 as mobile phase in a CAMAG chamber which was previously saturated for 30 min. CAMAG TLC scanner 3 was used for the densitometric scanning at 550 nm. Specific marker compounds were used for the quantification. Results and Conclusion: Among the screened medicinal plants, Zingiber officinale and Solanum torvum were found to have GABA. The percentage of GABA present in Z. officinale and S. torvum were found to be 0.0114% and 0.0119%, respectively. The present work confirmed that among the selected CNS active medicinal plants, only two plants contain GABA. We found a negative correlation with plant having CNS activity and accumulation of GABA. The GABA shunt is a conserved pathway in eukaryotes and prokaryotes but, although the role of GABA as a neurotransmitter in mammals is clearly established, its role in plants is still vague. PMID:25861139

  5. Production of γ-Amino Butyric Acid in Tea Leaves wit Treatment of Lactic Acid Bacteria

    NASA Astrophysics Data System (ADS)

    Watanabe, Yuko; Hayakawa, Kiyoshi; Ueno, Hiroshi

    Lactic acid bacteria was searched for producing termented tea that contained a lot of γ-amino butyric acid(GABA). Also examined were the growth condition, GABA production and changes in catechin contents in the tea leaves. Lactobacillus brevis L12 was found to be suitable for the production of fermented tea since it gave as much GABA as gabaron tea when tea leaves being suspended with water at 10% and incubated for 4 days at 25°C. The amount of GABA produced was more than calculated based upon the content of glutamic acid in tea leaves. It is probable to assume that glutamate derived from glutamine and theanine is converted into GABA.

  6. The Long and Winding Road to Gamma-Amino-Butyric Acid as Neurotransmitter.

    PubMed

    Avoli, Massimo; Krnjević, Krešimir

    2016-03-01

    This review centers on the discoveries made during more than six decades of neuroscience research on the role of gamma-amino-butyric acid (GABA) as neurotransmitter. In doing so, special emphasis is directed to the significant involvement of Canadian scientists in these advances. Starting with the early studies that established GABA as an inhibitory neurotransmitter at central synapses, we summarize the results pointing at the GABA receptor as a drug target as well as more recent evidence showing that GABAA receptor signaling plays a surprisingly active role in neuronal network synchronization, both during development and in the adult brain. Finally, we briefly address the involvement of GABA in neurological conditions that encompass epileptic disorders and mental retardation. RESUMÉ: Le chemin long et sinueux pour que le GABA soit reconnu comme un neurotransmetteur. Cette revue est axée sur les découvertes réalisées durant plus de six décennies de recherche en neurosciences sur l'acide gamma-aminobutyrique (GABA) comme neurotransmetteur. À cet effet, nous mettons une emphase particulière sur le rôle significatif de chercheurs canadiens dans ce domaine de recherche. En prenant comme point de départ les premières études qui ont établi que le GABA était un neurotransmetteur au niveau de synapses centrales, nous faisons le sommaire des résultats identifiant le récepteur GABA comme étant une cible thérapeutique ainsi que des données plus récentes montrant que la signalisation du récepteur GABAA joue, de façon surprenante, un rôle actif dans la synchronisation du réseau neuronal, tant au cours du développement que dans le cerveau adulte. Finalement, nous traitons brièvement du rôle de GABA dans les maladies neurologiques incluant les troubles épileptiques et l'arriération mentale. PMID:26763167

  7. Dorso-lateral prefrontal γ-amino butyric acid in men predicts individual differences in rash impulsivity

    PubMed Central

    Boy, Frederic; Evans, C. John; Edden, Richard A. E.; Lawrence, Andrew D.; Singh, Krish D.; Husain, Masud; Sumner, Petroc

    2011-01-01

    Background Impulsivity is a multifaceted personality construct associated with numerous psychiatric disorders. Recent research has characterized four facets of impulsivity: ‘urgency’ (the tendency to act rashly especially in the context of distress or cravings); ‘lack of premeditation’ (not envisaging the consequences of actions); ‘lack of perseverance’ (not staying focused on a task); ‘sensation seeking’ (engaging in exciting activities). Urgency is particularly associated with clinical populations and problematic disinhibited behaviour. Methods We used magnetic resonance spectroscopy (MRS) to measure concentration of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the dorso-lateral prefrontal cortex (dlPFC) in two cohorts of 12 and 13 participants. Results We find that variation in trait urgency in healthy men correlates with GABA concentration in the dlPFC. The result was replicated in an independent cohort. More GABA predicted lower urgency scores, consistent with a role in self-control for GABA-mediated inhibitory mechanisms in dlPFC. Conclusions These findings help account for individual differences in self-control, and thus clarify the relationship between GABA and a wide range of psychiatric disorders associated with impaired self-control. PMID:21757187

  8. Effect of γ-amino butyric acid on limpet populations: towards the future management and conservation of endangered patellid species.

    PubMed

    Rivera-Ingraham, G A; Espinosa, F; García-Gómez, J C

    2011-01-01

    Many neurotransmitters, such as γ-amino butyric acid (GABA), can act as chemical cues influencing settlement and metamorphosis in benthic marine invertebrates. This effect has been described especially in mollusks, such as mussels, clams, or haliotids. This study describes the first record of the effect of GABA on patellogastropod populations. Special attention was paid to the effect of the compound on recruitment processes. The experiment was carried out using 10 × 10 cm artificial limestone plates that were drilled into intertidal rocks at different inclinations, and periodically treated with a 1 mM GABA solution. A total of five limpet species was considered (four patellid limpet species and the pulmonate Siphonaria pectinata). Each individual recorded on the plates as well as within a 20 × 20 cm quadrant was measured, identified to species level, and its straight-line distance to the application point was registered. Treated surfaces were the first to possess both adults and recruits. Individuals also were found in a higher number around GABA-treated plates than around controls. The results indicated that the compound may not only enhance recruitment, but also might accelerate it. Recruits were located at higher distances from GABA treated plates than from control surfaces. This supports the hypothesis that this is the life history stage most sensitive to the compound. The behavior shown by the individuals belonging to the two endangered patellid species present in the study area (Patella ferruginea and Cymbula nigra) also were analyzed. For the former, the results indicated that the use of GABA may have similar effects on recruitment similar to the presence of adult conspecifics. This is the first report of the effect of GABA on patellid limpet recruitment and population dynamics. Conservational implications of the results are discussed. PMID:21107997

  9. Elevated spectroscopic glutamate/gamma-amino butyric acid in rats bred for learned helplessness.

    PubMed

    Sartorius, Alexander; Mahlstedt, Magdalena M; Vollmayr, Barbara; Henn, Fritz A; Ende, Gabriele

    2007-09-17

    The theory of depression is dominated by the monoamine hypothesis but there is increasing evidence that beyond monoamines, glutamate (Glu) and gamma-aminobutyric acid (GABA) play an essential role in the pathogenesis of depression. In this study, the effect of alterations of GABA and Glu were investigated in the congenital learned helplessness paradigm. Proton magnetic resonance spectroscopy is an important monitoring tool to bridge the findings in clinical and preclinical studies. We found increased Glu/GABA ratios in the hippocampus and prefrontal cortex of placebo-treated (saline intraperitoneally) congenital learned helplessness rats versus wild-type rats, and a treatment-induced (desipramine 10 mg/kg intraperitoneally or electroconvulsive shock) decrease of this monoamine ratio in both brain regions. Our results corroborate previous findings of an amino-acid influence on the pathomechanisms of mood disorders. PMID:17712276

  10. Isolation of Functional Components β-Glucan and γ-Amino Butyric Acid from Raw and Germinated Barnyard Millet (Echinochloa frumentaceae) and their Characterization.

    PubMed

    Sharma, Seema; Saxena, Dharmesh C; Riar, Charanjit S

    2016-09-01

    The study was carried out to analyze the characteristics of two functional constituents' viz. γ-amino butyric acid (GABA) and β-glucan extracted from raw and germination barnyard millet (var. PRJ-1). A significant (P ≤ 0.05) effect of germination (sprouting) was observed in yield, chemical composition, functional, rheological and antioxidant properties of β-glucan and GABA. The yield of GABA extract was 12.34 % and the content increased from 6.37 mg/100 g in raw to 35.70 mg/100 g in germinated sample. The DPPH, total antioxidant and hydrogen peroxide scavenging activities of GABA extract increased after germination from 45.34 to 65.34 %, 15.3 to 33.3 millimole/g and 38.4 to 64.7 millimole/g, respectively. The yield of β-glucan extract of raw and germinated flour was 6.05 and 5.01 % whereas the β-glucan contents were 83.30 and 79.64 %, respectively. The functional properties of β-glucan i.e., swelling power, water binding capacity and DPPH scavenging activity increased from 1.45 to 1.76 g/g, 2.13 to 2.32 g/g and 44.39 to 57.42 %, respectively, after germination. Similarly there was an increase in the storage modulus after germination process which attributes a better viscoelastic capacity of β-glucan at low frequencies. The results exploit that the β-glucan and GABA might promise a polymeric incipient to be implemented as food additives with variable functional and structural characteristics. PMID:27245684

  11. Ondansetron reverses anti-hypersensitivity from clonidine in rats following peripheral nerve injury: Role of γ-amino butyric acid in α2-adrenoceptor and 5-HT3 serotonin receptor analgesia

    PubMed Central

    Hayashida, Ken-ichiro; Kimura, Masafumi; Yoshizumi, Masaru; Hobo, Shotaro; Obata, Hideaki; Eisenach, James C.

    2012-01-01

    Introduction Monoaminergic pathways, impinging an α2-adrenoceptors and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions after neuropathic injury are unknown. Here we examine these interactions in rodents after nerve injury. Methods Male Sprague-Dawley rats following L5-L6 spinal nerve ligation (SNL) were used for either behavioral testing, in vivo microdialysis for γ-amino butyric acid (GABA) and acetylcholine release, or synaptosome preparation for GABA release. Results Intrathecal administration of the α2-adrenoceptor agonist (clonidine) and 5-HT3 receptor agonist (chlorophenylbiguanide) reduced hypersensitivity in SNL rats via GABA receptor-mediated mechanisms. Clonidine increased GABA and acetylcholine release in vivo in the spinal cord of SNL rats but not in normal rats. Clonidine-induced spinal GABA release in SNL rats was blocked by α2-adrenergic and nicotinic cholinergic antagonists. The 5-HT3 receptor antagonist ondansetron decreased and chlorophenylbiguanide increased spinal GABA release in both normal and SNL rats. In synaptosomes from the spinal dorsal horn of SNL rats, pre-synaptic GABA release was increased by nicotinic agonists and decreased by muscarinic and α2-adrenergic agonists. Spinally administered ondansetron significantly reduced clonidine-induced anti-hypersensitivity and spinal GABA release in SNL rats. Conclusion These results suggest that spinal GABA contributes to anti-hypersensitivity from intrathecal α2-adrenergic and 5-HT3 receptor agonists in the neuropathic pain state, that cholinergic neuroplasticity after nerve injury is critical for α2-adrenoceptor-mediated GABA release, and that blockade of spinal 5-HT3 receptors reduces α2-adrenoceptor-mediated anti-hypersensitivity via reducing total GABA release. PMID:22722575

  12. LeProT1, a transporter for proline, glycine betaine, and gamma-amino butyric acid in tomato pollen.

    PubMed Central

    Schwacke, R; Grallath, S; Breitkreuz, K E; Stransky, E; Stransky, H; Frommer, W B; Rentsch, D

    1999-01-01

    During maturation, pollen undergoes a period of dehydration accompanied by the accumulation of compatible solutes. Solute import across the pollen plasma membrane, which occurs via proteinaceous transporters, is required to support pollen development and also for subsequent germination and pollen tube growth. Analysis of the free amino acid composition of various tissues in tomato revealed that the proline content in flowers was 60 times higher than in any other organ analyzed. Within the floral organs, proline was confined predominantly to pollen, where it represented >70% of total free amino acids. Uptake experiments demonstrated that mature as well as germinated pollen rapidly take up proline. To identify proline transporters in tomato pollen, we isolated genes homologous to Arabidopsis proline transporters. LeProT1 was specifically expressed both in mature and germinating pollen, as demonstrated by RNA in situ hybridization. Expression in a yeast mutant demonstrated that LeProT1 transports proline and gamma-amino butyric acid with low affinity and glycine betaine with high affinity. Direct uptake and competition studies demonstrate that LeProT1 constitutes a general transporter for compatible solutes. PMID:10072398

  13. Mutations in y-aminobutyric acid (GABA) transaminase genes in plants or Pseudomonas syringae reduce bacterial virulence

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pseudomonas syringae pv. tomato DC3000 is a bacterial pathogen of Arabidopsis and tomato that grows in the apoplast. The non-protein amino acid '-amino butyric acid (GABA) is produced by Arabidopsis and tomato and is the most abundant amino acid in the apoplastic fluid of tomato. The DC3000 genome h...

  14. Upregulation of genes related to bone formation by γ-amino butyric acid and γ-oryzanol in germinated brown rice is via the activation of GABAB-receptors and reduction of serum IL-6 in rats

    PubMed Central

    Muhammad, Sani Ismaila; Maznah, Ismail; Mahmud, Rozi; Zuki, Abu Bakar Zakaria; Imam, Mustapha Umar

    2013-01-01

    Background Osteoporosis and other bone degenerative diseases are among the most challenging non-communicable diseases to treat. Previous works relate bone loss due to osteoporosis with oxidative stress generated by free radicals and inflammatory cytokines. Alternative therapy to hormone replacement has been an area of interest to researchers for almost three decades due to hormone therapy-associated side effects. Methods In this study, we investigated the effects of gamma-amino butyric acid (GABA), gamma-oryzanol (ORZ), acylated steryl glucosides (ASG), and phenolic extracts from germinated brown rice (GBR) on the expression of genes related to bone metabolism, such as bone morphogenic protein-2 (BMP-2), secreted protein acidic and rich in cysteine (SPARC), runt-related transcription factor 2 (RUNX-2), osteoblast-specific transcription factor osterix (Osx), periostin, osteoblast specific factor (Postn), collagen 1&2 (Col1&2), calcitonin receptor gene (CGRP); body weight measurement and also serum interleukin-6 (IL-6) and osteocalcin, in serum and bone. Rats were treated with GBR, ORZ, GABA, and ASG at (100 and 200 mg/kg); estrogen (0.2 mg/kg), or remifemin (10 and 20 mg/kg), compared to ovariectomized non-treated group as well as non-ovariectomized non-treated (sham) group. Enzyme-linked immunosorbent assay was used to measure the IL-6 and osteocalcin levels at week 2, 4, and 8, while the gene expression in the bone tissue was determined using the Genetic Analysis System (Beckman Coulter Inc., Brea, CA, USA). Results The results indicate that groups treated with GABA (100 and 200 mg/kg) showed significant upregulation of SPARC, calcitonin receptor, and BMP-2 genes (P < 0.05), while the ORZ-treated group (100 and 200 mg/kg) revealed significant (P < 0.05) upregulation of Osx, Postn, RUNX-2, and Col1&2. Similarly, IL-6 concentration decreased, while osteocalcin levels increased significantly (P < 0.05) in the treated groups as compared to ovariectomized non

  15. Proliferative effects of gamma-amino butyric acid on oral squamous cell carcinoma cells are associated with mitogen-activated protein kinase signaling pathways.

    PubMed

    Ma, Jing; Zhang, Yan; Wang, Jun; Zhao, Tianyu; Ji, Ping; Song, Jinlin; Zhang, Hongmei; Luo, Wenping

    2016-07-01

    Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult mammalian central nervous system, has been reported to play an important physiological role in peripheral non-neuronal tissues, such as tumors. However, whether deregulated GABA is associated with oral squamous cell carcinoma (OSCC) is currently unknown. In this study, we investigated the effects of GABA on the proliferation of the OSCC cell line, Tca8113. Immunohistochemical analyses were performed to examine the expression of GABA A type receptor pi subunit (GABRP) in human OSCC tissues, and reverse transcription polymerase chain reaction, immunofluorescence staining and western blot analysis were performed to examine the expression of GABRP in Tca8113 cells. The proliferative effects of GABA on Tca8113 cells were analyzed by CCK-8 assay and flow cytometry. The activation status of mitogen-activated protein kinases (MAPKs) was examined by western blot analysis. GABRP expression was observed in the cytoplasm with a higher level in poorly differentiated OSCC tissues. The mRNA and protein expression levels of GABRP were detected in the Tca8113 cells. The addition of GABA and the GABA A type receptor agonist, Muscimol, promoted cell proliferation and inhibited cell apoptosis through the activation of the p38 MAPK and the inhibition of the JNK MAPK signaling pathways. These results imply a novel role of GABA in OSCC. PMID:27222045

  16. Seed priming with BABA (β-amino butyric acid): a cost-effective method of abiotic stress tolerance in Vigna radiata (L.) Wilczek.

    PubMed

    Jisha, K C; Puthur, Jos T

    2016-03-01

    The effects of β-amino butyric acid (BABA) on abiotic stress tolerance potential of three Vigna radiata varieties were studied. The reduction in the growth of seedlings subjected to NaCl/polyethylene glycol (PEG) stress is alleviated by BABA seed priming, which also enhanced photosynthetic pigment content and photosynthetic and mitochondrial activities, and also modified the chlorophyll a fluorescence-related parameters. Moreover, BABA seed priming reduced malondialdehyde content in the seedlings and enhanced the accumulation of proline, total protein, total carbohydrate, nitrate reductase activity, and activities of antioxidant enzymes like guaiacol peroxidase and superoxide dismutase. Most of these positive features of BABA priming were predominantly exhibited when the plants were encountered with stress (NaCl/PEG). The BABA content in the BABA-treated green gram seeds and seedlings was also detected and quantified with high-performance thin layer chromatography (HPTLC), and it revealed that the priming effect of BABA initiated in seeds and further gets carried over to the seedlings. It was concluded that BABA seed priming improved the drought and salinity stress tolerance potential of all the three green gram varieties, and it was evident in the NaCl-tolerant variety Pusa Vishal as compared to Pusa Ratna (abiotic stress sensitive) and Pusa 9531(drought tolerant). Dual mode in cost effectiveness of BABA priming is evident from: (1) the positive features of priming are being exhibited more during the exposure of plants to stress, and (2) priming of seedlings can be carried out by BABA application to seeds at very low concentration and volume. PMID:25837010

  17. GABA as a rising gliotransmitter

    PubMed Central

    Yoon, Bo-Eun; Lee, C. Justin

    2014-01-01

    Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter that is known to be synthesized and released from GABAergic neurons in the brain. However, recent studies have shown that not only neurons but also astrocytes contain a considerable amount of GABA that can be released and activate GABA receptors in neighboring neurons. These exciting new findings for glial GABA raise further interesting questions about the source of GABA, its mechanism of release and regulation and the functional role of glial GABA. In this review, we highlight recent studies that identify the presence and release of GABA in glial cells, we show several proposed potential pathways for accumulation and modulation of glial intracellular and extracellular GABA content, and finally we discuss functional roles for glial GABA in the brain. PMID:25565970

  18. Accumulation, selection and covariation of amino acids in sieve tube sap of tansy (Tanacetum vulgare) and castor bean (Ricinus communis): evidence for the function of a basic amino acid transporter and the absence of a γ-amino butyric acid transporter.

    PubMed

    Bauer, Susanne N; Nowak, Heike; Keller, Frank; Kallarackal, Jose; Hajirezaei, Mohamad-Reza; Komor, Ewald

    2014-09-01

    Sieve tube sap was obtained from Tanacetum by aphid stylectomy and from Ricinus after apical bud decapitation. The amino acids in sieve tube sap were analyzed and compared with those from leaves. Arginine and lysine accumulated in the sieve tube sap of Tanacetum more than 10-fold compared to the leaf extracts and they were, together with asparagine and serine, preferably selected into the sieve tube sap, whereas glycine, methionine/tryptophan and γ-amino butyric acid were partially or completely excluded. The two basic amino acids also showed a close covariation in sieve tube sap. The acidic amino acids also grouped together, but antagonistic to the other amino acids. The accumulation ratios between sieve tube sap and leaf extracts were smaller in Ricinus than in Tanacetum. Arginine, histidine, lysine and glutamine were enriched and preferentially loaded into the phloem, together with isoleucine and valine. In contrast, glycine and methionine/tryptophan were partially and γ-amino butyric acid almost completely excluded from sieve tube sap. The covariation analysis grouped arginine together with several neutral amino acids. The acidic amino acids were loaded under competition with neutral amino acids. It is concluded from comparison with the substrate specificities of already characterized plant amino acid transporters, that an AtCAT1-like transporter functions in phloem loading of basic amino acids, whereas a transporter like AtGAT1 is absent in phloem. Although Tanacetum and Ricinus have different minor vein architecture, their phloem loading specificities for amino acids are relatively similar. PMID:24446756

  19. Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies

    PubMed Central

    Parviz, Mahsa; Vogel, Kara; Gibson, K. Michael; Pearl, Phillip L.

    2014-01-01

    Clinical disorders known to affect inherited gamma-amino butyric acid (GABA) metabolism are autosomal recessively inherited succinic semialdehyde dehydrogenase and GABA-transaminase deficiency. The clinical presentation of succinic semialdehyde dehydrogenase deficiency includes intellectual disability, ataxia, obsessive-compulsive disorder and epilepsy with a nonprogressive course in typical cases, although a progressive form in early childhood as well as deterioration in adulthood with worsening epilepsy are reported. GABA-transaminase deficiency is associated with a severe neonatal-infantile epileptic encephalopathy. PMID:25485164

  20. Perinatal exposure to germinated brown rice and its gamma amino-butyric acid-rich extract prevents high fat diet-induced insulin resistance in first generation rat offspring

    PubMed Central

    Adamu, Hadiza Altine; Imam, Mustapha Umar; Ooi, Der-Jiun; Esa, Norhaizan Mohd; Rosli, Rozita; Ismail, Maznah

    2016-01-01

    Background Evidence suggests perinatal environments influence the risk of developing insulin resistance. Objective The present study was aimed at determining the effects of intrauterine exposure to germinated brown rice (GBR) and GBR-derived gamma (γ) aminobutyric acid (GABA) extract on epigenetically mediated high fat diet–induced insulin resistance. Design Pregnant Sprague Dawley rats were fed high-fat diet (HFD), HFD+GBR, or HFD+GABA throughout pregnancy until 4 weeks postdelivery. The pups were weighed weekly and maintained on normal pellet until 8 weeks postdelivery. After sacrifice, biochemical markers of obesity and insulin resistance including oral glucose tolerance test, adiponectin, leptin, and retinol binding protein-4 (RBP4) were measured. Hepatic gene expression changes and the global methylation and histone acetylation levels were also evaluated. Results Detailed analyses revealed that mothers given GBR and GABA extract, and their offspring had increased adiponectin levels and reduced insulin, homeostasis model assessment of insulin resistance, leptin, oxidative stress, and RBP4 levels, while their hepatic mRNA levels of GLUT2 and IPF1 were increased. Furthermore, GBR and GABA extract lowered global DNA methylation levels and modulated H3 and H4 acetylation levels. Conclusions These results showed that intrauterine exposure to GBR-influenced metabolic outcomes in offspring of rats with underlying epigenetic changes and transcriptional implications that led to improved glucose homeostasis. PMID:26842399

  1. γ-Aminobutyric acid type A (GABA(A)) receptor subtype inverse agonists as therapeutic agents in cognition.

    PubMed

    Gabriella, Guerrini; Giovanna, Ciciani

    2010-01-01

    The gabaergic system has been identified as a relevant regulator of cognitive and emotional processing. In fact, the discovery that negative allosteric regulators (or inverse agonists) at GABA(A) (γ-aminobutyric acid) α5 subtype receptors improve learning and memory tasks, has further validated this concept. The localization of these extrasynaptic subtype receptors, mainly in the hippocampus, has suggested that they play a key role in the three stages of memory: acquisition, consolidation, and retrieval. The "α5 inverse agonist" binds to an allosteric site at GABA(A) receptor, provoking a reduction of chlorine current, but to elicit this effect, the necessary condition is the binding of agonist neurotransmitter (γ-amino butyric acid) at its orthosteric site. In this case, the GABA(A) receptor is not a "constitutively active receptor" and, however, the presence of spontaneous opening channels for native GABA(A) receptors is rare. Here, we present various classes of nonselective and α5 selective GABA(A) receptor ligands, and the in vitro and in vivo tests to elucidate their affinity and activity. The study of the GABA(A) α5 inverse agonists is one of the important tools, although not the only one, for the development of clinical strategies for treatment of Alzheimer disease and mild cognitive impairment. PMID:21050918

  2. Artificial Autopolyploidization Modifies the Tricarboxylic Acid Cycle and GABA Shunt in Arabidopsis thaliana Col-0.

    PubMed

    Vergara, Fredd; Kikuchi, Jun; Breuer, Christian

    2016-01-01

    Autopolyploidy is a process whereby the chromosome set is multiplied and it is a common phenomenon in angiosperms. Autopolyploidy is thought to be an important evolutionary force that has led to the formation of new plant species. Despite its relevance, the consequences of autopolyploidy in plant metabolism are poorly understood. This study compares the metabolic profiles of natural diploids and artificial autotetraploids of Arabidopsis thaliana Col-0. Different physiological parameters are compared between diploids and autotetraploids using nuclear magnetic resonance (NMR), elemental analysis (carbon:nitrogen balance) and quantitative real-time PCR (qRT-PCR). The main difference between diploid and autotetraploid A. thaliana Col-0 is observed in the concentration of metabolites related to the tricarboxylic acid cycle (TCA) and γ-amino butyric acid (GABA) shunt, as shown by multivariate statistical analysis of NMR spectra. qRT-PCR shows that genes related to the TCA and GABA shunt are also differentially expressed between diploids and autotetraploids following similar trends as their corresponding metabolites. Solid evidence is presented to demonstrate that autopolyploidy influences core plant metabolic processes. PMID:27212081

  3. Artificial Autopolyploidization Modifies the Tricarboxylic Acid Cycle and GABA Shunt in Arabidopsis thaliana Col-0

    NASA Astrophysics Data System (ADS)

    Vergara, Fredd; Kikuchi, Jun; Breuer, Christian

    2016-05-01

    Autopolyploidy is a process whereby the chromosome set is multiplied and it is a common phenomenon in angiosperms. Autopolyploidy is thought to be an important evolutionary force that has led to the formation of new plant species. Despite its relevance, the consequences of autopolyploidy in plant metabolism are poorly understood. This study compares the metabolic profiles of natural diploids and artificial autotetraploids of Arabidopsis thaliana Col-0. Different physiological parameters are compared between diploids and autotetraploids using nuclear magnetic resonance (NMR), elemental analysis (carbon:nitrogen balance) and quantitative real-time PCR (qRT-PCR). The main difference between diploid and autotetraploid A. thaliana Col-0 is observed in the concentration of metabolites related to the tricarboxylic acid cycle (TCA) and γ-amino butyric acid (GABA) shunt, as shown by multivariate statistical analysis of NMR spectra. qRT-PCR shows that genes related to the TCA and GABA shunt are also differentially expressed between diploids and autotetraploids following similar trends as their corresponding metabolites. Solid evidence is presented to demonstrate that autopolyploidy influences core plant metabolic processes.

  4. Artificial Autopolyploidization Modifies the Tricarboxylic Acid Cycle and GABA Shunt in Arabidopsis thaliana Col-0

    PubMed Central

    Vergara, Fredd; Kikuchi, Jun; Breuer, Christian

    2016-01-01

    Autopolyploidy is a process whereby the chromosome set is multiplied and it is a common phenomenon in angiosperms. Autopolyploidy is thought to be an important evolutionary force that has led to the formation of new plant species. Despite its relevance, the consequences of autopolyploidy in plant metabolism are poorly understood. This study compares the metabolic profiles of natural diploids and artificial autotetraploids of Arabidopsis thaliana Col-0. Different physiological parameters are compared between diploids and autotetraploids using nuclear magnetic resonance (NMR), elemental analysis (carbon:nitrogen balance) and quantitative real-time PCR (qRT-PCR). The main difference between diploid and autotetraploid A. thaliana Col-0 is observed in the concentration of metabolites related to the tricarboxylic acid cycle (TCA) and γ-amino butyric acid (GABA) shunt, as shown by multivariate statistical analysis of NMR spectra. qRT-PCR shows that genes related to the TCA and GABA shunt are also differentially expressed between diploids and autotetraploids following similar trends as their corresponding metabolites. Solid evidence is presented to demonstrate that autopolyploidy influences core plant metabolic processes. PMID:27212081

  5. GABA's Control of Stem and Cancer Cell Proliferation in Adult Neural and Peripheral Niches

    PubMed Central

    Young, Stephanie Z.; Bordey, Angélique

    2010-01-01

    Aside from traditional neurotransmission and regulation of secretion, γ-amino butyric acid (GABA) through GABAA receptors negatively regulates proliferation of pluripotent and neural stem cells in embryonic and adult tissue. There has also been evidence that GABAergic signaling and its control over proliferation is not only limited to the nervous system, but is widespread through peripheral organs containing adult stem cells. GABA has emerged as a tumor signaling molecule in the periphery that controls the proliferation of tumor cells and perhaps tumor stem cells. Here, we will discuss GABA's presence as a near-universal signal that may be altered in tumor cells resulting in modified mitotic activity. PMID:19509127

  6. The role of GABA in the regulation of GnRH neurons

    PubMed Central

    Watanabe, Miho; Fukuda, Atsuo; Nabekura, Junichi

    2014-01-01

    Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA) has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction. PMID:25506316

  7. Production of gaba (γ - Aminobutyric acid) by microorganisms: a review.

    PubMed

    Dhakal, Radhika; Bajpai, Vivek K; Baek, Kwang-Hyun

    2012-10-01

    GABA (γ-aminobutyric acid) is a four carbon non-protein amino acid that is widely distributed in plants, animals and microorganisms. As a metabolic product of plants and microorganisms produced by the decarboxylation of glutamic acid, GABA functions as an inhibitory neurotransmitter in the brain that directly affects the personality and the stress management. A wide range of traditional foods produced by microbial fermentation contain GABA, in which GABA is safe and eco-friendly, and also has the possibility of providing new health-benefited products enriched with GABA. Synthesis of GABA is catalyzed by glutamate decarboxylase, therefore, the optimal fermentation condition is mainly based on the biochemical properties of the enzyme. Major GABA producing microorganisms are lactic acid bacteria (LAB), which make food spoilage pathogens unable to grow and act as probiotics in the gastrointestinal tract. The major factors affecting the production of GABA by microbial fermentation are temperature, pH, fermentation time and different media additives, therefore, these factors are summarized to provide the most up-dated information for effective GABA synthesis. There has been a huge accumulation of knowledge on GABA application for human health accompanying with a demand on natural GABA supply. Only the GABA production by microorganisms can fulfill the demand with GABA-enriched health beneficial foods. PMID:24031948

  8. Inherited disorders of GABA metabolism

    PubMed Central

    Pearl, Phillip L; Hartka, Thomas R; Cabalza, Jessica L; Taylor, Jacob; Gibson, Michael K

    2013-01-01

    The inherited disorders of γ-amino butyric acid (GABA) metabolism require an increased index of clinical suspicion. The known genetic disorders are GABA-transaminase deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency and homocarnosinosis. A recent link has also been made between impaired GABA synthesis and nonsyndromic cleft lip, with or without cleft palate. SSADH deficiency is the most commonly occurring of the inherited disorders of neurotransmitters. The disorder has a nonspecific phenotype with myriad neurological and psychiatric manifestations, and usually has a nonprogressive temporal course. Diagnosis is made by the detection of γ-hydroxybutyrate excretion on urine organic acid testing. The most consistent magnetic resonance imaging abnormality is an increased signal in the globus pallidus. Magnetic resonance spectroscopy has demonstrated the first example of increased endogenous GABA in human brain parenchyma in this disorder. GABA-transaminase deficiency and homocarnosinosis appear to be very rare, but require cerebrospinal fluid for detection, thus allowing for the possibility that these entities, as in the other inherited neurotransmitter disorders, are under-recognized. PMID:23842532

  9. GABA release by hippocampal astrocytes

    PubMed Central

    Le Meur, Karim; Mendizabal-Zubiaga, Juan; Grandes, Pedro; Audinat, Etienne

    2012-01-01

    Astrocytes can directly influence neuronal activity through the release of various transmitters acting on membrane receptors expressed by neurons. However, in contrast to glutamate and ATP for instance, the release of GABA (γ-amino-butyric acid) by astrocytes is still poorly documented. Here, we used whole-cell recordings in rat acute brain slices and electron microscopy to test whether hippocampal astrocytes release the inhibitory transmitter GABA. We observed that slow transient inhibitory currents due to the activation of GABAA receptors occur spontaneously in principal neurons of the three main hippocampal fields (CA1, CA3, and dentate gyrus). These currents share characteristics with the slow NMDA receptor-mediated currents previously shown to result from astrocytic glutamate release: they occur in the absence of synaptic transmission and have variable kinetics and amplitudes as well as low frequencies. Osmotic pressure reduction, known to enhance transmitter release from astrocytes, similarly increased the frequency of non-synaptic GABA and glutamate currents. Simultaneous occurrence of slow inhibitory and excitatory currents was extremely rare. Yet, electron microscopy examination of immunostained hippocampal sections shows that about 80% of hippocampal astrocytes [positive for glial fibrillary acidic protein (GFAP)] were immunostained for GABA. Our results provide quantitative characteristics of the astrocyte-to-neuron GABAergic signaling. They also suggest that all principal neurons of the hippocampal network are under a dual, excitatory and inhibitory, influence of astrocytes. The relevance of the astrocytic release of GABA, and glutamate, on the physiopathology of the hippocampus remains to be established. PMID:22912614

  10. Fabrication of the Optical Fiber GABA Sensor Based on the NADP+ -Functionalized Quantum Dots.

    PubMed

    Zhao, Fei; Yoo, Jeongha; Kim, Jongsung

    2016-02-01

    A novel quantum dots (QDs)-based optical fiber biosensor has been developed to detect gamma-amino butyric acid (GABA) directly, via QD fluorescence quenching and recovery. QDs were immobilized on the surface of an optical-fiber through the EDC/Sulfo-NHS coupling reaction. The QDs were functionalized by 3-aminophenyl boronic acid and then by NADP+. The fluorescence of the NADP+ -functionalized QDs was quenched by electron transfer from QDs to NADP+. However, by the metabolic conversion of GABA to succinic acid by GABase, NADP+ was reduced to NADPH, which hindered the electron transfer. As a result, the fluorescence of the QDs could recover. The recovery rate of the fluorescence intensity of QDs depended on the concentration of GABA. This shows the possibility of detection of low concentrations of GABA via measurement of the fluorescence intensity. PMID:27433599

  11. Fast detection of extrasynaptic GABA with a whole-cell sniffer

    PubMed Central

    Christensen, Rasmus K.; Petersen, Anders V.; Schmitt, Nicole; Perrier, Jean-François

    2014-01-01

    Gamma-amino-butyric acid (GABA) is the main inhibitory transmitter of the brain. It operates by binding to specific receptors located both inside and outside synapses. The extrasynaptic receptors are activated by spillover from GABAergic synapses and by ambient GABA in the extracellular space. Ambient GABA is essential for adjusting the excitability of neurons. However, due to the lack of suitable methods, little is known about its dynamics. Here we describe a new technique that allows detection of GABA transients and measurement of the steady state GABA concentration with high spatial and temporal resolution. We used a human embryonic kidney (HEK) cell line that stably expresses GABAA receptors composed of α1, β2, and γ2 subunits. We recorded from such a HEK cell with the whole-cell patch-clamp technique. The presence of GABA near the HEK cell generated a measurable electric current whose magnitude increased with concentration. A fraction of the current did not inactivate during prolonged exposition to GABA. This technique, which we refer to as a “sniffer” allows the measurement of ambient GABA concentration inside nervous tissue with a resolution of few tens of nanomolars. In addition, the sniffer detects variations in the extrasynaptic GABA concentration with millisecond time resolution. Pilot experiments demonstrate that the sniffer is able to report spillover of GABA induced by synaptic activation in real time. This is the first report on a GABA sensor that combines the ability to detect fast transients and to measure steady concentrations. PMID:24860433

  12. Effect of γ-Aminobutyric Acid (GABA) Producing Bacteria on In vitro Rumen Fermentation, Biogenic Amine Production and Anti-oxidation Using Corn Meal as Substrate

    PubMed Central

    Ku, Bum Seung; Mamuad, Lovelia L.; Kim, Seon-Ho; Jeong, Chang Dae; Soriano, Alvin P.; Lee, Ho-Il; Nam, Ki-Chang; Ha, Jong K.; Lee, Sang Suk

    2013-01-01

    The effects and significance of γ-amino butyric acid (GABA) producing bacteria (GPB) on in vitro rumen fermentation and reduction of biogenic amines (histamine, methylamine, ethylamine, and tyramine) using corn meal as a substrate were determined. Ruminal samples collected from ruminally fistulated Holstein cows served as inoculum and corn was used as substrate at 2% dry matter (DM). Different inclusion rates of GPB and GABA were evaluated. After incubation, addition of GPB had no significant effect on in vitro fermentation pH and total gas production, but significantly increased the ammonia nitrogen (NH3-N) concentration and reduced the total biogenic amines production (p<0.05). Furthermore, antioxidation activity was improved as indicated by the significantly higher concentration of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) among treated samples when compared to the control (p<0.05). Additionally, 0.2% GPB was established as the optimum inclusion level. Taken together, these results suggest the potential of utilizing GPB as feed additives to improve growth performance in ruminants by reducing biogenic amines and increasing anti-oxidation. PMID:25049853

  13. Molecular aspects of age-related cognitive decline: the role of GABA signaling

    PubMed Central

    McQuail, Joseph A.; Frazier, Charles J.; Bizon, Jennifer L.

    2015-01-01

    Alterations in inhibitory interneurons contribute to cognitive deficits associated with several psychiatric and neurological diseases. Phasic and tonic inhibition imparted by γ-amino-butyric acid (GABA) receptors regulates neural activity and helps to establish the appropriate network dynamics in cortical circuits that support normal cognition. This review highlights basic science demonstrating that inhibitory signaling is altered in aging, and discusses the impact of age-related shifts in inhibition on different forms of memory function, including hippocampus-dependent spatial reference memory and prefrontal cortex (PFU)-dependent working memory. The clinical appropriateness and tractability of select therapeutic candidates for cognitive aging that target receptors mediating inhibition are also discussed. PMID:26070271

  14. GABA-mediated regulation of the activity-dependent olfactory bulb dopaminergic phenotype

    PubMed Central

    Akiba, Yosuke; Sasaki, Hayato; Huerta, Patricio T.; Estevez, Alvaro G.; Baker, Harriet; Cave, John W.

    2009-01-01

    Gamma-amino-butyric acid (GABA) regulates the proliferation and migration of olfactory bulb (OB) interneuron progenitors derived from the subventricular zone (SVZ), but the role of GABA in the differentiation of these progenitors has been largely unexplored. This study examined the role of GABA in the differentiation of OB dopaminergic interneurons using neonatal forebrain organotypic slice cultures prepared from transgenic mice expressing GFP under the control of the tyrosine hydroxylase (Th) gene promoter (ThGFP). KCl-mediated depolarization of the slices induced ThGFP expression. The addition of GABA to the depolarized slices further increased GFP fluorescence by inducing ThGFP expression in an additional set of periglomerular cells. These findings showed that GABA promoted differentiation of SVZ-derived OB dopaminergic interneurons and suggested that GABA indirectly regulated Th expression and OB dopaminergic neuron differentiation through an acceleration of the maturation rate for the dopaminergic progenitors. Additional studies revealed that the effect of GABA on ThGFP expression required activation of L- and P/Q-type Ca+2 channels as well as GABAA and GABAB receptors. These voltage-gated Ca+2 channels and GABA receptors have previously been shown to be required for the co-expressed GABAergic phenotype in the OB interneurons. Together, these findings suggest that Th expression and the differentiation of OB dopaminergic interneurons are coupled to the co-expressed GABAergic phenotype, and demonstrate a novel role for GABA in neurogenesis. PMID:19301430

  15. Allosteric modulation of retinal GABA receptors by ascorbic acid

    PubMed Central

    Calero, Cecilia I.; Vickers, Evan; Moraga Cid, Gustavo; Aguayo, Luis G.; von Gersdorff, Henrique; Calvo, Daniel J.

    2011-01-01

    Summary Ionotropic γ-aminobutyric acid receptors (GABAA and GABAC) belong to the cys-loop receptor family of ligand-gated ion channels. GABAC receptors are highly expressed in the retina, mainly localized at the axon terminals of bipolar cells. Ascorbic acid, an endogenous redox agent, modulates the function of diverse proteins, and basal levels of ascorbic acid in the retina are very high. However, the effect of ascorbic acid on retinal GABA receptors has not been studied. Here we show that the function of GABAC and GABAA receptors is regulated by ascorbic acid. Patch-clamp recordings from bipolar cell terminals in goldfish retinal slices revealed that GABAC receptor-mediated currents activated by tonic background levels of extracellular GABA, and GABAC currents elicited by local GABA puffs, are both significantly enhanced by ascorbic acid. In addition, a significant rundown of GABA-puff evoked currents was observed in the absence of ascorbic acid. GABA-evoked Cl- currents mediated by homomeric ρ1 GABAC receptors expressed in Xenopus laevis oocytes were also potentiated by ascorbic acid in a concentration-dependent, stereospecific, reversible, and voltage-independent manner. Studies involving the chemical modification of sulfhydryl groups showed that the two cys-loop cysteines and histidine 141, all located in the ρ1 subunit extracellular domain, each play a key role in the modulation of GABAC receptors by ascorbic acid. Additionally, we show that retinal GABAA IPSCs and heterologously expressed GABAA receptor currents are similarly augmented by ascorbic acid. Our results suggest that ascorbic acid may act as an endogenous agent capable of potentiating GABAergic neurotransmission in the CNS. PMID:21715633

  16. Regulation of GABA-modulin phosphorylation and GABA receptor binding by excitatory amino acids

    SciTech Connect

    Vaccarino, F.; Guidotti, A.

    1987-05-01

    Primary cultures of cerebellar granule cells phosphorylate numerous proteins including GABA-modulin (GM), which is a putative allosteric modulator of GABA receptors. Cell depolarization and treatment with dicarboxylic excitatory amino acids, which activate PI turnover, Ca/sup 2 +/ influx and guanylate cyclase in granule cells increase the phosphorylation of specific proteins. To determine GM phosphorylation by endogenous protein kinases in living granule cell cultures, GM was isolated by immunoprecipitation and reverse-phase HPLC. High K/sup +/, veratridine, glutamate and NMDA treatment stimulated GM phosphorylation over 2-fold. This increase was abolished by the absence of extracellular Ca/sup 2 +/ and was antagonized by Mg/sup 2 +/ ions and by AVP. The excitatory amino acid action was mimicked by phorbol esters but not by forskolin or by cGMP, and thus may be mediated by an activation of protein kinase C (PKC). Moreover, excitatory amino acids increase /sup 3/H-labelled phorbol ester binding sites in granule cell membrane. The same cultures, treated with glutamate or kainate, showed a 50-fold greater efficacy of muscimol for the stimulation of benzodiazepine (BZ) binding. These data-suggest that excitatory amino acid stimulation of neurons triggers PKC translocation and the activated enzyme phosphorylates GM. The extent of GM phosphorylation may regulate the coupling between GABA and BZ binding sites.

  17. Production of gaba (γ – Aminobutyric acid) by microorganisms: a review

    PubMed Central

    Dhakal, Radhika; Bajpai, Vivek K.; Baek, Kwang-Hyun

    2012-01-01

    GABA (γ-aminobutyric acid) is a four carbon non-protein amino acid that is widely distributed in plants, animals and microorganisms. As a metabolic product of plants and microorganisms produced by the decarboxylation of glutamic acid, GABA functions as an inhibitory neurotransmitter in the brain that directly affects the personality and the stress management. A wide range of traditional foods produced by microbial fermentation contain GABA, in which GABA is safe and eco-friendly, and also has the possibility of providing new health-benefited products enriched with GABA. Synthesis of GABA is catalyzed by glutamate decarboxylase, therefore, the optimal fermentation condition is mainly based on the biochemical properties of the enzyme. Major GABA producing microorganisms are lactic acid bacteria (LAB), which make food spoilage pathogens unable to grow and act as probiotics in the gastrointestinal tract. The major factors affecting the production of GABA by microbial fermentation are temperature, pH, fermentation time and different media additives, therefore, these factors are summarized to provide the most up-dated information for effective GABA synthesis. There has been a huge accumulation of knowledge on GABA application for human health accompanying with a demand on natural GABA supply. Only the GABA production by microorganisms can fulfill the demand with GABA-enriched health beneficial foods. PMID:24031948

  18. The Arabidopsis her1 mutant implicates GABA in E-2-hexenal responsiveness.

    PubMed

    Mirabella, Rossana; Rauwerda, Han; Struys, Eduard A; Jakobs, Cornelis; Triantaphylidès, Christian; Haring, Michel A; Schuurink, Robert C

    2008-01-01

    When wounded or attacked by herbivores or pathogens, plants produce a blend of six-carbon alcohols, aldehydes and esters, known as C6-volatiles. Undamaged plants, when exposed to C6-volatiles, respond by inducing defense-related genes and secondary metabolites, suggesting that C6-volatiles can act as signaling molecules regulating plant defense responses. However, to date, the molecular mechanisms by which plants perceive and respond to these volatiles are unknown. To elucidate such mechanisms, we decided to isolate Arabidopsis thaliana mutants in which responses to C6-volatiles were altered. We observed that treatment of Arabidopsis seedlings with the C6-volatile E-2-hexenal inhibits root elongation. Among C6-volatiles this response is specific to E-2-hexenal, and is not dependent on ethylene, jasmonic and salicylic acid. Using this bioassay, we isolated 18 E-2-hexenal-response (her) mutants that showed sustained root growth after E-2-hexenal treatment. Here, we focused on the molecular characterization of one of these mutants, her1. Microarray and map-based cloning revealed that her1 encodes a gamma-amino butyric acid transaminase (GABA-TP), an enzyme that degrades GABA. As a consequence of the mutation, her1 plants accumulate high GABA levels in all their organs. Based on the observation that E-2-hexenal treatment induces GABA accumulation, and that high GABA levels confer resistance to E-2-hexenal, we propose a role for GABA in mediating E-2-hexenal responses. PMID:17971036

  19. Co-Localization of GABA Shunt Enzymes for the Efficient Production of Gamma-Aminobutyric Acid via GABA Shunt Pathway in Escherichia coli.

    PubMed

    Pham, Van Dung; Somasundaram, Sivachandiran; Park, Si Jae; Lee, Seung Hwan; Hong, Soon Ho

    2016-04-28

    Gamma-aminobutyric acid (GABA) is a non-protein amino acid, which is an important inhibitor of neurotransmission in the human brain. GABA is also used as the precursor of biopolymer Nylon-4 production. In this study, the carbon flux from the tricarboxylic acid cycle was directed to the GABA shunt pathway for the production of GABA from glucose. The GABA shunt enzymes succinate-semialdehyde dehydrogenase (GabD) and GABA aminotransferase (GabT) were co-localized along with the GABA transporter (GadC) by using a synthetic scaffold complex. The co-localized enzyme scaffold complex produced 0.71 g/l of GABA from 10 g/l of glucose. Inactivation of competing metabolic pathways in mutant E. coli strains XBM1 and XBM6 increased GABA production 13% to reach 0.80 g/l GABA by the enzymes co-localized and expressed in the mutant strains. The recombinant E. coli system developed in this study demonstrated the possibility of the pathway of the GABA shunt as a novel GABA production pathway. PMID:26838342

  20. Synthesis and Proton NMR Spectroscopy of Intra-Vesicular Gamma-Aminobutyric Acid (GABA)*

    PubMed Central

    Wang, Luke Y.-J.; Tong, Rong; Kohane, Daniel S.

    2014-01-01

    We report the synthesis of vesicles containing gamma-aminobutyric acid (GABA), and their proton nuclear magnetic resonance (1H NMR) spectra. These vesicles were constructed to more closely mimic the intracellular environment wherein GABA exists. For this study, these GABA-containing vesicles were examined under 1H NMR as a potential platform for future studies on the differences between aqueous phantoms, ex vivo brain extracts, and in vivo magnetic resonance spectroscopy results. We found that intra-vesicular GABA faithfully yielded the chemical shifts and J-coupling constants of free aqueous GABA, alongside the chemical shift signals of the vesicle wall. PMID:24109882

  1. A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.

    PubMed

    Lingeshwar, Poorella; Kaur, Gurpreet; Singh, Neetu; Singh, Seema; Mishra, Akanksha; Shukla, Shubha; Ramakrishna, Rachumallu; Laxman, Tulsankar Sachin; Bhatta, Rabi Sankar; Siddiqui, Hefazat H; Hanif, Kashif

    2016-02-01

    Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of γ-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1α was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 ± 4.80 mm Hg, p < 0.001; 28.37 ± 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1α in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH. PMID:26608704

  2. Acid Stimulation (Sour Taste) Elicits GABA and Serotonin Release from Mouse Taste Cells

    PubMed Central

    Huang, Yijen A.; Pereira, Elizabeth; Roper, Stephen D.

    2011-01-01

    Several transmitter candidates including serotonin (5-HT), ATP, and norepinephrine (NE) have been identified in taste buds. Recently, γ-aminobutyric acid (GABA) as well as the associated synthetic enzymes and receptors have also been identified in taste cells. GABA reduces taste-evoked ATP secretion from Receptor cells and is considered to be an inhibitory transmitter in taste buds. However, to date, the identity of GABAergic taste cells and the specific stimulus for GABA release are not well understood. In the present study, we used genetically-engineered Chinese hamster ovary (CHO) cells stably co-expressing GABAB receptors and Gαqo5 proteins to measure GABA release from isolated taste buds. We recorded robust responses from GABA biosensors when they were positioned against taste buds isolated from mouse circumvallate papillae and the buds were depolarized with KCl or a stimulated with an acid (sour) taste. In contrast, a mixture of sweet and bitter taste stimuli did not trigger GABA release. KCl- or acid-evoked GABA secretion from taste buds was Ca2+-dependent; removing Ca2+ from the bathing medium eliminated GABA secretion. Finally, we isolated individual taste cells to identify the origin of GABA secretion. GABA was released only from Presynaptic (Type III) cells and not from Receptor (Type II) cells. Previously, we reported that 5-HT released from Presynaptic cells inhibits taste-evoked ATP secretion. Combined with the recent findings that GABA depresses taste-evoked ATP secretion [1], the present results indicate that GABA and 5-HT are inhibitory transmitters in mouse taste buds and both likely play an important role in modulating taste responses. PMID:22028776

  3. An analysis of [3H]gamma-aminobutyric acid (GABA) binding in the human brain.

    PubMed

    Lloyd, K G; Dreksler, S

    1979-03-01

    The binding of [3H]GABA to membranes prepared from human brains obtained post morten was examined. This binding was independent of patient sex, age (16--80 years), postmortem interval (4--33 h) or storage time when frozen (0-64 months). In preparations from cerebellar cortex various compounds displaced [3H]GABA binding with the following order of potency: muscimol greater than 3-aminopropanesulfonic acid greater than GABA greater than imidazoleacet acid greater than delta-amino-n-valeric acid greater than 3-hydroxyGABA greater than bicuculline. Other compounds active 'in vitro' included strychnine, homocarnosine and some (e.g. clozapine, thioridazine, pimozide) but not all (chlorpromazine, haloperiodol) neuroleptics. Compounds inactive 'in vitro' included aminooxyacetic acid, baclofen, picrotoxin, anticholinergics, metrazole, anticonvulsants and naloxone. Triton X-100 augmented the [3H]GABA binding (25 nM) by about 10--20-fold in most brain regions. [3H]GABA binding (IC50) was altered in Huntington's chorea and Reye's syndrome, but not in schizophrenics (4-neuroleptic-treated patients) or sudden infant death syndrome. The data presented strongly support the proposal that the measurement of [3H]GABA binding in postmortem human brain offers a reflection of the state of the physiologically relevant GABA receptor. PMID:218679

  4. A functional role for both γ-aminobutyric acid (GABA) transporter-1 and GABA transporter-3 in the modulation of extracellular GABA and GABAergic tonic conductances in the rat hippocampus

    PubMed Central

    Kersanté, Flavie; Rowley, Samuel C S; Pavlov, Ivan; Gutièrrez-Mecinas, María; Semyanov, Alexey; Reul, Johannes M H M; Walker, Matthew C; Linthorst, Astrid C E

    2013-01-01

    Tonic γ-aminobutyric acid (GABA)A receptor-mediated signalling controls neuronal network excitability in the hippocampus. Although the extracellular concentration of GABA (e[GABA]) is critical in determining tonic conductances, knowledge on how e[GABA] is regulated by different GABA transporters (GATs) in vivo is limited. Therefore, we studied the role of GATs in the regulation of hippocampal e[GABA] using in vivo microdialysis in freely moving rats. Here we show that GAT-1, which is predominantly presynaptically located, is the major GABA transporter under baseline, quiescent conditions. Furthermore, a significant contribution of GAT-3 in regulating e[GABA] was revealed by administration of the GAT-3 inhibitor SNAP-5114 during simultaneous blockade of GAT-1 by NNC-711. Thus, the GABA transporting activity of GAT-3 (the expression of which is confined to astrocytes) is apparent under conditions in which GAT-1 is blocked. However, sustained neuronal activation by K+-induced depolarization caused a profound spillover of GABA into the extrasynaptic space and this increase in e[GABA] was significantly potentiated by sole blockade of GAT-3 (i.e. even when uptake of GAT-1 is intact). Furthermore, experiments using tetrodotoxin to block action potentials revealed that GAT-3 regulates extrasynaptic GABA levels from action potential-independent sources when GAT-1 is blocked. Importantly, changes in e[GABA] resulting from both GAT-1 and GAT-3 inhibition directly precipitate changes in tonic conductances in dentate granule cells as measured by whole-cell patch-clamp recording. Thus, astrocytic GAT-3 contributes to the regulation of e[GABA] in the hippocampus in vivo and may play an important role in controlling the excitability of hippocampal cells when network activity is increased. PMID:23381899

  5. A fluorescence-coupled assay for gamma aminobutyric acid (GABA) reveals metabolic stress-induced modulation of GABA content in neuroendocrine cancer.

    PubMed

    Ippolito, Joseph E; Piwnica-Worms, David

    2014-01-01

    Pathways involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA) have been implicated in the pathogenesis of high grade neuroendocrine (NE) neoplasms as well as neoplasms from a non-NE lineage. Using The Cancer Genome Atlas, overexpression of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1), was found to be associated with decreased disease free-survival in prostate adenocarcinoma and decreased overall survival in clear cell renal cell carcinomas. Furthermore, GAD1 was found to be expressed in castrate-resistant prostate cancer cell lines, but not androgen-responsive cell lines. Using a novel fluorescence-coupled enzymatic microplate assay for GABA mediated through reduction of resazurin in a prostate neuroendocrine carcinoma (PNEC) cell line, acid microenvironment-induced stress increased GABA levels while alkaline microenvironment-induced stress decreased GABA through modulation of GAD1 and glutamine synthetase (GLUL) activities. Moreover, glutamine but not glucose deprivation decreased GABA through modulation of GLUL. Consistent with evidence in prokaryotic and eukaryotic organisms that GABA synthesis mediated through GAD1 may play a crucial role in surviving stress, GABA may be an important mediator of stress survival in neoplasms. These findings identify GABA synthesis and metabolism as a potentially important pathway for regulating cancer cell stress response as well as a potential target for therapeutic strategies. PMID:24551133

  6. A tonoplast Glu/Asp/GABA exchanger that affects tomato fruit amino acid composition.

    PubMed

    Snowden, Christopher J; Thomas, Benjamin; Baxter, Charles J; Smith, J Andrew C; Sweetlove, Lee J

    2015-03-01

    Vacuolar accumulation of acidic metabolites is an important aspect of tomato fruit flavour and nutritional quality. The amino acids Asp and Glu accumulate to high concentrations during ripening, while γ-aminobutyrate (GABA) shows an approximately stoichiometric decline. Given that GABA can be catabolised to form Glu and subsequently Asp, and the requirement for the fruit to maintain osmotic homeostasis during ripening, we hypothesised the existence of a tonoplast transporter that exports GABA from the vacuole in exchange for import of either Asp or Glu. We show here that the tomato vacuolar membrane possesses such a transport property: transport of Glu across isolated tonoplast vesicle membranes was trans-stimulated in counterexchange mode by GABA, Glu and Asp. We identified SlCAT9 as a candidate protein for this exchanger using quantitative proteomics of a tonoplast-enriched membrane fraction. Transient expression of a SlCAT9-YFP fusion in tobacco confirmed a tonoplast localisation. The function of the protein was examined by overexpression of SlCAT9 in transgenic tomato plants. Tonoplast vesicles isolated from transgenic plants showed higher rates of Glu and GABA transport than wild-type (WT) only when assayed in counterexchange mode with Glu, Asp, or GABA. Moreover, there were substantial increases in the content of all three cognate amino acids in ripe fruit from the transgenic plants. We conclude that SlCAT9 is a tonoplast Glu/Asp/GABA exchanger that strongly influences the accumulation of these amino acids during fruit development. PMID:25602029

  7. Role of GABAB Receptor and L-Arg in GABA-Induced Vasorelaxation in Non-diabetic and Streptozotocin-Induced Diabetic Rat Vessels

    PubMed Central

    Kharazmi, Fatemah; Soltani, Nepton; Rezaei, Sana; Keshavarz, Mansoor; Farsi, Leila

    2015-01-01

    Background: Hypertension is considered an independent risk factor for cardiovascular mortality in diabetic patients. The present study was designed to determine the role of gamma amino butyric acid B (GABAB) receptor and L-arginine (L-Arg) in GABA-induced vasorelaxation in normal and streptozotocin-induced diabetic rat vessels. Methods: Diabetes was induced by a single i.p. injection of streptozotocin (STZ, 60 mg/kg). Eight weeks later, superior mesenteric arteries of all groups were isolated and perfused according to the McGregor method. Results: Baseline perfusion pressure of STZ diabetic rats was significantly higher than non-diabetic rats in both intact and denuded endothelium. In the presence of faclofen, a selective GABAB receptor blocker, GABA-induced relaxation in intact and denuded endothelium mesenteric beds of STZ diabetic rats was suppressed, but this response in non-diabetic rats was not suppressed. Our results showed that in the presence of L-Arg, a nitric oxide precursor, GABA induced vasorelaxation in both diabetic and non-diabetic vessels. Conclusion: From the results of this study, it may be concluded that the vasorelaxatory effect of GABA in diabetic vessel is mediated by the GABAB receptor and nitric oxide, but it seems that in non-diabetic vessel GABAB receptor does not play any role in GABA-induced vasorelaxation, but nitric oxide induced GABA relaxation in non-diabetic vessel. PMID:25864813

  8. Contributions of GABA to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

    PubMed Central

    Silveri, Marisa M.

    2015-01-01

    There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol abuse disorders. PMID:24631274

  9. Differential effects of GABA in modulating nociceptive vs. non-nociceptive synapses.

    PubMed

    Wang, Y; Summers, T; Peterson, W; Miiller, E; Burrell, B D

    2015-07-01

    GABA (γ-amino-butyric acid) -mediated signaling is normally associated with synaptic inhibition due to ionotropic GABA receptors that gate an inward Cl(-) current, hyperpolarizing the membrane potential. However, there are also situations where ionotropic GABA receptors trigger a Cl(-) efflux that results in depolarization. The well-characterized central nervous system of the medicinal leech was used to study the functional significance of opposing effects of GABA at the synaptic circuit level. Specifically, we focused on synapses made by the nociceptive N cell and the non-nociceptive P (pressure) cell that converge onto a common postsynaptic target. It is already known that GABA hyperpolarizes the P cell, but depolarizes the N cell and that inhibition of ionotropic GABA receptors by bicuculline (BIC) has opposing effects on the synapses made by these two inputs; enhancing P cell synaptic transmission, but depressing N cell synapses. The goal of the present study was to determine whether the opposing effects of GABA were due to differences in Cl(-) homeostasis between the two presynaptic neurons. VU 0240551 (VU), an inhibitor of the Cl(-) exporter K-Cl co-transporter isoform 2 (KCC2), attenuated GABA-mediated hyperpolarization of the non-nociceptive afferent while bumetanide (BUM), an inhibitor of the Cl(-) importer Na-K-Cl co-transporter isoform 1 (NKCC1), reduced GABA-mediated depolarization of the nociceptive neuron. VU treatment also enhanced P cell synaptic signaling, similar to the previously observed effects of BIC and consistent with the idea that GABA inhibits synaptic signaling at the presynaptic level. BUM treatment depressed N cell synapses, again similar to what is observed following BIC treatment and suggests that GABA has an excitatory effect on these synapses. The opposing effects of GABA could also be observed at the behavioral level with BIC and VU increasing responsiveness to non-nociceptive stimulation while BIC and BUM decreased responsiveness

  10. Contents of Neo-flavored Tea (GABA Kintaro) Containing γ-Aminobutyric Acid

    NASA Astrophysics Data System (ADS)

    Shiraki, Yoshiya

    The contents of γ-aminobutyric acid (GABA), catechins, theaflavins, caffeine and pheophorbide-a in neo-flavored tea (GABA Kintaro tea) were analyzed. 1)The amounts of GABA were increased over 1.5mg/g by means of infrared ray irradiation with agitation treatment. 2)There was a tendency for the amount of catechins to be decreased by this treatment, whereas the amount of theaflavins tended to increase with the same treatment. The composition of these contents in this GABA Kintaro tea was almost the same as that of black tea. 3)There was a tendency for the amount of caffeine to be decreased by this treatment. 4)There was a tendency for the amount of pheophorbide-a to be increased by this treatment. 5)The result of this study showed that the amounts of GABA and theaflavins in this GABA Kintaro tea were higher than ordinary green tea but contained few catechins.It became clear that the amount of pheophorbide-a in this GABA Kintaro tea was less than the standard value established in processed chlorella.

  11. γ-Aminobutyric acid (GABA) homeostasis regulates pollen germination and polarized growth in Picea wilsonii.

    PubMed

    Ling, Yu; Chen, Tong; Jing, Yanping; Fan, Lusheng; Wan, Yinglang; Lin, Jinxing

    2013-11-01

    γ-Aminobutyric acid (GABA) is a four-carbon non-protein amino acid found in a wide range of organisms. Recently, GABA accumulation has been shown to play a role in the stress response and cell growth in angiosperms. However, the effect of GABA deficiency on pollen tube development remains unclear. Here, we demonstrated that specific concentrations of exogenous GABA stimulated pollen tube growth in Picea wilsonii, while an overdose suppressed pollen tube elongation. The germination percentage of pollen grains and morphological variations in pollen tubes responded in a dose-dependent manner to treatment with 3-mercaptopropionic acid (3-MP), a glutamate decarboxylase inhibitor, while the inhibitory effects could be recovered in calcium-containing medium supplemented with GABA. Using immunofluorescence labeling, we found that the actin cables were disorganized in 3-MP treated cells, followed by the transition of endo/exocytosis activating sites from the apex to the whole tube shank. In addition, variations in the deposition of cell wall components were detected upon labeling with JIM5, JIM7, and aniline blue. Our results demonstrated that calcium-dependent GABA signaling regulates pollen germination and polarized tube growth in P. wilsonii by affecting actin filament patterns, vesicle trafficking, and the configuration and distribution of cell wall components. PMID:23900837

  12. Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

    PubMed Central

    Ciranna, L

    2006-01-01

    The neurotransmitter serotonin (5-HT), widely distributed in the central nervous system (CNS), is involved in a large variety of physiological functions. In several brain regions 5-HT is diffusely released by volume transmission and behaves as a neuromodulator rather than as a “classical” neurotransmitter. In some cases 5-HT is co-localized in the same nerve terminal with other neurotransmitters and reciprocal interactions take place. This review will focus on the modulatory action of 5-HT on the effects of glutamate and γ-amino-butyric acid (GABA), which are the principal neurotransmitters mediating respectively excitatory and inhibitory signals in the CNS. Examples of interaction at pre-and/or post-synaptic levels will be illustrated, as well as the receptors involved and their mechanisms of action. Finally, the physiological meaning of neuromodulatory effects of 5-HT will be briefly discussed with respect to pathologies deriving from malfunctioning of serotonin system. PMID:18615128

  13. Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system.

    PubMed

    Awad, R; Levac, D; Cybulska, P; Merali, Z; Trudeau, V L; Arnason, J T

    2007-09-01

    In Canada, the use of botanical natural health products (NHPs) for anxiety disorders is on the rise, and a critical evaluation of their safety and efficacy is required. The purpose of this study was to determine whether commercially available botanicals directly affect the primary brain enzymes responsible for gamma-aminobutyric acid (GABA) metabolism. Anxiolytic plants may interact with either glutamic acid decarboxylase (GAD) or GABA transaminase (GABA-T) and ultimately influence brain GABA levels and neurotransmission. Two in vitro rat brain homogenate assays were developed to determine the inhibitory concentrations (IC50) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (IC50 values greater than 1 mg/mL) and are therefore unlikely to affect GABA metabolism as tested. The aqueous extract of Melissa officinalis (lemon balm) exhibited the greatest inhibition of GABA-T activity (IC50 = 0.35 mg/mL). Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity by over 40% at a dose of 1 mg/mL. On the other hand, both Matricaria recutita (German chamomile) and Humulus lupulus (hops) showed significant inhibition of GAD activity (0.11-0.65 mg/mL). Several of these species may therefore warrant further pharmacological investigation. The relation between enzyme activity and possible in vivo mode of action is discussed. PMID:18066140

  14. Metabolic pathways regulated by γ-aminobutyric acid (GABA) contributing to heat tolerance in creeping bentgrass (Agrostis stolonifera).

    PubMed

    Li, Zhou; Yu, Jingjin; Peng, Yan; Huang, Bingru

    2016-01-01

    γ-Aminobutyric acid is a non-protein amino acid involved in various metabolic processes. The objectives of this study were to examine whether increased GABA could improve heat tolerance in cool-season creeping bentgrass through physiological analysis, and to determine major metabolic pathways regulated by GABA through metabolic profiling. Plants were pretreated with 0.5 mM GABA or water before exposed to non-stressed condition (21/19 °C) or heat stress (35/30 °C) in controlled growth chambers for 35 d. The growth and physiological analysis demonstrated that exogenous GABA application significantly improved heat tolerance of creeping bentgrass. Metabolic profiling found that exogenous application of GABA led to increases in accumulations of amino acids (glutamic acid, aspartic acid, alanine, threonine, serine, and valine), organic acids (aconitic acid, malic acid, succinic acid, oxalic acid, and threonic acid), sugars (sucrose, fructose, glucose, galactose, and maltose), and sugar alcohols (mannitol and myo-inositol). These findings suggest that GABA-induced heat tolerance in creeping bentgrass could involve the enhancement of photosynthesis and ascorbate-glutathione cycle, the maintenance of osmotic adjustment, and the increase in GABA shunt. The increased GABA shunt could be the supply of intermediates to feed the tricarboxylic acid cycle of respiration metabolism during a long-term heat stress, thereby maintaining metabolic homeostasis. PMID:27455877

  15. Metabolic pathways regulated by γ-aminobutyric acid (GABA) contributing to heat tolerance in creeping bentgrass (Agrostis stolonifera)

    PubMed Central

    Li, Zhou; Yu, Jingjin; Peng, Yan; Huang, Bingru

    2016-01-01

    γ-Aminobutyric acid is a non-protein amino acid involved in various metabolic processes. The objectives of this study were to examine whether increased GABA could improve heat tolerance in cool-season creeping bentgrass through physiological analysis, and to determine major metabolic pathways regulated by GABA through metabolic profiling. Plants were pretreated with 0.5 mM GABA or water before exposed to non-stressed condition (21/19 °C) or heat stress (35/30 °C) in controlled growth chambers for 35 d. The growth and physiological analysis demonstrated that exogenous GABA application significantly improved heat tolerance of creeping bentgrass. Metabolic profiling found that exogenous application of GABA led to increases in accumulations of amino acids (glutamic acid, aspartic acid, alanine, threonine, serine, and valine), organic acids (aconitic acid, malic acid, succinic acid, oxalic acid, and threonic acid), sugars (sucrose, fructose, glucose, galactose, and maltose), and sugar alcohols (mannitol and myo-inositol). These findings suggest that GABA-induced heat tolerance in creeping bentgrass could involve the enhancement of photosynthesis and ascorbate-glutathione cycle, the maintenance of osmotic adjustment, and the increase in GABA shunt. The increased GABA shunt could be the supply of intermediates to feed the tricarboxylic acid cycle of respiration metabolism during a long-term heat stress, thereby maintaining metabolic homeostasis. PMID:27455877

  16. GABA, 5-HT and amino acids in the rotifers Brachionus plicatilis and Brachionus rotundiformis.

    PubMed

    Gallardo, W G; Hagiwara, A; Hara, K; Soyano, K; Snell, T W

    2000-11-01

    gamma-Aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) have been shown to increase the reproduction of the Brachionus plicatilis (NH3L strain). In the present study, the endogenous presence of GABA and 5-HT in the rotifers B. plicatilis (NH3L and Kamiura strains) and Brachionus rotundiformis (Langkawi strain) were confirmed by dot blot immunoassay and high-performance liquid chromatography (HPLC). HPLC showed that GABA and 5-HT concentrations in the three rotifer strains range from 71 to 188 pmol/mg and from 12 to 64 pmol/mg, respectively. A total of 33 amino acids were also detected in B. plicatilis and B. rotundiformis, with glutamic acid, serine, glycine, taurine, threonine, alanine, arginine, proline, valine and isoleucine in high concentrations relative to other amino acids. PMID:11118940

  17. Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA

    PubMed Central

    Wang, Ping; Eshaq, Randa S.; Meshul, Charles K.; Moore, Cynthia; Hood, Rebecca L.; Leidenheimer, Nancy J.

    2015-01-01

    GABAA receptors mediate fast inhibitory neurotransmission in the brain. Dysfunction of these receptors is associated with various psychiatric/neurological disorders and drugs targeting this receptor are widely used therapeutic agents. Both the efficacy and plasticity of GABAA receptor-mediated neurotransmission depends on the number of surface GABAA receptors. An understudied aspect of receptor cell surface expression is the post-translational regulation of receptor biogenesis within the endoplasmic reticulum (ER). We have previously shown that exogenous GABA can act as a ligand chaperone of recombinant GABAA receptors in the early secretory pathway leading us to now investigate whether endogenous GABA facilitates the biogenesis of GABAA receptors in primary cerebral cortical cultures. In immunofluorescence labeling experiments, we have determined that neurons expressing surface GABAA receptors contain both GABA and its degradative enzyme GABA transaminase (GABA-T). Treatment of neurons with GABA-T inhibitors, a treatment known to increase intracellular GABA levels, decreases the interaction of the receptor with the ER quality control protein calnexin, concomittantly increasing receptor forward-trafficking and plasma membrane insertion. The effect of GABA-T inhibition on the receptor/calnexin interaction is not due to the activation of surface GABAA or GABAB receptors. Consistent with our hypothesis that GABA acts as a cognate ligand chaperone in the ER, immunogold-labeling of rodent brain slices reveals the presence of GABA within the rough ER. The density of this labeling is similar to that present in mitochondria, the organelle in which GABA is degraded. Lastly, the effect of GABA-T inhibition on the receptor/calnexin interaction was prevented by pretreatment with a GABA transporter inhibitor. Together, these data indicate that endogenous GABA acts in the rough ER as a cognate ligand chaperone to facilitate the biogenesis of neuronal GABAA receptors. PMID

  18. An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABAA receptor site.

    PubMed Central

    Chambon, J P; Feltz, P; Heaulme, M; Restle, S; Schlichter, R; Biziere, K; Wermuth, C G

    1985-01-01

    In view of finding a new gamma-aminobutyric acid (GABA) receptor ligand we synthesized an arylaminopyridazine derivative of GABA, SR 95103 [2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride]. SR 95103 displaced [3H]GABA from rat brain membranes with an apparent Ki of 2.2 microM and a Hill number near 1.0. SR 95103 (1-100 microM) antagonized the GABA-mediated enhancement of [3H]diazepam binding in a concentration-dependent manner without affecting [3H]diazepam binding per se. SR 95103 competitively antagonized GABA-induced membrane depolarization in rat spinal ganglia. In all these experiments, the potency of SR 95103 was close to that of bicuculline. SR 95103 (100 microM) did not interact with a variety of central receptors--in particular the GABAB, the strychnine, and the glutamate receptors--did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and glutamic acid decarboxylase activities. Intraperitoneally administered SR 95103 elicited clonicotonic seizures in mice (ED50 = 180 mg/kg). On the basis of these results it is postulated that St 95103 is a competitive antagonist of GABA at the GABAA receptor site. In addition to being an interesting lead structure for the search of GABA ligands, SR 95103 could also be a useful tool to investigate GABA receptor subtypes because it is freely soluble in water and chemically stable. Images PMID:2984669

  19. γ-Aminobutyric acid (GABA) concentration inversely correlates with basal perfusion in human occipital lobe.

    PubMed

    Donahue, Manus J; Rane, Swati; Hussey, Erin; Mason, Emily; Pradhan, Subechhya; Waddell, Kevin W; Ally, Brandon A

    2014-03-01

    Commonly used neuroimaging approaches in humans exploit hemodynamic or metabolic indicators of brain function. However, fundamental gaps remain in our ability to relate such hemo-metabolic reactivity to neurotransmission, with recent reports providing paradoxical information regarding the relationship among basal perfusion, functional imaging contrast, and neurotransmission in awake humans. Here, sequential magnetic resonance spectroscopy (MRS) measurements of the primary inhibitory neurotransmitter, γ-aminobutyric acid (GABA+macromolecules normalized by the complex N-acetyl aspartate-N-acetyl aspartyl glutamic acid: [GABA(+)]/[NAA-NAAG]), and magnetic resonance imaging (MRI) measurements of perfusion, fractional gray-matter volume, and arterial arrival time (AAT) are recorded in human visual cortex from a controlled cohort of young adult male volunteers with neurocognitive battery-confirmed comparable cognitive capacity (3 T; n=16; age=23±3 years). Regression analyses reveal an inverse correlation between [GABA(+)]/[NAA-NAAG] and perfusion (R=-0.46; P=0.037), yet no relationship between AAT and [GABA(+)]/[NAA-NAAG] (R=-0.12; P=0.33). Perfusion measurements that do not control for AAT variations reveal reduced correlations between [GABA(+)]/[NAA-NAAG] and perfusion (R=-0.13; P=0.32). These findings largely reconcile contradictory reports between perfusion and inhibitory tone, and underscore the physiologic origins of the growing literature relating functional imaging signals, hemodynamics, and neurotransmission. PMID:24398941

  20. Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain.

    PubMed

    Vazquez-DeRose, Jacqueline; Schwartz, Michael D; Nguyen, Alexander T; Warrier, Deepti R; Gulati, Srishti; Mathew, Thomas K; Neylan, Thomas C; Kilduff, Thomas S

    2016-03-01

    Hypocretin/orexin (HCRT) neurons provide excitatory input to wake-promoting brain regions including the basal forebrain (BF). The dual HCRT receptor antagonist almorexant (ALM) decreases waking and increases sleep. We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals. To test this hypothesis, rats were given bilateral IgG-192-saporin injections, which predominantly targets cholinergic BF neurons. BFx and intact rats were then given oral ALM, the benzodiazepine agonist zolpidem (ZOL) or vehicle (VEH) at lights-out. ALM was less effective than ZOL at inducing sleep in BFx rats compared to controls. BF adenosine (ADO), γ-amino-butyric acid (GABA), and glutamate levels were then determined via microdialysis from intact, freely behaving rats following oral ALM, ZOL or VEH. ALM increased BF ADO and GABA levels during waking and mixed vigilance states, and preserved sleep-associated increases in GABA under low and high sleep pressure conditions. ALM infusion into the BF also enhanced cortical ADO release, demonstrating that HCRT input is critical for ADO signaling in the BF. In contrast, oral ZOL and BF-infused ZOL had no effect on ADO levels in either BF or cortex. ALM increased BF ADO (an endogenous sleep-promoting substance) and GABA (which is increased during normal sleep), and required an intact BF for maximal efficacy, whereas ZOL blocked sleep-associated BF GABA release, and required no functional contribution from the BF to induce sleep. ALM thus induces sleep by facilitating the neural mechanisms underlying the normal transition to sleep. PMID:25431268

  1. Dopamine-related drugs act presynaptically to potentiate GABA(A) receptor currents in VTA dopamine neurons.

    PubMed

    Michaeli, Avner; Yaka, Rami

    2011-01-01

    Electrical activity of ventral tegmental area (VTA) dopamine (DA) neurons is immediately inhibited following in vivo administration of cocaine and other DA-related drugs. While various forms of synaptic modulation were demonstrated in the VTA following exposure to DA-related drugs, comprehensive understanding of their ability to inhibit the activity of DA neurons, however, is still lacking. In this study, using whole-cell patch-clamp recordings from rat brain slices, a novel form of synaptic modulation induced by DA-related drugs was isolated. DA exposure was shown to cause potentiation of γ-amino-butyric acid (GABA) receptor type A (GABA(A)R)-mediated evoked inhibitory postsynaptic currents (eIPSCs), recorded from VTA DA neurons, under conditions of potassium channels blockade. The potentiation of these eIPSCs lasted for more than twenty minutes, could be mimicked by activation of D2-like but not D1-like DA receptors, and was accompanied by an increase in the frequency of GABA(A)R-mediated spontaneous miniature inhibitory postsynaptic currents (mIPSCs). Furthermore, exposure to inhibitors of DA transporter (DAT) led to potentiation of GABA(A) currents in a manner similar to the DA-mediated potentiation. Finally, a prolonged presence of l-NAME, an inhibitor of nitric-oxide (NO) signaling was found to conceal the potentiation of GABA(A) currents induced by the DA-related drugs. Taken together, this study demonstrates a new modulatory form of VTA GABA(A) neurotransmission mediated by DA-related drugs. These results also suggest better understanding of the initial inhibitory action of DA-related drugs on the activity of DA neurons in the VTA. PMID:21527263

  2. Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina.

    PubMed Central

    Cutting, G R; Lu, L; O'Hara, B F; Kasch, L M; Montrose-Rafizadeh, C; Donovan, D M; Shimada, S; Antonarakis, S E; Guggino, W B; Uhl, G R

    1991-01-01

    Type A gamma-aminobutyric acid (GABAA) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. We have used these highly conserved regions to identify additional members of this family by using the polymerase chain reaction (PCR). One PCR product was used to isolate a full-length cDNA from a human retina cDNA library. The mature protein predicted from this cDNA sequence in 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABAA subunits. This gene is expressed primarily in the retina but transcripts are also detected in the brain, lung, and thymus. Injection of Xenopus oocytes with RNA transcribed in vitro produces a GABA-responsive chloride conductance and expression of the cDNA in COS cells yields GABA-displaceable muscimol binding. These features are consistent with our identification of a GABA subunit, GABA rho 1, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family. Images PMID:1849271

  3. Selective antagonism of the GABA(A) receptor by ciprofloxacin and biphenylacetic acid.

    PubMed

    Green, M A; Halliwell, R F

    1997-10-01

    1. Previous studies have shown that ciprofloxacin and biphenylacetic acid (BPAA) synergistically inhibit y-aminobutyric acid (GABA)A receptors. In the present study, we have investigated the actions of these two drugs on other neuronal ligand-gated ion channels. 2. Agonist-evoked depolarizations were recorded from rat vagus and optic nerves in vitro by use of an extracellular recording technique. 3. GABA (50 microM)-evoked responses, in the vagus nerve in vitro, were inhibited by bicuculline (0.3-10 microM) and picrotoxin (0.3-10 microM), with IC50 values and 95% confidence intervals (CI) of 1.2 microM (1.1-1.4) and 3.6 microM (3.0-4.3), respectively, and were potentiated by sodium pentobarbitone (30 microM) and diazepam (1 microM) to (mean+/-s.e.mean) 168+/-18% and 117+/-4% of control, respectively. 5-Hydroxytryptamine (5-HT; 0.5 microM)-evoked responses were inhibited by MDL 72222 (1 microM) to 10+/-4% of control; DMPP (10 microM)-evoked responses were inhibited by hexamethonium (100 microM) to 12+/-5% of control, and alphabetaMeATP (30 microM)-evoked responses were inhibited by PPADS (10 microM) to 21+/-5% of control. Together, these data are consistent with activation of GABA(A), 5-HT3, nicotinic ACh and P2X receptors, respectively. 4 Ciprofloxacin (10-3000 microM) inhibited GABA(A)-mediated responses in the vagus nerve with an IC50 (and 95% CI) of 202 microM (148-275). BPAA (1-1000 microM) had little or no effect on the GABA(A)-mediated response but concentration-dependently potentiated the effects of ciprofloxacin by up to 33,000 times. 5. Responses mediated by 5-HT3, nicotinic ACh and P2X receptors in the vagus nerve and strychnine-sensitive glycine receptors in the optic nerve were little or unaffected by ciprofloxacin (100 microM), BPAA (100 microM) or the combination of these drugs (both at 100 microM). 6. GABA (1 mM)-evoked responses in the optic nerve were inhibited by bicuculline with an IC50 of 3.6 microM (2.8-4.5), a value not significantly different

  4. Glutamate and GABA contributions to medial prefrontal cortical activity to emotion: implications for mood disorders.

    PubMed

    Stan, Ana D; Schirda, Claudiu V; Bertocci, Michele A; Bebko, Genna M; Kronhaus, Dina M; Aslam, Haris A; LaBarbara, Eduard J; Tanase, Costin; Lockovich, Jeanette C; Pollock, Myrna H; Stiffler, Richelle S; Phillips, Mary L

    2014-09-30

    The dorsomedial prefrontal cortex (MdPFC) and anterior cingulate cortices (ACC) play a critical role in implicit emotion regulation; however the understanding of the specific neurotransmitters that mediate such role is lacking. In this study, we examined relationships between MdPFC concentrations of two neurotransmitters, glutamate and γ-amino butyric acid (GABA), and BOLD activity in ACC during performance of an implicit facial emotion-processing task. Twenty healthy volunteers, aged 20-35 years, were scanned while performing an implicit facial emotion-processing task, whereby presented facial expressions changed from neutral to one of the four emotions: happy, anger, fear, or sad. Glutamate concentrations were measured before and after the emotion-processing task in right MdPFC using magnetic resonance spectroscopy (MRS). GABA concentrations were measured in bilateral MdPFC after the emotion-processing task. Multiple regression models were run to determine the relative contribution of glutamate and GABA concentration, age, and gender to BOLD signal in ACC to each of the four emotions. Multiple regression analyses revealed a significant negative correlation between MdPFC GABA concentration and BOLD signal in subgenual ACC (p<0.05, corrected) to sad versus shape contrast. For the anger versus shape contrast, there was a significant negative correlation between age and BOLD signal in pregenual ACC (p<0.05, corrected) and a positive correlation between MdPFC glutamate concentration (pre-task) and BOLD signal in pregenual ACC (p<0.05, corrected). Our findings are the first to provide insight into relationships between MdPFC neurotransmitter concentrations and ACC BOLD signal, and could further understanding of molecular mechanisms underlying emotion processing in healthy and mood-disordered individuals. PMID:24973815

  5. The inhibitory role of γ-aminobutyric acid (GABA) on immunomodulation of Pacific oyster Crassostrea gigas.

    PubMed

    Li, Meijia; Qiu, Limei; Wang, Lingling; Wang, Weilin; Xin, Lusheng; Li, Yiqun; Liu, Zhaoqun; Song, Linsheng

    2016-05-01

    γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter to suppress the immune-mediated pro-inflammatory reactions, and it has been used in the treatment of many inflammation-related diseases in vertebrates, while its immunomodulatory role in invertebrates has never been reported. In the present study, GABA was found to exist in the hemolymph of Pacific oyster Crassostrea gigas, and its concentration decreased slightly from 8.00 ± 0.37 μmol L(-1) at normal condition to 7.73 ± 0.15 μmol L(-1) at 6 h after LPS stimulation, and then increased to 9.34 ± 0.15 μmol L(-1), 8.86 ± 0.68 μmol L(-1) at 12 h and 48 h, respectively. After LPS stimulation, the mRNA expressions of pro-inflammatory cytokines (CgIL-17 and CgTNF) and immune effectors (CgSOD and CgBPI), and the protein expression of NOS increased significantly, and these increased trends were remarkably inhibited by GABA stimulation. At the same time, the phagocytosis rate and apoptosis rate of immunocytes also increased obviously after LPS stimulation, whereas the increase was repressed with the addition of GABA. The results collectively demonstrated that GABA was an indispensable inhibitory agent for both humoral and cellular immune response, which mainly functioned at the late phase of immune response to avoid the excess immune reactions and maintain the immune homeostasis. PMID:26975413

  6. Guanidino acids act as rho1 GABA(C) receptor antagonists.

    PubMed

    Chebib, Mary; Gavande, Navnath; Wong, Kit Yee; Park, Anna; Premoli, Isabella; Mewett, Kenneth N; Allan, Robin D; Duke, Rujee K; Johnston, Graham A R; Hanrahan, Jane R

    2009-10-01

    GABA(C) receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, beta-alanine and taurine were evaluated at human rho(1)GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-guanidinopropionic acid (IC(50) = 2.2 microM) and guanidinoacetic acid (IC(50) = 5.4 microM; K (B) = 7.75 microM [pK (B) = 5.11 +/- 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the beta-alanine and GABA guanidino analogs showed reduced activity, indicating the distance between the carboxyl carbon and terminal nitrogen of the guanidino group is critical for activity. Substituting the C2-position of guanidinoacetic acid with various alkyl groups reduced activity indicating that steric effects may impact on activity. The results of this study contribute to the structure-activity-relationship profile required in developing novel therapeutic agents. PMID:19387831

  7. Development of the GABA-ergic signaling system and its role in larval swimming in sea urchin.

    PubMed

    Katow, Hideki; Abe, Kouki; Katow, Tomoko; Zamani, Alemeh; Abe, Hirokazu

    2013-05-01

    The present study aimed to elucidate the development and γ-amino butyric acid (GABA)-ergic regulation of larval swimming in the sea urchin Hemicentrotus pulcherrimus by cloning glutamate decarboxylase (Hp-gad), GABAA receptor (Hp-gabrA) and GABAA receptor-associated protein (Hp-gabarap), and by performing immunohistochemistry. The regulation of larval swimming was increasingly dependent on the GABAergic system, which was active from the 2 days post-fertilization (d.p.f.) pluteus stage onwards. GABA-immunoreactive cells were detected as a subpopulation of secondary mesenchyme cells during gastrulation and eventually constituted the ciliary band and a subpopulation of blastocoelar cells during the pluteus stage. Hp-gad transcription was detected by RT-PCR during the period when Hp-Gad-positive cells were seen as a subpopulation of blastocoelar cells and on the apical side of the ciliary band from the 2 d.p.f. pluteus stage. Consistent with these observations, inhibition of GAD with 3-mercaptopropioninc acid inhibited GABA immunoreactivity and larval swimming dose dependently. Hp-gabrA amplimers were detected weakly in unfertilized eggs and 4 d.p.f. plutei but strongly from fertilized eggs to 2 d.p.f. plutei, and Hp-GabrA, together with GABA, was localized at the ciliary band in association with dopamine receptor D1 from the two-arm pluteus stage. Hp-gabarap transcription and protein expression were detected from the swimming blastula stage. Inhibition of the GABAA receptor by bicuculline inhibited larval swimming dose dependently. Inhibition of larval swimming by either 3-mercaptopropionic acid or bicuculline was more severe in older larvae (17 and 34 d.p.f. plutei) than in younger ones (1 d.p.f. prism larvae). PMID:23307803

  8. Effect of diphenylhydantoin on gamma aminobutyric acid (GABA) and succinate activity in rat Purkinje cells.

    PubMed Central

    Hitchcock, E; Gabra-Sanders, T

    1977-01-01

    A study has been made of the effect of diphenylhydantoin (DPH) upon the levels of gamma aminobutyric acid (GABA) and succinic dehydrogenase in rat Purkinje cells. DPH was administered over 26 days in chronic experiments using controls receiving the same injection vehicle without DPH. Animals in this group received daily 1.25 mg/kg body weight, 12.5 mg/kg body weight, and 50 mg/kg body weight DPH. Acute experiments were carried out over the course of not more than four days, three groups of animals receiving 75 mg/kg body weight, 87.5 mg/kg body weight, and 100 mg/kg body weight DPH. No effect upon succinic dehydrogenase could be demonstrated at any dose level. There was a significant progressive loss of GABA with increasing dosage of DPH. Images PMID:903771

  9. Levofloxacin, an optical isomer of ofloxacin, has attenuated epileptogenic activity in mice and inhibitory potency in GABA receptor binding.

    PubMed

    Akahane, K; Tsutomi, Y; Kimura, Y; Kitano, Y

    1994-01-01

    The combination of some new quinolone antibacterials with 4-biphenylacetic acid (BPAA) functionally inhibits the gamma-amino-butyric acid (GABA) receptors and thereby induces clonic convulsions. We examined the effects of ofloxacin and its optical isomers on this quinolone-induced neurotoxicity. Norfloxacin at 10(-5) M alone or at 10(-7) M in combination with BPAA (10(-4) M) inhibited [3H]muscimol binding to rat brain synaptic membranes. Ofloxacin and its optical isomers did not affect muscimol binding by themselves. While they slightly reduced muscimol binding at 10(-4) M in combination with BPAA, the inhibitory activity of the l-isomer levofloxacin (DR-3355) on muscimol binding was slightly, but significantly, weaker than that of the d-isomer DR-3354 and ofloxacin. Intracisternal injection of norfloxacin (5 micrograms), ofloxacin, levofloxacin or DR-3354 (50 micrograms each) induced clonic convulsions in mice. The incidence of these convulsions was enhanced by the combination with BPAA (50 micrograms). The epileptogenic activity of levofloxacin was also weaker than that of DR-3354 or ofloxacin when quinolones were given alone or in combination with BPAA. These results suggest that epileptogenic activity of quinolones is closely related to the inhibitory potency in GABA receptor binding and that levofloxacin may have lower neurotoxicity than ofloxacin and DR-3354. PMID:7842825

  10. Efficient production of gamma-aminobutyric acid using Escherichia coli by co-localization of glutamate synthase, glutamate decarboxylase, and GABA transporter.

    PubMed

    Dung Pham, Van; Somasundaram, Sivachandiran; Lee, Seung Hwan; Park, Si Jae; Hong, Soon Ho

    2016-01-01

    Gamma-aminobutyric acid (GABA) is an important bio-product, which is used in pharmaceutical formulations, nutritional supplements, and biopolymer monomer. The traditional GABA process involves the decarboxylation of glutamate. However, the direct production of GABA from glucose is a more efficient process. To construct the recombinant strains of Escherichia coli, a novel synthetic scaffold was introduced. By carrying out the co-localization of glutamate synthase, glutamate decarboxylase, and GABA transporter, we redirected the TCA cycle flux to GABA pathway. The genetically engineered E. coli strain produced 1.08 g/L of GABA from 10 g/L of initial glucose. Thus, with the introduction of a synthetic scaffold, we increased GABA production by 2.2-fold. The final GABA concentration was increased by 21.8% by inactivating competing pathways. PMID:26620318

  11. Effects of NaCl Replacement with Gamma-Aminobutyric acid (GABA) on the Quality Characteristics and Sensorial Properties of Model Meat Products

    PubMed Central

    Chun, Ji-Yeon; Cho, Hyung-Yong; Min, Sang-Gi

    2014-01-01

    This study investigated the effects of γ-aminobutylic acid (GABA) on the quality and sensorial properties of both the GABA/NaCl complex and model meat products. GABA/NaCl complex was prepared by spray-drying, and the surface dimensions, morphology, rheology, and saltiness were characterized. For model meat products, pork patties were prepared by replacing NaCl with GABA. For characteristics of the complex, increasing GABA concentration increased the surface dimensions of the complex. However, GABA did not affect the rheological properties of solutions containing the complex. The addition of 2% GABA exhibited significantly higher saltiness than the control (no GABA treatment). In the case of pork patties, sensory testing indicated that the addition of GABA decreased the saltiness intensity. Both the intensity of juiciness and tenderness of patties containing GABA also scored lower than the control, based on the NaCl reduction. These results were consistent with the quality characteristics (cooking loss and texture profile analysis). Nevertheless, overall acceptability of the pork patties showed that up to 1.5%, patties containing GABA did not significantly differ from the control. Consequently, the results indicated that GABA has a potential application in meat products, but also manifested a deterioration of quality by the NaCl reduction, which warrants further exploration. PMID:26761294

  12. α(5)GABA(A) receptors mediate primary afferent fiber tonic excitability in the turtle spinal cord.

    PubMed

    Loeza-Alcocer, Emanuel; Canto-Bustos, Martha; Aguilar, Justo; González-Ramírez, Ricardo; Felix, Ricardo; Delgado-Lezama, Rodolfo

    2013-11-01

    γ-Amino butyric acid (GABA) plays a key role in the regulation of central nervous system by activating synaptic and extrasynaptic GABAA receptors. It is acknowledged that extrasynaptic GABAA receptors located in the soma, dendrites, and axons may be activated tonically by low extracellular GABA concentrations. The activation of these receptors produces a persistent conductance that can hyperpolarize or depolarize nerve cells depending on the Cl(-) equilibrium potential. In an in vitro preparation of the turtle spinal cord we show that extrasynaptic α5GABAA receptors mediate the tonic state of excitability of primary afferents independently of the phasic primary afferent depolarization mediated by synaptic GABAA receptors. Blockade of α5GABAA receptors with the inverse agonist L-655,708 depressed the dorsal root reflex (DRR) without affecting the phasic increase in excitability of primary afferents. Using RT-PCR and Western blotting, we corroborated the presence of the mRNA and the α5GABAA protein in the dorsal root ganglia of the turtle spinal cord. The receptors were localized in primary afferents in dorsal root, dorsal root ganglia, and peripheral nerve terminals using immunoconfocal microscopy. Considering the implications of the DRR in neurogenic inflammation, α5GABAA receptors may serve as potential pharmacological targets for the treatment of pain. PMID:23966669

  13. Effect of GABA on oxidative stress in the skeletal muscles and plasma free amino acids in mice fed high-fat diet.

    PubMed

    Xie, Z X; Xia, S F; Qiao, Y; Shi, Y H; Le, G W

    2015-06-01

    Increased levels of plasma free amino acids (pFAAs) can disturb the blood glucose levels in patients with obesity, diabetes mellitus and metabolic syndrome (MS) and are associated with enhanced protein oxidation. Oxidation of proteins, especially in the muscles, can promote protein degradation and elevate the levels of pFAAs. Gamma-aminobutyric acid (GABA), a food additive, can reduce high-fat diet (HFD)-induced hyperglycaemia; however, the mechanisms remain unclear. The aim of this study was to evaluate the effects of GABA on protein oxidation and pFAAs changes. One hundred male C57BL/6 mice were randomly divided into five groups that were fed with control diet, HFD and HFD supplied with 0.2%, 0.12% and 0.06% GABA in drinking water for 20 weeks respectively. HFD feeding led to muscular oxidative stress, protein oxidation, pFAA disorders, hyperglycaemia and augmented plasma GABA levels. Treatment with GABA restored normally fasting blood glucose level and dose-dependently inhibited body weight gains, muscular oxidation and protein degradation. While medium and low doses of GABA mitigated HFD-induced pFAA disorders, the high dose of GABA deteriorated the pFAA disorders. Medium dose of GABA increased the levels of GABA, but high dose of GABA reduced the levels of plasma GABA and increased the activity of succinic semialdehyde dehydrogenase in the liver. Therefore, treatment with GABA mitigated HFD-induced hyperglycaemia probably by repairing HFD-induced muscular oxidative stress and pFAA disorders in mice. Our data also suggest that an optimal dose of GABA is crucial for the prevention of excess GABA-related decrease in the levels of pFAA and GABA as well as obesity. PMID:25266692

  14. Identification of amino acids involved in histamine potentiation of GABA A receptors.

    PubMed

    Thiel, Ulrike; Platt, Sarah J; Wolf, Steffen; Hatt, Hanns; Gisselmann, Günter

    2015-01-01

    Histamine is a neurotransmitter involved in a number of physiological and neuronal functions. In mammals, such as humans, and rodents, the histaminergic neurons found in the tuberomamillary nucleus project widely throughout the central nervous system. Histamine acts as positive modulator of GABAA receptors (GABAARs) and, in high concentrations (10 mM), as negative modulator of the strychnine-sensitive glycine receptor. However, the exact molecular mechanisms by which histamine acts on GABAARs are unknown. In our study, we aimed to identify amino acids potentially involved in the modulatory effect of histamine on GABAARs. We expressed GABAARs with 12 different point mutations in Xenopus laevis oocytes and characterized the effect of histamine on GABA-induced currents using the two-electrode voltage clamp technique. Our data demonstrate that the amino acid residues β2(N265) and β2(M286), which are important for modulation by propofol, are not involved in the action of histamine. However, we found that histamine modulation is dependent on the amino acid residues α1(R120), β2(Y157), β2(D163), β3(V175), and β3(Q185). We showed that the amino acid residues β2(Y157) and β3(Q185) mediate the positive modulatory effect of histamine on GABA-induced currents, whereas α1(R120) and β2(D163) form a potential histamine interaction site in GABAARs. PMID:26074818

  15. 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

  16. Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases.

    PubMed

    Shetty, Ashok K; Bates, Adrian

    2016-05-01

    Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gamma-amino butyric acid positive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmission in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much consideration because of their ability for dispersion, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for easing neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer׳s disease and Parkinson׳s disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to considering the possible clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence-like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphasized. This article is part of a Special Issue

  17. GABA shunt and polyamine degradation pathway on γ-aminobutyric acid accumulation in germinating fava bean (Vicia faba L.) under hypoxia.

    PubMed

    Yang, Runqiang; Guo, Qianghui; Gu, Zhenxin

    2013-01-01

    GABA shunt and polyamine degradation pathway on γ-aminobutyric acid (GABA) accumulation in germinating fava bean under hypoxia was investigated. GABA content, GAD and DAO activity were significantly increased under hypoxia treatment. Glu and polyamine contents enhanced largely and thus supplied as sufficient substrates for GABA formation. In contrast, GABA content decreased, mainly in the embryo, after removing the hypoxia stress. DAO activity, Glu and polyamines contents decreased, while an increment of GAD activity was observed. This indicated that GAD activity can be not only regulated by hypoxia, but by the rapid growth of embryo after the recovery from hypoxia stress. When treated with AG, DAO activity was almost inhibited completely, and the GABA content decreased by 32.96% and 32.07% after treated for 3 and 5 days, respectively. Hence, it can be inferred that about 30% of GABA formed in germinating fava bean under hypoxia was supplied by polyamine degradation pathway. PMID:23017406

  18. SYSTEMIC ADMINISTRATION OF KAINIC ACID INCREASES GABA LEVELS IN PERFUSATE FROM THE HIPPOCAMPUS OF RATS IN VIVO

    EPA Science Inventory

    The ventral hippocampi of male, Fischer-344 rats were implanted with microdialysis probes and the effects of systemically administered kainic acid (KA) (8 mg/kg, s.c.) on the in vivo release of amino acids were measured for four hours after administration. n order to measure GABA...

  19. Exogenous γ-aminobutyric Acid (GABA) Application Improved Early Growth, Net Photosynthesis, and Associated Physio-Biochemical Events in Maize

    PubMed Central

    Li, Wu; Liu, Jianhua; Ashraf, Umair; Li, Gaoke; Li, Yuliang; Lu, Wenjia; Gao, Lei; Han, Fuguang; Hu, Jianguang

    2016-01-01

    γ-aminobutyric acid (GABA) is an endogenous signaling molecule and involved in growth regulations and plant development, however, a little information is available on the consequences of exogenous GABA application on growth, development, and associated physio-biochemical processes in maize. The present study examined the GABA-induced regulations in early growth, net photosynthetic rate, gas exchange, osmoregulation, and enzymatic activities in three maize cultivars, i.e., Yuecainuo 6, Zhengtian 68, and Yuecainuo 2. Two levels of GABA, i.e., 0 mg L-1 and 50 mg L-1, in solution form, with total application volume of 100 ml per pot containing 15 maize seedlings were exogenously applied. Results revealed that exogenous GABA application improved seedling growth in terms of seedling length and biomass accumulation in all maize cultivars at both 3 and 7 days after treatment (DAT). It also promoted net photosynthesis and variably affected gas exchange attributes, i.e., stomatal conductance (Gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr), as well as leaves SPAD value. Furthermore, lipid peroxidation [in terms of malondialdehyde (MDA)] under GABA treated maize seedlings were also remained variable; however, osmolyte accumulation (protein and proline) and activities of anti-oxidants enzymes, i.e., super-oxide dismutase and peroxidase were also affected differently at both 3 and 7 DAT in all maize cultivars. Furthermore, enzymes involved in nitrogen metabolism, e.g., nitrate reductase and glutamine synthetase were improved. These results suggest the involvement of GABA in various physio-metablical mechanisms which might lead to improvement in morphological growth of maize. In future, research is still needed at molecular and genetic levels to unravel the involvement of GABA-mediated regulations in growth and its associated physio-biochemical mechanisms. PMID:27446149

  20. Exogenous γ-aminobutyric Acid (GABA) Application Improved Early Growth, Net Photosynthesis, and Associated Physio-Biochemical Events in Maize.

    PubMed

    Li, Wu; Liu, Jianhua; Ashraf, Umair; Li, Gaoke; Li, Yuliang; Lu, Wenjia; Gao, Lei; Han, Fuguang; Hu, Jianguang

    2016-01-01

    γ-aminobutyric acid (GABA) is an endogenous signaling molecule and involved in growth regulations and plant development, however, a little information is available on the consequences of exogenous GABA application on growth, development, and associated physio-biochemical processes in maize. The present study examined the GABA-induced regulations in early growth, net photosynthetic rate, gas exchange, osmoregulation, and enzymatic activities in three maize cultivars, i.e., Yuecainuo 6, Zhengtian 68, and Yuecainuo 2. Two levels of GABA, i.e., 0 mg L(-1) and 50 mg L(-1), in solution form, with total application volume of 100 ml per pot containing 15 maize seedlings were exogenously applied. Results revealed that exogenous GABA application improved seedling growth in terms of seedling length and biomass accumulation in all maize cultivars at both 3 and 7 days after treatment (DAT). It also promoted net photosynthesis and variably affected gas exchange attributes, i.e., stomatal conductance (Gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr), as well as leaves SPAD value. Furthermore, lipid peroxidation [in terms of malondialdehyde (MDA)] under GABA treated maize seedlings were also remained variable; however, osmolyte accumulation (protein and proline) and activities of anti-oxidants enzymes, i.e., super-oxide dismutase and peroxidase were also affected differently at both 3 and 7 DAT in all maize cultivars. Furthermore, enzymes involved in nitrogen metabolism, e.g., nitrate reductase and glutamine synthetase were improved. These results suggest the involvement of GABA in various physio-metablical mechanisms which might lead to improvement in morphological growth of maize. In future, research is still needed at molecular and genetic levels to unravel the involvement of GABA-mediated regulations in growth and its associated physio-biochemical mechanisms. PMID:27446149

  1. Molecular and Therapeutic Potential and Toxicity of Valproic Acid

    PubMed Central

    Chateauvieux, Sébastien; Morceau, Franck; Dicato, Mario; Diederich, Marc

    2010-01-01

    Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties. PMID:20798865

  2. Determination of γ-Aminobutyric Acid (GABA) in Rambutan Fruit cv. Rongrian by HPLC-ELSD and Separation of GABA from Rambutan Fruit Using Dowex 50W-X8 Column.

    PubMed

    Meeploy, Maneerat; Deewatthanawong, Rujira

    2016-03-01

    A high-performance liquid chromatography method coupled with an evaporative light scattering detector (ELSD) was validated for the determination of γ-aminobutyric acid (GABA) in rambutan fruit without any sample pretreatment or derivatization. In the concentration range of 0.05-1.0 mg/mL GABA, the ELSD response was linear with a correlation coefficient (r) >0.999. Limit of detection and limit of quantitation were found to be 0.7 and 2.0 µg/mL, respectively. The method enabled the complete separation of GABA in the aqueous extract of rambutan flesh from the impurity peaks at 45.7 min. The recoveries of sample added GABA were obtained in the range of 92.0-99.3%. Intraday and interday relative standard deviations were <5.3%. Repeatability of the extraction process showed the acceptable precision. From the analysis of GABA content in rambutan flesh, 0.71 ± 0.23 mg of GABA was found in 1 g fresh weight. The recovery of GABA after passing through the Dowex 50W-X8 column was 96.65%. The analytical methodology could be potentially applied to the detection and quantification of GABA in other fruits and complex matrices when a sufficient quantity is available. PMID:26590236

  3. GABA-BZD Receptor Modulating Mechanism of Panax quinquefolius against 72-h Sleep Deprivation Induced Anxiety like Behavior: Possible Roles of Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation

    PubMed Central

    Chanana, Priyanka; Kumar, Anil

    2016-01-01

    Rationale: Panax quinquefolius (American Ginseng) is known for its therapeutic potential against various neurological disorders, but its plausible mechanism of action still remains undeciphered. GABA (Gamma Amino Butyric Acid) plays an important role in sleep wake cycle homeostasis. Thus, there exists rationale in exploring the GABA-ergic potential of Panax quinquefolius as neuroprotective strategy in sleep deprivation induced secondary neurological problems. Objective: The present study was designed to explore the possible GABA-ergic mechanism in the neuro-protective effect of Panax quinquefolius against 72-h sleep deprivation induced anxiety like behavior, oxidative stress, mitochondrial dysfunction, HPA-axis activation and neuroinflammation. Materials and Methods: Male laca mice were sleep deprived for 72-h by using Grid suspended over water method. Panax quinquefolius (American Ginseng 50, 100, and 200 mg/kg) was administered alone and in combination with GABA modulators (GABA Cl− channel inhibitor, GABA-benzodiazepine receptor inhibitor and GABAA agonist) for 8 days, starting 5 days prior to 72-h sleep deprivation period. Various behavioral (locomotor activity, mirror chamber test), biochemical (lipid peroxidation, reduced glutathione, catalase, nitrite levels), mitochondrial complexes, neuroinflammation marker (Tumor Necrosis Factor, TNF-alpha), serum corticosterone, and histopathological sections of brains were assessed. Results: Seventy two hours sleep deprivation significantly impaired locomotor activity, caused anxiety-like behavior, conditions of oxidative stress, alterations in mitochondrial enzyme complex activities, raised serum corticosterone levels, brain TNFα levels and led to neuroinflammation like signs in discrete brain areas as compared to naive group. Panax quinquefolius (100 and 200 mg/kg) treatment restored the behavioral, biochemical, mitochondrial, molecular and histopathological alterations. Pre-treatment of GABA Cl− channel

  4. Lesions of nucleus accumbens affect morphine-induced release of ascorbic acid and GABA but not of glutamate in rats.

    PubMed

    Sun, Ji Y; Yang, Jing Y; Wang, Fang; Wang, Jian Y; Song, Wu; Su, Guang Y; Dong, Ying X; Wu, Chun F

    2011-10-01

    Our previous studies have shown that local perfusion of morphine causes an increase of extracellular ascorbic acid (AA) levels in nucleus accumbens (NAc) of freely moving rats. Lines of evidence showed that glutamatergic and GABAergic were associated with morphine-induced effects on the neurotransmission of the brain, especially on the release of AA. In the present study, the effects of morphine on the release of extracellular AA, γ-aminobutyric acid (GABA) and glutamate (Glu) in the NAc following bilateral NAc lesions induced by kainic acid (KA) were studied by using the microdialysis technique, coupled to high performance liquid chromatography with electrochemical detection (HPLC-ECD) and fluorescent detection (HPLC-FD). The results showed that local perfusion of morphine (100 µM, 1 mM) in NAc dose-dependently increased AA and GABA release, while attenuated Glu release in the NAc. Naloxone (0.4 mM) pretreated by local perfusion to the NAc, significantly blocked the effects of morphine. After NAc lesion by KA (1 µg), morphine-induced increase in AA and GABA were markedly eliminated, while decrease in Glu was not affected. The loss effect of morphine on AA and GABA release after KA lesion could be recovered by GABA agonist, musimol. These results indicate that morphine-induced AA release may be mediated at least by µ-opioid receptor. Moreover, this effect of morphine possibly depend less on the glutamatergic afferents, but more on the GABAergic circuits within this nucleus. Finally, AA release induced by local perfusion of morphine may be GABA-receptor mediated and synaptically localized in the NAc. PMID:20731632

  5. Impact of Precooling and Controlled-Atmosphere Storage on γ-Aminobutyric Acid (GABA) Accumulation in Longan (Dimocarpus longan Lour.) Fruit.

    PubMed

    Zhou, Molin; Ndeurumio, Kessy H; Zhao, Lei; Hu, Zhuoyan

    2016-08-24

    Longan (Dimocarpus longan Lour.) fruit cultivars 'Chuliang' and 'Shixia' were analyzed for γ-aminobutyric acid (GABA) accumulation after precooling and in controlled-atmosphere storage. Fruit were exposed to 5% O2 plus 3%, 5%, or 10% CO2 at 4 °C, and GABA and associated enzymes, aril firmness, and pericarp color were measured. Aril softening and pericarp browning were delayed by 5% CO2 + 5% O2. GABA concentrations and glutamate decarboxylase (GAD; EC 4.1.1.15) activities declined during storage at the higher-CO2 treatments. However, GABA aminotransferase (GABA-T; EC 2.6.1.19) activities in elevated CO2-treated fruit fluctuated during storage. GABA concentrations increased after precooling treatments. GAD activity and GABA-T activity were different between cultivars after precooling. GABA concentrations in fruit increased after 3 days of 10% CO2 + 5% O2 treatment and then declined as storage time increased. GABA accumulation was associated with stimulation of GAD activity rather than inhibition of GABA-T activity. PMID:27412947

  6. Synthesis of 4-substituted nipecotic acid derivatives and their evaluation as potential GABA uptake inhibitors.

    PubMed

    Hellenbrand, Tim; Höfner, Georg; Wein, Thomas; Wanner, Klaus T

    2016-05-01

    In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N-substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the ω-position of the alkenyl- or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac-57, the other a notable inhibitory potency at mGAT4, rac-84, both displaying a slight subtype selectivity for the individual transporters, could be identified. PMID:27039250

  7. Variance analysis of gamma-aminobutyric acid (GABA)-ergic inhibitory postsynaptic currents from melanotropes of Xenopus laevis.

    PubMed Central

    Borst, J G; Kits, K S; Bier, M

    1994-01-01

    We have studied the variance in the decay of large spontaneous gamma-aminobutyric acid (GABA)-ergic inhibitory postsynaptic currents (IPSCs) in melanotropes of Xenopus laevis to obtain information about the number of GABAA receptor channels that bind GABA during the IPSCs. The average decay of the IPSCs is well described by the sum of two exponential functions. This suggests that a three-state Markov model is sufficient to describe the decay phase, with one of the three states being an absorbing state, entered when GABA dissociates from the GABAA receptor. We have compared the variance in the decay of large spontaneous IPSCs with the variance calculated for two different three-state models: a model with one open state, one closed state, and one absorbing state (I), and a model with two open states and one absorbing state (II). The data were better described by the more efficient model II. This suggests that the efficacy of GABA at synaptic GABAA receptor channels is high and that only a small number of channels are involved in generating the GABA-ergic IPSCs. PMID:7918986

  8. Biphenylacetic acid enhances the antagonistic action of fluoroquinolones on the GABA(A)-mediated responses of the isolated guinea-pig ileum.

    PubMed

    Koutsoviti-Papadopoulou, M; Nikolaidis, E; Kounenis, G

    2001-09-01

    This paper examines the effect of biphenylacetic acid on the antagonistic action of norfloxacin and enoxacin on the GABA(A)-mediated responses of the isolated guinea-pig ileum. GABA produced transient contractions followed by relaxation. The contractile effect of exogenously applied GABA was concentration-dependent with EC(50)= 9.8 x 10(-6) M. This contractile effect was not significantly modified by biphenylacetic acid, and the EC(50) value for GABA in the presence of 10(-5) M biphenylacetic acid was 1.15 x 10(-5) M. The GABA contractile effect was inhibited, dose-dependently, by either norfloxacin or enoxacin, but only at concentrations higher than 10(-5) M. The response of the ileum to GABA (at EC(50)) was reduced to 35 and 36% by pretreatment with 10(-5) M norfloxacin or enoxacin, respectively. However, in the presence of 10(-5) M biphenylacetic acid, the response of the ileum to GABA was reduced to 2.2% by pretreatment with 10(-5) M enoxacin, while it was completely abolished by pretreatment with 10(-5) M norfloxacin and the IC(50) values were 5.5 x 10(-7) and 1.5 x 10(-6) M for norfloxacin and enoxacin, respectively. These data show that biphenylacetic acid whilst having no effect at the GABA(A)-mediated contractile response of the guinea-pig ileum, enhances the antagonistic effect of both enoxacin and norfloxacin. This suggests that combined administration of fluoroquinolones and biphenylacetic acid synergistically inhibits GABA(A)-receptors at the intestinal level. PMID:11529690

  9. Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gamma-aminobutyric acid (GABA) metabolism in the mouse.

    PubMed

    Nau, H; Löscher, W

    1982-03-01

    The slow onset and carry-over effect of valproic acid (VPA) therapy observed in some clinical as well as experimental animal studies have been examined by parallel pharmacokinetic and pharmacological investigations in a mouse model. VPA was rapidly transferred into brain and was cleared from that tissue with rates which exceeded plasma clearance rates. Of several VPA metabolites present in plasma, only one could be found in the brain: 2-propyl-2-pentenoic acid. This metabolite was cleared from plasma and from brain slower than the parent drug. gamma-Aminobutyric acid (GABA) concentrations were increased within 15 min after VPA injection and remained significantly elevated for at least 8 h. A similar time course was found in regard to the increase of the electroconvulsive threshold (maximal seizures) induced by VPA administration. The activity of glutamic acid decarboxylase rose parallel to the elevation of brain GABA levels, whereas the activity of GABA aminotransferase was not affected. Whereas the rapid onset of the effect on electroconvulsive threshold and on GABA metabolism can be explained by the rapid entrance of VPA into brain, the carry-over effects observed correlated with the kinetics of the metabolite 2-propyl-2-pentenoic acid better than with those of VPA due to the persistence of this metabolite in brain. PMID:6801254

  10. Expression of the γ-Aminobutyric Acid (GABA) Plasma Membrane Transporter-1 in Monkey and Human Retina

    PubMed Central

    Casini, Giovanni; Rickman, Dennis W.; Brecha, Nicholas C.

    2010-01-01

    Purpose To determine the expression pattern of the predominant γ-aminobutyric acid (GABA) plasma membrane transporter GAT-1 in Old World monkey (Macaca mulatta) and human retina. Methods GAT-1 was localized in retinal sections by using immunohistochemical techniques with fluorescence and confocal microscopy. Double-labeling studies were performed with the GAT-1 antibody using antibodies to GABA, vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), and the bipolar cell marker Mab115A10. Results The pattern of GAT-1 immunostaining was similar in human and monkey retinas. Numerous small immunoreactive somata were in the inner nuclear layer (INL) and were present rarely in the inner plexiform layer (IPL) of all retinal regions. Medium GAT-1 somata were in the ganglion cell layer in the parafoveal and peripheral retinal regions. GAT-1 fibers were densely distributed throughout the IPL. Varicose processes, originating from both the IPL and somata in the INL, arborized in the outer plexiform layer (OPL), forming a sparse network in all retinal regions, except the fovea. Sparsely occurring GAT-1 processes were in the nerve fiber layer in parafoveal regions and near the optic nerve head but not in the optic nerve. In the INL, 99% of the GAT-1 somata contained GABA, and 66% of the GABA immunoreactive somata expressed GAT-1. GAT-1 immunoreactivity was in all VIP-containing cells, but it was absent in TH-immunoreactive amacrine cells and in Mab115A10 immunoreactive bipolar cells. Conclusions GAT-1 in primate retinas is expressed by amacrine and displaced amacrine cells. The predominant expression of GAT-1 in the inner retina is consistent with the idea that GABA transporters influence neurotransmission and thus participate in visual information processing in the retina. PMID:16565409

  11. A Glutamic Acid-Producing Lactic Acid Bacteria Isolated from Malaysian Fermented Foods

    PubMed Central

    Zareian, Mohsen; Ebrahimpour, Afshin; Bakar, Fatimah Abu; Mohamed, Abdul Karim Sabo; Forghani, Bita; Ab-Kadir, Mohd Safuan B.; Saari, Nazamid

    2012-01-01

    l-glutamaic acid is the principal excitatory neurotransmitter in the brain and an important intermediate in metabolism. In the present study, lactic acid bacteria (218) were isolated from six different fermented foods as potent sources of glutamic acid producers. The presumptive bacteria were tested for their ability to synthesize glutamic acid. Out of the 35 strains showing this capability, strain MNZ was determined as the highest glutamic-acid producer. Identification tests including 16S rRNA gene sequencing and sugar assimilation ability identified the strain MNZ as Lactobacillus plantarum. The characteristics of this microorganism related to its glutamic acid-producing ability, growth rate, glucose consumption and pH profile were studied. Results revealed that glutamic acid was formed inside the cell and excreted into the extracellular medium. Glutamic acid production was found to be growth-associated and glucose significantly enhanced glutamic acid production (1.032 mmol/L) compared to other carbon sources. A concentration of 0.7% ammonium nitrate as a nitrogen source effectively enhanced glutamic acid production. To the best of our knowledge this is the first report of glutamic acid production by lactic acid bacteria. The results of this study can be further applied for developing functional foods enriched in glutamic acid and subsequently γ-amino butyric acid (GABA) as a bioactive compound. PMID:22754309

  12. Dual effects of slightly acidic electrolyzed water (SAEW) treatment on the accumulation of γ-aminobutyric acid (GABA) and rutin in germinated buckwheat.

    PubMed

    Hao, Jianxiong; Wu, Tongjiao; Li, Huiying; Wang, Wei; Liu, Haijie

    2016-06-15

    In the present study, the dual effects of slightly acidic electrolyzed water (SAEW) treatment on γ-aminobutyric acid (GABA) and rutin accumulation of germinated buckwheat were evaluated during germination. The results showed that SAEW treatment (pH 5.83, ACC of 20.3 mg/L) could promote the accumulation of GABA and rutin in germinated buckwheat. The GABA and rutin contents of SAEW-germinated buckwheat reached 143.20 and 739.9 mg/100 g respectively, which is significantly higher than those of control (P<0.05). Moreover, SAEW treatment could increase the activity of glutamic acid decarboxylase (GAD) and phenylalanine ammonialyase (PAL) and thus result in the GABA and rutin accumulation of germinated buckwheat. The results suggested that SAEW treatment could promote the rutin accumulation of germinated buckwheat by influencing phenylpropanoid secondary metabolic pathway instead of the inhibition of rutin degrading enzyme (RDE) activity. In addition, SAEW treatment had no adverse impact on the sprouts growth and could reduce the microbial populations of germinated buckwheat during germination. PMID:26868552

  13. Detection of amino acid neurotransmitters by surface enhanced Raman scattering and hollow core photonic crystal fiber

    NASA Astrophysics Data System (ADS)

    Tiwari, Vidhu S.; Khetani, Altaf; Monfared, Ali Momenpour T.; Smith, Brett; Anis, Hanan; Trudeau, Vance L.

    2012-03-01

    The present work explores the feasibility of using surface enhanced Raman scattering (SERS) for detecting the neurotransmitters such as glutamate (GLU) and gamma-amino butyric acid (GABA). These amino acid neurotransmitters that respectively mediate fast excitatory and inhibitory neurotransmission in the brain, are important for neuroendocrine control, and upsets in their synthesis are also linked to epilepsy. Our SERS-based detection scheme enabled the detection of low amounts of GLU (10-7 M) and GABA (10-4 M). It may complement existing techniques for characterizing such kinds of neurotransmitters that include high-performance liquid chromatography (HPLC) or mass spectrography (MS). This is mainly because SERS has other advantages such as ease of sample preparation, molecular specificity and sensitivity, thus making it potentially applicable to characterization of experimental brain extracts or clinical diagnostic samples of cerebrospinal fluid and saliva. Using hollow core photonic crystal fiber (HC-PCF) further enhanced the Raman signal relative to that in a standard cuvette providing sensitive detection of GLU and GABA in micro-litre volume of aqueous solutions.

  14. A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder.

    PubMed

    Yin, Honglei; Pantazatos, Spiro P; Galfalvy, Hanga; Huang, Yung-Yu; Rosoklija, Gorazd B; Dwork, Andrew J; Burke, Ainsley; Arango, Victoria; Oquendo, Maria A; Mann, Joseph John

    2016-04-01

    Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples. © 2016 Wiley Periodicals, Inc. PMID:26892569

  15. Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2-substituted pyrrolidine-2-yl-acetic acids.

    PubMed

    Steffan, Tobias; Renukappa-Gutke, Thejavathi; Höfner, Georg; Wanner, Klaus T

    2015-03-15

    In this paper, we disclose the design and synthesis of a series of 2-substituted pyrrolidine-2-yl-acetic acid as core structures and the N-arylalkyl derivatives thereof as potential GABA transport inhibitors. The 2-position in the side chain of pyrrolidine-2-yl-acetic acid derivatives was substituted with alkyl, hydroxy and amino groups to modulate the activity and selectivity to mGAT1 and mGAT4 proteins. SAR studies of the compounds performed for the four mouse GABA transporter proteins (mGAT1-mGAT4) implied significant potencies and subtype selectivities for 2-hydroxy-2-pyrrolidine-2-yl-acetic acid derivatives. The racemate rac-(u)-13c exhibited the highest potency (pIC50 5.67) at and selectivity for mGAT1 in GABA uptake assays. In fact, the potency of rac-(u)-13c at hGAT-1 (pIC50 6.14) was even higher than its potency at mGAT1. These uptake results for rac-(u)-13c are in line with the binding affinities to the aforesaid proteins mGAT1 (pKi 6.99) and hGAT-1 (pKi 7.18) determined by MS Binding Assay based on NO711 as marker quantified by LC-ESI-MS-MS analysis. Interestingly, the 2-hydroxy-2-pyrrolidine-2-yl-acetic acid rac-(u)-13d containing 2-{[tris(4-methoxyphenyl)]methoxy} ethyl group at the nitrogen atom of the pyrrolidine ring showed high potency at mGAT4 and a comparatively better selectivity for this protein (>15 against mGAT3) than the well known mGAT4 uptake inhibitor (S)-SNAP-5114. PMID:25698617

  16. Determination of theanine, GABA, and other amino acids in green, oolong, black, and Pu-erh teas with dabsylation and high-performance liquid chromatography.

    PubMed

    Syu, Kai-Yang; Lin, Chih-Li; Huang, Hsiu-Chen; Lin, Jen-Kun

    2008-09-10

    Dabsyl chloride (dimethylaminoazobenzene sulfonyl chloride), a useful chromophoric labeling reagent for amino acids and amines, was developed in this laboratory in 1975. Although several methods have been developed to determine various types of amino acids, a quick and easy method of determining theanine, GABA, and other amino acids has not been developed in one HPLC system. In this paper are analyzed the free amino acid contents of theanine and GABA in different teas (green tea, black tea, oolong tea, Pu-erh tea, and GABA tea) with a dabsylation and reverse phase high-performance liquid chromatography (HPLC) system coupled with a detector at 425 nm absorbance. Two reverse phase columns, Hypersil GOLD and Zorbax ODS, were used and gave different resolutions of dabsyl amino acids in the gradient elution program. The data suggest that the tea source or the steps of tea-making may contribute to the theanine contents variations. High theanine contents of high-mountain tea were observed in both green tea and oolong tea. Furthermore, the raw (natural fermented) Pu-erh tea contained more theanine than ripe (wet fermented) Pu-erh tea, and the GABA contents in normal teas were generally lower than that in GABA tea. PMID:18652476

  17. Gestational changes of GABA levels and GABA binding in the human uterus

    SciTech Connect

    Erdoe, S.L.; Villanyi, P.; Laszlo, A.

    1989-01-01

    The concentrations of gamma-aminobutyric acid (GABA), the activities of L-glutamate decarboxylase and GABA-transaminase, and the nature of the sodium-independent binding of GABA were examined in uterine tissue pieces obtained surgically from pregnant and non-pregnant women. GABA concentrations were reduced, while the activity of GABA-transaminase and the specific binding of (/sup 3/H)GABA significantly increased in specimens from pregnant subjects. These findings suggest some gestation-related functional role for the GABA system in the human uterus.

  18. Why Are Cortical GABA Neurons Relevant to Internal Focus in Depression? A cross-level model linking cellular, biochemical, and neural network findings

    PubMed Central

    2014-01-01

    Major Depression is a complex and severe psychiatric disorder whose symptomatology encompasses a critical shift in awareness, specifically in the balance from external to internal mental focus. This is reflected by unspecific somatic symptoms and the predominance of the own cognitions manifested in increased self-focus and rumination. We posit here that sufficient empirical data has accumulated to build a coherent biological model that links these psychological concepts and symptom dimensions to observed biochemical, cellular, regional and neural network deficits. Specifically, deficits in inhibitory gamma amino butyric acid (GABA) regulating excitatory cell input/output and local cell circuit processing of information in key brain regions may underlie the shift that is observed in depressed subjects in resting state activities between the perigenual anterior cingulate cortex (PACC) and the dorsolateral prefrontal cortex (DLPFC). This regional dysbalance translates at the network level in a dysbalance between default-mode and executive networks, which psychopathologically surfaces as a shift in focus from external to internal mental content and associated symptoms (See overview in Figure 1). We focus here on primary evidence at each of those levels and on putative mechanistic links between those levels. Apart from its implications for neuropsychiatric disorders, our model provides for the first time a set of hypotheses for cross-level mechanisms of how internal and external mental contents may be constituted and balanced in healthy subjects, and thus also contributes to the neuroscientific debate on the neural correlates of consciousness. PMID:25048001

  19. Stable isotope dilution HILIC-MS/MS method for accurate quantification of glutamic acid, glutamine, pyroglutamic acid, GABA and theanine in mouse brain tissues.

    PubMed

    Inoue, Koichi; Miyazaki, Yasuto; Unno, Keiko; Min, Jun Zhe; Todoroki, Kenichiro; Toyo'oka, Toshimasa

    2016-01-01

    In this study, we developed the stable isotope dilution hydrophilic interaction liquid chromatography with tandem mass spectrometry (HILIC-MS/MS) technique for the accurate, reasonable and simultaneous quantification of glutamic acid (Glu), glutamine (Gln), pyroglutamic acid (pGlu), γ-aminobutyric acid (GABA) and theanine in mouse brain tissues. The quantification of these analytes was accomplished using stable isotope internal standards and the HILIC separating mode to fully correct the intramolecular cyclization during the electrospray ionization. It was shown that linear calibrations were available with high coefficients of correlation (r(2)  > 0.999, range from 10 pmol/mL to 50 mol/mL). For application of the theanine intake, the determination of Glu, Gln, pGlu, GABA and theanine in the hippocampus and central cortex tissues was performed based on our developed method. In the region of the hippocampus, the concentration levels of Glu and pGlu were significantly reduced during reality-based theanine intake. Conversely, the concentration level of GABA increased. This result showed that transited theanine has an effect on the metabolic balance of Glu analogs in the hippocampus. PMID:26033549

  20. Role of a gamma-aminobutryic acid (GABA) receptor mutation in the evolution and spread of Diabrotica virgifera virgifera resistance to cyclodiene insecticides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An alanine to serine amino acid substitution within the Rdl subunit of the gamma-aminobutyric acid (GABA) receptor confers resistance to cyclodiene insecticides in many species. The corn rootworm, Diabrotica virgifera virgifera, is a damaging pest of cultivated corn that was partially controlled by ...

  1. Enhancing Contents of γ-Aminobutyric Acid (GABA) and Other Micronutrients in Dehulled Rice during Germination under Normoxic and Hypoxic Conditions.

    PubMed

    Ding, Junzhou; Yang, Tewu; Feng, Hao; Dong, Mengyi; Slavin, Margaret; Xiong, Shanbai; Zhao, Siming

    2016-02-10

    Biofortification of staple grains with high contents of essential micronutrients is an important strategy to overcome micronutrient malnutrition. However, few attempts have targeted at γ-aminobutyric acid (GABA), a functional nutrient for aging populations. In this study, two rice cultivars, Heinuo and Xianhui 207, were used to investigate changes in GABA and other nutritional compounds of dehulled rice after germination under normoxic and hypoxic conditions. Forty-one metabolites were identified in both cultivars treated by normoxic germination, whereas the germinated dehulled rice of Heinuo and Xianhui 207 under hypoxic treatment had 43 and 41 metabolites identified, respectively. GABA increased in dehulled rice after germination, especially under hypoxia. Meanwhile, a number of other health-beneficial and/or flavor-related compounds such as lysine and d-mannose increased after the hypoxic treatment. The accumulation of GABA exhibited genotype-specific modes in both normoxic and hypoxic treatments. With regard to GABA production, Xianhui 207 was more responsive to the germination process than Heinuo, whereas Heinuo was more responsive to hypoxia than Xianhui 207. This study provides a promising approach to biofortify dehulled rice with increased GABA and other nutrients through metabolomic-based regulation. PMID:26765954

  2. Adenosine-to-inosine RNA editing affects trafficking of the gamma-aminobutyric acid type A (GABA(A)) receptor.

    PubMed

    Daniel, Chammiran; Wahlstedt, Helene; Ohlson, Johan; Björk, Petra; Ohman, Marie

    2011-01-21

    Recoding by adenosine-to-inosine RNA editing plays an important role in diversifying proteins involved in neurotransmission. We have previously shown that the Gabra-3 transcript, coding for the α3 subunit of the GABA(A) receptor is edited in mouse, causing an isoleucine to methionine (I/M) change. Here we show that this editing event is evolutionarily conserved from human to chicken. Analyzing recombinant GABA(A) receptor subunits expressed in HEK293 cells, our results suggest that editing at the I/M site in α3 has functional consequences on receptor expression. We demonstrate that I/M editing reduces the cell surface and the total number of α3 subunits. The reduction in cell surface levels is independent of the subunit combination as it is observed for α3 in combination with either the β2 or the β3 subunit. Further, an amino acid substitution at the corresponding I/M site in the α1 subunit has a similar effect on cell surface presentation, indicating the importance of this site for receptor trafficking. We show that the I/M editing during brain development is inversely related to the α3 protein abundance. Our results suggest that editing controls trafficking of α3-containing receptors and may therefore facilitate the switch of subunit compositions during development as well as the subcellular distribution of α subunits in the adult brain. PMID:21030585

  3. Gamma-aminobutyric acid and glutamic acid levels in the auditory pathway of rats with chronic tinnitus: a direct determination using high resolution point-resolved proton magnetic resonance spectroscopy (1H-MRS)

    PubMed Central

    Brozoski, Thomas; Odintsov, Boris; Bauer, Carol

    2012-01-01

    Damage to the auditory system following high-level sound exposure reduces afferent input. Homeostatic mechanisms appear to compensate for the loss. Overcompensation may produce the sensation of sound without an objective physical correlate, i.e., tinnitus. Several potential compensatory neural processes have been identified, such as increased spontaneous activity. The cellular mechanisms enabling such compensatory processes may involve down-regulation of inhibitory neurotransmission mediated by γ-amino butyric acid (GABA), and/or up-regulation of excitatory neurotransmission, mediated by glutamic acid (Glu). Because central processing systems are integrated and well-regulated, compensatory changes in one system may produce reactive changes in others. Some or all may be relevant to tinnitus. To examine the roles of GABA and Glu in tinnitus, high resolution point-resolved proton magnetic resonance spectroscopy (1H-MRS) was used to quantify their levels in the dorsal cochlear nucleus (DCN), inferior colliculus (IC), medial geniculate body (MGB), and primary auditory cortex (A1) of rats. Chronic tinnitus was produced by a single high-level unilateral exposure to noise, and was measured using a psychophysical procedure sensitive to tinnitus. Decreased GABA levels were evident only in the MGB, with the greatest decrease, relative to unexposed controls, obtained in the contralateral MGB. Small GABA increases may have been present bilaterally in A1 and in the contralateral DCN. Although Glu levels showed considerable variation, Glu was moderately and bilaterally elevated both in the DCN and in A1. In the MGB Glu was increased ipsilaterally but decreased contralaterally. These bidirectional and region-specific alterations in GABA and Glu may reflect large-scale changes in inhibitory and excitatory equilibrium accompanying chronic tinnitus. The present results also suggest that targeting both neurotransmitter systems may be optimal in developing more effective therapeutics

  4. Promoters inducible by aromatic amino acids and γ-aminobutyrate (GABA) for metabolic engineering applications in Saccharomyces cerevisiae.

    PubMed

    Kim, Sujin; Lee, Kyusung; Bae, Sang-Jeong; Hahn, Ji-Sook

    2015-03-01

    A wide range of promoters with different strengths and regulatory mechanisms are valuable tools in metabolic engineering and synthetic biology. While there are many constitutive promoters available, the number of inducible promoters is still limited for pathway engineering in Saccharomyces cerevisiae. Here, we constructed aromatic amino-acid-inducible promoters based on the binding sites of Aro80 transcription factor, which is involved in the catabolism of aromatic amino acids through transcriptional activation of ARO9 and ARO10 genes in response to aromatic amino acids. A dynamic range of tryptophan-inducible promoter strengths can be obtained by modulating the number of Aro80 binding sites, plasmid copy numbers, and tryptophan concentrations. Using low and high copy number plasmid vectors and different tryptophan concentrations, a 29-fold range of fluorescence intensities of enhanced green fluorescent protein (EGFP) reporter could be achieved from a synthetic U4C ARO9 promoter, which is composed of four repeats of Aro80 binding half site (CCG) and ARO9 core promoter element. The U4C ARO9 promoter was applied to express alsS and alsD genes from Bacillus subtilis for acetoin production in S. cerevisiae, resulting in a gradual increase in acetoin titers depending on tryptophan concentrations. Furthermore, we demonstrated that γ-aminobutyrate (GABA)-inducible UGA4 promoter, regulated by Uga3, can also be used in metabolic engineering as a dose-dependent inducible promoter. The wide range of controllable expression levels provided by these tryptophan- and GABA-inducible promoters might contribute to fine-tuning gene expression levels and timing for the optimization of pathways in metabolic engineering. PMID:25573467

  5. gamma-Aminobutyric acid (GABA)-induced currents of skate Muller (glial) cells are mediated by neuronal-like GABAA receptors.

    PubMed Central

    Malchow, R P; Qian, H H; Ripps, H

    1989-01-01

    Radial glia (Muller cells) of the vertebrate retina appear to be intimately involved in regulating the actions of amino acid neurotransmitters. One of the amino acids thought to be important in mediating retinal information flow is gamma-aminobutyric acid (GABA). The findings of this study indicate that enzymatically isolated skate Muller cells are depolarized by GABA and the GABAA agonist muscimol and that the actions of these agents are reduced by bicuculline and picrotoxin. Membrane currents induced by GABA under voltage clamp were dose dependent, were associated with an increase in membrane conductance, and showed marked desensitization when the concentration of GABA exceeded 2.5 microM. The responses had a reversal potential close to that calculated for chloride, indicating that the currents were generated by ions passing through channels. These data support the view that skate Muller cells possess functional GABAA receptors. The presence of such receptors on retinal glia may have important implications for the role of Muller cells in maintaining the constancy of the extracellular milieu, for neuron-glia interactions within the retina, and for theories concerning the generation of the electroretinogram. Images PMID:2567001

  6. Imidase catalyzing desymmetric imide hydrolysis forming optically active 3-substituted glutaric acid monoamides for the synthesis of gamma-aminobutyric acid (GABA) analogs.

    PubMed

    Nojiri, Masutoshi; Hibi, Makoto; Shizawa, Hiroaki; Horinouchi, Nobuyuki; Yasohara, Yoshihiko; Takahashi, Satomi; Ogawa, Jun

    2015-12-01

    The recent use of optically active 3-substituted gamma-aminobutyric acid (GABA) analogs in human therapeutics has identified a need for an efficient, stereoselective method of their synthesis. Here, bacterial strains were screened for enzymes capable of stereospecific hydrolysis of 3-substituted glutarimides to generate (R)-3-substituted glutaric acid monoamides. The bacteria Alcaligenes faecalis NBRC13111 and Burkholderia phytofirmans DSM17436 were discovered to hydrolyze 3-(4-chlorophenyl) glutarimide (CGI) to (R)-3-(4-chlorophenyl) glutaric acid monoamide (CGM) with 98.1% enantiomeric excess (e.e.) and 97.5% e.e., respectively. B. phytofirmans DSM17436 could also hydrolyze 3-isobutyl glutarimide (IBI) to produce (R)-3-isobutyl glutaric acid monoamide (IBM) with 94.9% e.e. BpIH, an imidase, was purified from B. phytofirmans DSM17436 and found to generate (R)-CGM from CGI with specific activity of 0.95 U/mg. The amino acid sequence of BpIH had a 75% sequence identity to that of allantoinase from A. faecalis NBRC13111 (AfIH). The purified recombinant BpIH and AfIH catalyzed (R)-selective hydrolysis of CGI and IBI. In addition, a preliminary investigation of the enzymatic properties of BpIH and AfIH revealed that both enzymes were stable in the range of pH 6-10, with an optimal pH of 9.0, stable at temperatures below 40 °C, and were not metalloproteins. These results indicate that the use of this class of hydrolase to generate optically active 3-substituted glutaric acid monoamide could simplify the production of specific chiral GABA analogs for drug therapeutics. PMID:26205522

  7. Genetics Home Reference: succinic semialdehyde dehydrogenase deficiency

    MedlinePlus

    ... a chemical that transmits signals in the brain (neurotransmitter) called gamma-amino butyric acid (GABA). The primary ... Diseases National Organization for Rare Disorders (NORD) Pediatric Neurotransmitter Disease Association GeneReviews (1 link) Succinic Semialdehyde Dehydrogenase ...

  8. Glucose and amino acid metabolism in rat brain during sustained hypoglycemia

    SciTech Connect

    Wong, K.L.; Tyce, G.M.

    1983-04-01

    The metabolism of glucose in brains during sustained hypoglycemia was studied. (U-/sup 14/C)Glucose (20 microCi) was injected into control rats, and into rats at 2.5 hr after a bolus injection of 2 units of insulin followed by a continuous infusion of 0.2 units/100 g rat/hr. This regimen of insulin injection was found to result in steady-state plasma glucose levels between 2.5 and 3.5 mumol per ml. In the brains of control rats carbon was transferred rapidly from glucose to glutamate, glutamine, gamma-aminobutyric acid and aspartate and this carbon was retained in the amino acids for at least 60 min. In the brains of hypoglycemic rats, the conversion of carbon from glucose to amino acids was increased in the first 15 min after injection. After 15 min, the specific activity of the amino acids decreased in insulin-treated rats but not in the controls. The concentrations of alanine, glutamate, and gamma-amino-butyric acid decreased, and the concentration of aspartate increased, in the brains of the hypoglycemic rats. The concentration of pyridoxal-5'-phosphate, a cofactor in many of the reactions whereby these amino acids are formed from tricarboxylic acid cycle intermediates, was less in the insulin-treated rats than in the controls. These data provide evidence that glutamate, glutamine, aspartate, and GABA can serve as energy sources in brain during insulin-induced hypoglycemia.

  9. Hydroxy-1,2,5-oxadiazolyl moiety as bioisoster of the carboxy function. A computational study on gamma-aminobutyric acid (GABA) related compounds.

    PubMed

    Tosco, Paolo; Lolli, Marco L

    2008-04-01

    Recently, our research group has proposed the hydroxyfurazanyl (4-hydroxy-1,2,5-oxadiazole-3-yl) moiety as a new non-classical isoster of the carboxy function in the design of gamma-aminobutyric acid (GABA) analogues. Some compounds showed significant activity at the GABA(A) receptor, representing the only examples of pentatomic heterocycles bearing an omega-aminoalkyl flexible side chain in the position vicinal to the hydroxy group displaying agonist activity at this receptor subtype. In this work, an ab initio analysis of the structural and electronic features of furazan-3-ol is presented, in order to provide a theoretical basis to the claimed bioisosterism with the carboxy function. An ab initio conformational study with the C-PCM implicit solvent model was carried out to elucidate the reasons of the peculiar behaviour of the furazan models. Alongside, another conformational search through molecular dynamics in explicit solvent was accomplished, in order to validate the first method. The electronic features of the 4-hydroxy-1,2,5-oxadiazole-3-yl substructure seem to account for a marked stabilising effect of the putative bioactive conformation at the GABA(A) receptor subtype. The 1,2,5-thiadiazole analogue, which shares the same conformational preference of its oxygenated counterpart, was identified as a potential candidate for synthesis and pharmacological testing. Figure 4-(omega-aminoalkyl)-1,2,5-oxadiazole-3-ol analogues of GABA. PMID:18247067

  10. Retinoic Acid, GABA-ergic, and TGF-β Signaling Systems Are Involved in Human Cleft Palate Fibroblast Phenotype

    PubMed Central

    Baroni, Tiziano; Bellucci, Catia; Lilli, Cinzia; Pezzetti, Furio; Carinci, Francesco; Becchetti, Ennio; Carinci, Paolo; Stabellini, Giordano; Calvitti, Mario; Lumare, Eleonora; Bodo, Maria

    2006-01-01

    During embryogenesis, a complex interplay between extracellular matrix (ECM) molecules, regulatory molecules, and growth factors mediates morphogenetic processes involved in palatogenesis. Transforming growth factor-β (TGF-β), retinoic acid (RA), and γ-aminobutyric acid (GABA)ergic signaling systems are also potentially involved. Using [3H]glucosamine and [35S]methionine incorporation, anion exchange chromatography, semiquantitative radioactive RT-PCR, and a TGF-β binding assay, we aimed to verify the presence of phenotypic differences between primary cultures of secondary palate (SP) fibroblasts from 2-year-old subjects with familial nonsyndromic cleft lip and/or palate (CLP-SP fibroblasts) and age-matched normal SP (N-SP) fibroblasts. The effects of RA—which, at pharmacologic doses, induces cleft palate in newborns of many species—were also studied. We found an altered ECM production in CLP-SP fibroblasts that synthesized and secreted more glycosaminoglycans (GAGs) and fibronectin (FN) compared with N-SP cells. In CLP-SP cells, TGF-β3 mRNA expression and TGF-β receptor number were higher and RA receptor-α (RARA) gene expression was increased. Moreover, we demonstrated for the first time that GABA receptor (GABRB3) mRNA expression was upregulated in human CLP-SP fibroblasts. In N-SP and CLP-SP fibroblasts, RA decreased GAG and FN secretion and increased TGF-β3 mRNA expression but reduced the number of TGF-β receptors. TGF-β receptor type I mRNA expression was decreased, TGF-β receptor type II was increased, and TGF-β receptor type III was not affected. RA treatment increased RARA gene expression in both cell populations but upregulated GABRB3 mRNA expression only in N-SP cells. These results show that CLP-SP fibroblasts compared with N-SP fibroblasts exhibit an abnormal phenotype in vitro and respond differently to RA treatment, and suggest that altered crosstalk between RA, GABAergic, and TGF-β signaling systems could be involved in human cleft

  11. Closing the loop on the GABA shunt in plants: are GABA metabolism and signaling entwined?

    PubMed Central

    Michaeli, Simon; Fromm, Hillel

    2015-01-01

    γ-Aminobutyric acid (GABA) is a non-proteinogenic amino acid that is found in uni- and multi-cellular organisms and is involved in many aspects of plant life cycle. GABA metabolism occurs by the action of evolutionary conserved enzymes that constitute the GABA shunt, bypassing two steps of the TCA cycle. The central position of GABA in the interface between plant carbon and nitrogen metabolism is well established. In parallel, there is evidence to support a role for GABA as a signaling molecule in plants. Here we cover some of the recent findings on GABA metabolism and signaling in plants and further suggest that the metabolic and signaling aspects of GABA may actually be inseparable. PMID:26106401

  12. GABA interaction with lipids in organic medium

    SciTech Connect

    Beltramo, D.; Kivatinitz, S.; Lassaga, E.; Arce, A.

    1987-08-10

    The interaction of TH-GABA and UC-glutamate with lipids in an aqueous organic partition system was studied. With this partition system TH-GABA and UC-glutamate were able to interact with sphingomyelin, sulfatide, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine and phosphatidic acid but not with cholesterol or ceramide. In an homogeneous aqueous medium the authors could not demonstrate any interaction between TH-GABA-lipids. The apparent dissociation constants (K/sub d/) for TH-GABA-lipids or UC-glutamate-lipids interactions inorganic medium were in the millimolar range and maximal charge between 3 and 7 moles of GABA or glutamate by mole of lipid. Amino acids such as glutamic acid, US -alanine and glycine displaced TH-GABA with the same potency as GABA itself; thus these results show that the interaction lacks pharmacological specificity. To detect this interaction lipid concentrations higher than 2 M were required and in the partition system TH-GABA and lipid phosphorus were both concentrated at the interface. Therefore, lipids tested with a biphasic partition system do not fulfill the classical criteria for a neurotransmitter receptor at least not for GABA and glutamate. 15 references, 1 figure, 3 tables.

  13. Use of sourdough fermentation and pseudo-cereals and leguminous flours for the making of a functional bread enriched of gamma-aminobutyric acid (GABA).

    PubMed

    Coda, Rossana; Rizzello, Carlo Giuseppe; Gobbetti, Marco

    2010-02-28

    Lactobacillus plantarum C48 and Lactococcus lactis subsp. lactis PU1, previously selected for the biosynthesis of gamma-aminobutyric acid (GABA), were used for sourdough fermentation of cereal, pseudo-cereal and leguminous flours. Chickpea, amaranth, quinoa and buckwheat were the flours most suitable to be enriched of GABA. The parameters of sourdough fermentation were optimized. Addition of 0.1mM pyridoxal phosphate, dough yield of 160, inoculum of 5 x 10(7)CFU/g of starter bacteria and fermentation for 24h at 30 degrees C were found to be the optimal conditions. A blend of buckwheat, amaranth, chickpea and quinoa flours (ratio 1:1:5.3:1) was selected and fermented with baker's yeast (non-conventional flour bread, NCB) or with Lb. plantarum C48 sourdough (non-conventional flour sourdough bread, NCSB) and compared to baker's yeast started wheat flour bread (WFB). NCSB had the highest concentration of free amino acids and GABA (ca. 4467 and 504 mg/kg, respectively). The concentration of phenolic compounds and antioxidant activity of NCSB bread was the highest, as well as the rate of in vitro starch hydrolysis was the lowest. Texture analysis showed that sourdough fermentation enhances several characteristics of NCSB with respect to NCB, thus approaching the features of WFB. Sensory analysis showed that sourdough fermentation allowed to get good palatability and overall taste appreciation. PMID:20071045

  14. Electric field directed nucleic acid hybridization on microchips.

    PubMed Central

    Edman, C F; Raymond, D E; Wu, D J; Tu, E; Sosnowski, R G; Butler, W F; Nerenberg, M; Heller, M J

    1997-01-01

    Selection and adjustment of proper physical parameters enables rapid DNA transport, site selective concentration, and accelerated hybridization reactions to be carried out on active microelectronic arrays. These physical parameters include DC current, voltage, solution conductivity and buffer species. Generally, at any given current and voltage level, the transport or mobility of DNA is inversely proportional to electrolyte or buffer conductivity. However, only a subset of buffer species produce both rapid transport, site specific concentration and accelerated hybridization. These buffers include zwitterionic and low conductivity species such as: d- and l-histidine; 1- and 3-methylhistidines; carnosine; imidazole; pyridine; and collidine. In contrast, buffers such as glycine, beta-alanine and gamma-amino-butyric acid (GABA) produce rapid transport and site selective concentration but do not facilitate hybridization. Our results suggest that the ability of these buffers (histidine, etc.) to facilitate hybridization appears linked to their ability to provide electric field concentration of DNA; to buffer acidic conditions present at the anode; and in this process acquire a net positive charge which then shields or diminishes repulsion between the DNA strands, thus promoting hybridization. PMID:9396795

  15. The Uptake of GABA in Trypanosoma cruzi.

    PubMed

    Galvez Rojas, Robert L; Ahn, Il-Young; Suárez Mantilla, Brian; Sant'Anna, Celso; Pral, Elizabeth Mieko Furusho; Silber, Ariel Mariano

    2015-01-01

    Gamma aminobutyric acid (GABA) is widely known as a neurotransmitter and signal transduction molecule found in vertebrates, plants, and some protozoan organisms. However, the presence of GABA and its role in trypanosomatids is unknown. Here, we report the presence of intracellular GABA and the biochemical characterization of its uptake in Trypanosoma cruzi, the etiological agent of Chagas' disease. Kinetic parameters indicated that GABA is taken up by a single transport system in pathogenic and nonpathogenic forms. Temperature dependence assays showed a profile similar to glutamate transport, but the effect of extracellular cations Na(+) , K(+) , and H(+) on GABA uptake differed, suggesting a different uptake mechanism. In contrast to reports for other amino acid transporters in T. cruzi, GABA uptake was Na(+) dependent and increased with pH, with a maximum activity at pH 8.5. The sensitivity to oligomycin showed that GABA uptake is dependent on ATP synthesis. These data point to a secondary active Na(+) /GABA symporter energized by Na(+) -exporting ATPase. Finally, we show that GABA occurs in the parasite's cytoplasm under normal culture conditions, indicating that it is regularly taken up from the culture medium or synthesized through an still undescribed metabolic pathway. PMID:25851259

  16. Gamma-aminobutyric acid (GABA) and neuropeptides in neural areas mediating motion-induced emesis

    NASA Technical Reports Server (NTRS)

    Damelio, F.; Daunton, Nancy G.; Fox, Robert A.

    1991-01-01

    Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid and the neuropeptides substance P and Met-enkephalin in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), dorsal motor nucleus of the vagus nerve (DMNV), and lateral vestibular nucleus (LVN). Glutamic acid decarboxylase immunoreactive (GAD-IR) terminals and fibers were observed in the AP and particularly in the ASP. A gradual decrease in the density of terminals was seen towards the solitary complex. The DMNV revealed irregularly scattered GAD-IR terminals within the neuropil or closely surrounding neuronal cell bodies. The LVN, particularly the dorsal division, showed numerous axon terminals which were mostly localize around large neurons and their proximal dendrites. Substance P immunoreactive (SP-IR) terminals and fibers showed high density in the solitary complex, in particular within the lateral division. The ASP showed medium to low density of SP-IR fibers and terminals. The AP exhibited a small number of fibers and terminals irregularly distributed. The DMNV revealed a high density of SP-IR terminals and fibers that were mainly concentrated in the periphery. Very few terminals were detected in the LVN. Met-enkephalin immunoreactive (Met-Enk-IR) fibers and terminals showed high density and uniform distribution in the DMNV. Scattered terminals and fibers were observed in the AP, ASP, and NTS (particularly the lateral division). The very few fibers were observed in the LVN surrounded the neuronal cell bodies. The present report is part of a study designed to investigate the interaction between neuropeptides and conventional neurotransmitters under conditions producing motion sickness and in the process of sensory-motor adaptation.

  17. L-DOPA Reverses the Increased Free Amino Acids Tissue Levels Induced by Dopamine Depletion and Rises GABA and Tyrosine in the Striatum.

    PubMed

    Solís, Oscar; García-Sanz, Patricia; Herranz, Antonio S; Asensio, María-José; Moratalla, Rosario

    2016-07-01

    Perturbations in the cerebral levels of various amino acids are associated with neurological disorders, and previous studies have suggested that such alterations have a role in the motor and non-motor symptoms of Parkinson's disease. However, the direct effects of chronic L-DOPA treatment, that produces dyskinesia, on neural tissue amino acid concentrations have not been explored in detail. To evaluate whether striatal amino acid concentrations are altered in peak dose dyskinesia, 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian mice were treated chronically with L-DOPA and tissue amino acid concentrations were assessed by HPLC analysis. These experiments revealed that neither 6-OHDA nor L-DOPA treatment are able to alter glutamate in the striatum. However, glutamine increases after 6-OHDA and returns back to normal levels with L-DOPA treatment, suggesting increased striatal glutamatergic transmission with lack of dopamine. In addition, glycine and taurine levels are increased following dopamine denervation and restored to normal levels by L-DOPA. Interestingly, dyskinetic animals showed increased levels of GABA and tyrosine, while aspartate striatal tissue levels are not altered. Overall, our results indicate that chronic L-DOPA treatment, besides normalizing the altered levels of some amino acids after 6-OHDA, robustly increases striatal GABA and tyrosine levels which may in turn contribute to the development of L-DOPA-induced dyskinesia. PMID:26966009

  18. Role for pro-inflammatory cytokines in regulating expression of GABA transporter type 1 and 3 in specific brain regions of kainic acid-induced status epilepticus.

    PubMed

    Su, Jing; Yin, Jian; Qin, Wei; Sha, Suxu; Xu, Jun; Jiang, Changbin

    2015-03-01

    In general, pro-inflammatory cytokines (PICs) contribute to regulation of epilepsy-associated pathophysiological processes in the central nerve system. In this report, we examined the specific activation of PICs, namely IL-1β, IL-6 and TNF-α in rat brain after kainic acid (KA)-induced status epilepticus (SE). Also, we examined the role played by PICs in regulating expression of GABA transporter type 1 and 3 (GAT-1 and GAT-3, respectively), which are the two important subtypes of GATs responsible for the regulation of extracellular GABA levels in the brain. Our results show that IL-1β, IL-6 and TNF-α were significantly increased in the parietal cortex, hippocampus and amygdala of KA-rats as compared with sham control animals (P < 0.05, KA rats vs. control rats). KA-induced SE also significantly increased (P < 0.05 vs. controls) the protein expression of GAT-1 and GAT-3 in those brain regions. In addition, central administration of antagonists to IL-1β and TNF-α receptors significantly attenuated amplified GAT-1 and GAT-3 (P < 0.05 vs. vehicle control for each antagonist group). However, antagonist to IL-6 receptor failed to attenuate enhancement in expression of GAT-1 and GAT-3 induced by KA-induced SE. Overall, our data demonstrate that PIC pathways are activated in the specific brain regions during SE which thereby selectively leads to upregulation of GABA transporters. As a result, it is likely that de-inhibition of GABA system is increased in the brain. This support a role for PICs in engagement of the adaptive mechanisms associated with epileptic activity, and has pharmacological implications to target specific PICs for neuronal dysfunction and vulnerability related to epilepsy. PMID:25708016

  19. [GABA-ergic system in defense against excitatory kynurenines].

    PubMed

    Lapin, I P

    1997-01-01

    Protection against the excitatory action of L-kynurenine and quinolinic acid in mice is related to the activation of GABA-B and dopamine receptors of the brain and to much lesser degree to the activation of GABA-A receptors. It is hardly believable that the anticonvulsant effect of phenibut (beta-phenyl-GABA), baclofen (CL-phenibut), sodium hydroxybutyrate and taurine against seizures induced by these two kynurenines is determined by alterations in metabolism of GABA. PMID:9503572

  20. GABA induces functionally active low-affinity GABA receptors on cultured cerebellar granule cells.

    PubMed

    Meier, E; Drejer, J; Schousboe, A

    1984-12-01

    The effect of gamma-aminobutyric acid (GABA) and its agonists muscimol and 4,5,6,7-tetrahydroisoxazolo[5-4-c]pyridin-3-ol (THIP) on the development of GABA receptors on cerebellar granule cells was studied by cultivation of the cells in media containing these substances. It was found that the presence of 50 microM GABA in the culture media led to the induction of low-affinity GABA receptors (KD 546 +/- 117 nM) in addition to the high-affinity receptors (KD 7 +/- 0.5 nM) which were present regardless of the presence of GABA in the culture media. The functional activity of the GABA receptors was tested by investigating the ability of GABA to modulate evoked glutamate release from the cells. It was found that GABA could inhibit evoked glutamate release (ED50 10 +/- 3 microM) only when the cells had been cultured in the presence of 50 microM GABA, 50 microM muscimol, or 150 microM THIP, i.e., under conditions where low-affinity GABA receptors were present on the cells. This inhibitory effect of GABA could be blocked by 120 microM bicuculline and mimicked by 50 microM muscimol or 150 microM THIP whereas 150 microM (-)-baclofen had no effect. It is concluded that GABA acting extracellularly induces formation of low-affinity receptors on cerebellar granule cells and that these receptors are necessary for mediating an inhibitory effect of GABA on evoked glutamate release. The pharmacological properties of these GABA receptors indicate that they belong to the so-called GABAA receptors. PMID:6149269

  1. GABA[subscript A] Receptor Downregulation in Brains of Subjects with Autism

    ERIC Educational Resources Information Center

    Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Thuras, Paul D.

    2009-01-01

    Gamma-aminobutyric acid A (GABA[subscript A]) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the…

  2. Alteration of brain levels of neurotransmitters and amino acids in male F344 rats induced by three-week repeated inhalation exposure to 1-bromopropane.

    PubMed

    Suda, Megumi; Honma, Takeshi; Miyagawa, Muneyuki; Wang, Rui-Sheng

    2008-08-01

    The present study investigated the effects of 1-bromopropane (1BP) on brain neuroactive substances of rats to determine the extent of its toxicity to the central nervous system (CNS). We measured the changes in neurotransmitters (acetylcholine, catecholamine, serotonin and amino acids) and their metabolites or precursors in eight brain regions after inhalation exposure to 1BP at 50 to 1,000 ppm for 8 h per day for 7 d per week for 3 wk. Rats were sacrificed at 2 h (Case 1), or at 19 h (Case 2) after the end of exposure. In Case 1, the level of 5-hydroxyindoleacetic acid (5HIAA) was lowered in some brain regions by 1BP exposure. The decrease of 5HIAA in the frontal cortex was statistically significant at 50 ppm 1BP exposure. In Case 2, gamma-amino butyric acid (GABA) and taurine were decreased in many brain regions of exposed rats, and a significant decrease of taurine in the midbrain occurred at 50 ppm 1BP exposure. In both cases of 2-h and 19-h intervals from the end of exposure to sacrifice, aspartate and glutamine levels were elevated in many brain regions, but the acetylcholine level did not change in any brain region. Three-week repeated exposure to 1BP produced significantly changes in amino acid contents of rat brains, particularly at 1,000 ppm. PMID:18716383

  3. Targeting γ-aminobutyric acid (GABA) carriers to the brain: potential relevance as antiepileptic pro-drugs.

    PubMed

    Semreen, Mohammad H; El-Shorbagi, Abdel-Nasser; Al-Tel, Taleb H; Alsalahat, Izzeddin M M

    2010-05-01

    The search for antiepileptic compounds with more selective activity continues to be an area of intensive investigation in medicinal chemistry. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives, 3a-g, potential prodrugs incorporating the neurotransmitter GABA were synthesized and studied for crossing the blood-brain barrier (BBB). Compounds were prepared from primary amines and carbon disulfide to give dithiocarbamates 2a-g which upon reaction in situ with formaldehyde provided the intermediates Ia-g. Addition of Ia-g onto GABA furnished the title compounds 3a-g. The structures were verified by spectral data and the amounts of the compounds in the brain were investigated by using HPLC. The concentration profiles of the tested compounds in mice brain were determined and the in vivo anticonvulsant activity was measured. PMID:20632978

  4. Role of a γ-aminobutryic acid (GABA) receptor mutation in the evolution and spread of Diabrotica virgifera virgifera resistance to cyclodiene insecticides.

    PubMed

    Wang, H; Coates, B S; Chen, H; Sappington, T W; Guillemaud, T; Siegfried, B D

    2013-10-01

    The western corn rootworm, Diabrotica virgifera virgifera, is a damaging pest of cultivated corn that was controlled by applications of cyclodiene insecticides from the late 1940s until resistance evolved ∼10 years later. Range expansion from the western plains into eastern USA coincides with resistance development. An alanine to serine amino acid substitution within the Rdl subunit of the gamma-aminobutyric acid (GABA) receptor confers resistance to cyclodiene insecticides in many species. We found that the non-synonymous single nucleotide polymorphism (SNP) G/T at the GABA receptor cDNA position 838 (G/T(838)) of D. v. virgifera resulted in the alanine to serine change, and the codominant SNP allele T(838) was genetically linked to survival of beetles in aldrin bioassays. A phenotypic gradient of decreasing susceptibility from west to east was correlated with higher frequencies of the resistance-conferring T(838) allele in the eastern-most populations. This pattern exists in opposition to perceived selective pressures since the more eastern and most resistant populations probably experienced reduced exposure. The reasons for the observed distribution are uncertain, but historical records of the range expansion combined with the distribution of susceptible and resistant phenotypes and genotypes provide an opportunity to better understand factors affecting the species' range expansion. PMID:23841833

  5. Pharmacology of GABA.

    PubMed

    Meldrum, B

    1982-01-01

    GABA-ergic systems are involved in all the main functions of the brain. In most brain regions impairment of this system produces epileptic activity. GABA-mediated inhibitory function can be enhanced by drugs of at least seven different types. They act on the metabolism or synaptic release of GABA, or its reuptake into neurones of glia, or on various components of the GABA receptor complex (GABA recognition site, "benzodiazepine" receptor or chloride ionophore). Among such compounds, those which act most specifically and potently on GABA receptors remain primarily research tools. Among compounds in clinical use, valproate, benzodiazepines, and anticonvulsant barbiturates al enhance GABA-mediated inhibition. In the future, new inhibitors of GABA uptake, new GABA agonists and potent inhibitors of GABA-transaminase are likely to become available. Trials of drugs enhancing GABA-ergic function have been made in a wide variety of neurological disorders. In most forms of epilepsy a therapeutic effect is evident. Real benefit from GABA therapies has not been demonstrated in the principal disorders of movement (Huntington's chorea, Parkinson's disease, dystonias), except in so far as they have a myoclonic or paroxysmal component. Among psychiatric disorders the acute symptoms of schizophrenia are exacerbated by enhanced GABA-ergic function. Abstinence syndromes (alcohol, barbiturate or narcotic withdrawal) are ameliorated by drugs enhancing GABA-ergic function, and there is some evidence for a beneficial action in anxiety states and mania. Attempts to relate the molecular neurobiology of GABA with clinical pharmacology are of very recent origin. Improved understanding of the variety of GABA receptor mechanisms will provide the key to the more selective pharmacological manipulations that are required for therapeutic success. PMID:6214305

  6. Linking Metabolism to Membrane Signaling: The GABA-Malate Connection.

    PubMed

    Gilliham, Matthew; Tyerman, Stephen D

    2016-04-01

    γ-Aminobutyric acid (GABA) concentration increases rapidly in tissues when plants encounter abiotic or biotic stress, and GABA manipulation affects growth. This, coupled to GABA's well-described role as a neurotransmitter in mammals, led to over a decade of speculation that GABA is a signal in plants. The discovery of GABA-regulated anion channels in plants provides compelling mechanistic proof that GABA is a legitimate plant-signaling molecule. Here we examine research avenues unlocked by this finding and propose that these plant 'GABA receptors' possess novel properties ideally suited to translating changes in metabolic status into physiological responses. Specifically, we suggest they have a role in signaling altered cycling of tricarboxylic acid (TCA) intermediates during stress via eliciting changes in electrical potential differences across membranes. PMID:26723562

  7. Brain regional distribution of GABA(A) receptors exhibiting atypical GABA agonism: roles of receptor subunits.

    PubMed

    Halonen, Lauri M; Sinkkonen, Saku T; Chandra, Dev; Homanics, Gregg E; Korpi, Esa R

    2009-11-01

    The major inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA), has only partial efficacy at certain subtypes of GABA(A) receptors. To characterize these minor receptor populations in rat and mouse brains, we used autoradiographic imaging of t-butylbicyclophosphoro[(35)S]thionate ([(35)S]TBPS) binding to GABA(A) receptors in brain sections and compared the displacing capacities of 10mM GABA and 1mM 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a competitive GABA-site agonist. Brains from GABA(A) receptor alpha1, alpha4, delta, and alpha4+delta subunit knockout (KO) mouse lines were used to understand the contribution of these particular receptor subunits to "GABA-insensitive" (GIS) [(35)S]TBPS binding. THIP displaced more [(35)S]TBPS binding than GABA in several brain regions, indicating that THIP also inhibited GIS-binding. In these regions, GABA prevented the effect of THIP on GIS-binding. GIS-binding was increased in the cerebellar granule cell layer of delta KO and alpha4+delta KO mice, being only slightly diminished in that of alpha1 KO mice. In the thalamus and some other forebrain regions of wild-type mice, a significant amount of GIS-binding was detected. This GIS-binding was higher in alpha4 KO mice. However, it was fully abolished in alpha1 KO mice, indicating that the alpha1 subunit was obligatory for the GIS-binding in the forebrain. Our results suggest that native GABA(A) receptors in brain sections showing reduced displacing capacity of [(35)S]TBPS binding by GABA (partial agonism) minimally require the assembly of alpha1 and beta subunits in the forebrain and of alpha6 and beta subunits in the cerebellar granule cell layer. These receptors may function as extrasynaptic GABA(A) receptors. PMID:19397945

  8. Brain γ-aminobutyric acid (GABA) detection in vivo with the J-editing (1) H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement, macromolecule contamination and test-retest reliability.

    PubMed

    Shungu, Dikoma C; Mao, Xiangling; Gonzales, Robyn; Soones, Tacara N; Dyke, Jonathan P; van der Veen, Jan Willem; Kegeles, Lawrence S

    2016-07-01

    Abnormalities in brain γ-aminobutyric acid (GABA) have been implicated in various neuropsychiatric and neurological disorders. However, in vivo GABA detection by (1) H MRS presents significant challenges arising from the low brain concentration, overlap by much stronger resonances and contamination by mobile macromolecule (MM) signals. This study addresses these impediments to reliable brain GABA detection with the J-editing difference technique on a 3-T MR system in healthy human subjects by: (i) assessing the sensitivity gains attainable with an eight-channel phased-array head coil; (ii) determining the magnitude and anatomic variation of the contamination of GABA by MM; and (iii) estimating the test-retest reliability of the measurement of GABA with this method. Sensitivity gains and test-retest reliability were examined in the dorsolateral prefrontal cortex (DLPFC), whereas MM levels were compared across three cortical regions: DLPFC, the medial prefrontal cortex (MPFC) and the occipital cortex (OCC). A three-fold higher GABA detection sensitivity was attained with the eight-channel head coil compared with the standard single-channel head coil in DLPFC. Despite significant anatomical variation in GABA + MM and MM across the three brain regions (p < 0.05), the contribution of MM to GABA + MM was relatively stable across the three voxels, ranging from 41% to 49%, a non-significant regional variation (p = 0.58). The test-retest reliability of GABA measurement, expressed as either the ratio to voxel tissue water (W) or to total creatine, was found to be very high for both the single-channel coil and the eight-channel phased-array coil. For the eight-channel coil, for example, Pearson's correlation coefficient of test vs. retest for GABA/W was 0.98 (R(2)  = 0.96, p = 0.0007), the percentage coefficient of variation (CV) was 1.25% and the intraclass correlation coefficient (ICC) was 0.98. Similar reliability was also found for the co-edited resonance

  9. How and why does tomato accumulate a large amount of GABA in the fruit?

    PubMed Central

    Takayama, Mariko; Ezura, Hiroshi

    2015-01-01

    Gamma-aminobutyric acid (GABA) has received much attention as a health-promoting functional compound, and several GABA-enriched foods have been commercialized. In higher plants, GABA is primarily metabolized via a short pathway called the GABA shunt. The GABA shunt bypasses two steps (the oxidation of α-ketoglutarate to succinate) of the tricarboxylic acid (TCA) cycle via reactions catalyzed by three enzymes: glutamate decarboxylase, GABA transaminase, and succinic semialdehyde dehydrogenase. The GABA shunt plays a major role in primary carbon and nitrogen metabolism and is an integral part of the TCA cycle under stress and non-stress conditions. Tomato is one of the major crops that accumulate a relatively high level of GABA in its fruits. The GABA levels in tomato fruits dramatically change during fruit development; the GABA levels increase from flowering to the mature green stage and then rapidly decrease during the ripening stage. Although GABA constitutes up to 50% of the free amino acids at the mature green stage, the molecular mechanism of GABA accumulation and the physiological function of GABA during tomato fruit development remain unclear. In this review, we summarize recent studies of GABA accumulation in tomato fruits and discuss the potential biological roles of GABA in tomato fruit development. PMID:26322056

  10. Effects of yoga on the autonomic nervous system, gamma-aminobutyric-acid, and allostasis in epilepsy, depression, and post-traumatic stress disorder.

    PubMed

    Streeter, C C; Gerbarg, P L; Saper, R B; Ciraulo, D A; Brown, R P

    2012-05-01

    A theory is proposed to explain the benefits of yoga practices in diverse, frequently comorbid medical conditions based on the concept that yoga practices reduce allostatic load in stress response systems such that optimal homeostasis is restored. It is hypothesized that stress induces (1) imbalance of the autonomic nervous system (ANS) with decreased parasympathetic nervous system (PNS) and increased sympathetic nervous system (SNS) activity, (2) underactivity of the gamma amino-butyric acid (GABA) system, the primary inhibitory neurotransmitter system, and (3) increased allostatic load. It is further hypothesized that yoga-based practices (4) correct underactivity of the PNS and GABA systems in part through stimulation of the vagus nerves, the main peripheral pathway of the PNS, and (5) reduce allostatic load. Depression, epilepsy, post traumatic stress disorder (PTSD), and chronic pain exemplify medical conditions that are exacerbated by stress, have low heart rate variability (HRV) and low GABAergic activity, respond to pharmacologic agents that increase activity of the GABA system, and show symptom improvement in response to yoga-based interventions. The observation that treatment resistant cases of epilepsy and depression respond to vagal nerve stimulation corroborates the need to correct PNS underactivity as part of a successful treatment plan in some cases. According to the proposed theory, the decreased PNS and GABAergic activity that underlies stress-related disorders can be corrected by yoga practices resulting in amelioration of disease symptoms. This has far-reaching implications for the integration of yoga-based practices in the treatment of a broad array of disorders exacerbated by stress. PMID:22365651

  11. Different control mechanisms of growth hormone (GH) secretion between gamma-amino- and gamma-hydroxy-butyric acid: neuroendocrine evidence in Parkinson's disease.

    PubMed

    Volpi, R; Chiodera, P; Caffarra, P; Scaglioni, A; Saccani, A; Coiro, V

    1997-10-01

    The observation that baclofen stimulates growth hormone (GH) secretion in normal men, but not in parkinsonian patients led us to test the GH releasing effect of other gamma-amino-butyric acid (GABA)ergic agents with different mechanisms of action in Parkinson's disease. For this purpose 10 normal men and 10 de novo parkinsonian patients were tested with sodium valproate (800 mg PO), gamma-hydroxybutyric acid (GHB) (25 mg/kg body weight PO) and baclofen (10 mg PO). All drugs induced a significant increment in serum GH levels in the normal controls. On the other hand, GH secretion in parkinsonian patients did not change after baclofen or sodium valproate administration, whereas it showed normal responsiveness to GHB. These data suggest that the mechanism underlying the GH response to GHB is different from that (or those) mediating sodium valproate and/or baclofen action. In addition, the former, but not the latter mechanism appears to be preserved in the parkinsonian brain. PMID:9373886

  12. Library screening by means of mass spectrometry (MS) binding assays-exemplarily demonstrated for a pseudostatic library addressing γ-aminobutyric acid (GABA) transporter 1 (GAT1).

    PubMed

    Sindelar, Miriam; Wanner, Klaus T

    2012-09-01

    In the present study, the application of mass spectrometry (MS) binding assays as a tool for library screening is reported. For library generation, dynamic combinatorial chemistry (DCC) was used. These libraries can be screened by means of MS binding assays when appropriate measures are taken to render the libraries pseudostatic. That way, the efficiency of MS binding assays to determine ligand binding in compound screening with the ease of library generation by DCC is combined. The feasibility of this approach is shown for γ-aminobutyric acid (GABA) transporter 1 (GAT1) as a target, representing the most important subtype of the GABA transporters. For the screening, hydrazone libraries were employed that were generated in the presence of the target by reacting various sets of aldehydes with a hydrazine derivative that is delineated from piperidine-3-carboxylic acid (nipecotic acid), a common fragment of known GAT1 inhibitors. To ensure that the library generated is pseudostatic, a large excess of the nipecotic acid derivative is employed. As the library is generated in a buffer system suitable for binding and the target is already present, the mixtures can be directly analyzed by MS binding assays-the process of library generation and screening thus becoming simple to perform. The binding affinities of the hits identified by deconvolution were confirmed in conventional competitive MS binding assays performed with single compounds obtained by separate synthesis. In this way, two nipecotic acid derivatives exhibiting a biaryl moiety, 1-{2-[2'-(1,1'-biphenyl-2-ylmethylidene)hydrazine]ethyl}piperidine-3-carboxylic acid and 1-(2-{2'-[1-(2-thiophenylphenyl)methylidene]hydrazine}ethyl)piperidine-3-carboxylic acid, were found to be potent GAT1 ligands exhibiting pK(i) values of 6.186 ± 0.028 and 6.229 ± 0.039, respectively. This method enables screening of libraries, whether generated by conventional chemistry or DCC, and is applicable to all kinds of targets including

  13. Impact of exogenous GABA treatments on endogenous GABA metabolism in anthurium cut flowers in response to postharvest chilling temperature.

    PubMed

    Aghdam, Morteza Soleimani; Naderi, Roohangiz; Jannatizadeh, Abbasali; Babalar, Mesbah; Sarcheshmeh, Mohammad Ali Askari; Faradonbe, Mojtaba Zamani

    2016-09-01

    Anthurium flowers are susceptible to chilling injury, and the optimum storage temperature is 12.5-20 °C. The γ-aminobutyric acid (GABA) shunt pathway may alleviate chilling stress in horticultural commodities by providing energy (ATP), reducing molecules (NADH), and minimizing accumulation of reactive oxygen species (ROS). In this experiment, the impact of a preharvest spray treatment with 1 mM GABA and postharvest treatment of 5 mM GABA stem-end dipping on GABA shunt pathway activity of anthurium cut flowers (cv. Sirion) in response to cold storage (4 °C for 21 days) was investigated. GABA treatments resulted in lower glutamate decarboxylase (GAD) and higher GABA transaminase (GABA-T) activities in flowers during cold storage, which was associated with lower GABA content and coincided with higher ATP content. GABA treatments also enhanced accumulation of endogenous glycine betaine (GB) in flowers during cold storage, as well as higher spathe relative water content (RWC). These findings suggest that GABA treatments may alleviate chilling injury of anthurium cut flowers by enhancing GABA shunt pathway activity leading to provide sufficient ATP and promoting endogenous GB accumulation. PMID:27135813

  14. Guinea Pig Horizontal Cells Express GABA, the GABA-Synthesizing Enzyme GAD65, and the GABA Vesicular Transporter

    PubMed Central

    Guo, Chenying; Hirano, Arlene A.; Stella, Salvatore L.; Bitzer, Michaela; Brecha, Nicholas C.

    2013-01-01

    γ-Aminobutyric acid (GABA) is likely expressed in horizontal cells of all species, although conflicting physiological findings have led to considerable controversy regarding its role as a transmitter in the outer retina. This study has evaluated key components of the GABA system in the outer retina of guinea pig, an emerging retinal model system. The presence of GABA, its rate-limiting synthetic enzyme glutamic acid decarboxylase (GAD65 and GAD67 isoforms), the plasma membrane GABA transporters (GAT-1 and GAT-3), and the vesicular GABA transporter (VGAT) was evaluated by using immunohistochemistry with well-characterized antibodies. The presence of GAD65 mRNA was also evaluated by using laser capture microdissection and reverse transcriptase-polymerase chain reaction. Specific GABA, GAD65, and VGAT immunostaining was localized to horizontal cell bodies, as well as to their processes and tips in the outer plexiform layer. Furthermore, immunostaining of retinal whole mounts and acutely dissociated retinas showed GAD65 and VGAT immunoreactivity in both A-type and B-type horizontal cells. However, these cells did not contain GAD67, GAT-1, or GAT-3 immunoreactivity. GAD65 mRNA was detected in horizontal cells, and sequencing of the amplified GAD65 fragment showed approximately 85% identity with other mammalian GAD65 mRNAs. These studies demonstrate the presence of GABA, GAD65, and VGAT in horizontal cells of the guinea pig retina, and support the idea that GABA is synthesized from GAD65, taken up into synaptic vesicles by VGAT, and likely released by a vesicular mechanism from horizontal cells. PMID:20235161

  15. [Autoantibodies to glutamate and GABA in opiate addiction].

    PubMed

    Vetrile, L A; Fomina, V G; Nevidimova, T I; Vetlugina, T P; Batukhtina, E I; Savochkina, D N; Zakharova, I A; Davydova, T V

    2015-01-01

    Blood serum from 129 patients with opium addiction at different stages of the disease and 63 donors (control group) was examined for the presence of autoantibodies to the exciting and inhibitory amino acids glutamate and GABA. It was shown enhanced production of autoantibodies to glutamate and GABA. Dependence of the level and frequency of detec- tion of autoantibodies to glutamate and GABA on the stage of the disease was revealed. PMID:26852594

  16. Effects of prenatal exposure to 2,4-D/2,4,5-T mixture on postnatal changes in rat brain glutamate, GABA protein, and nucleic acid levels

    SciTech Connect

    Mohammad, F.K.; Omer, V.E.V.

    1988-02-01

    The opportunity of maternal exposure to various chemicals in the work place and the general environments have increased, and the fetus and neonate may be at greater risk than the adult. However, the embryotoxic and teratogenic effects of the chlorinated phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), the main chemicals in Agent Orange, are well documented only in laboratory animals. The brain of the developing fetus is vulnerable to the toxic effects of the phenoxy herbicides which readily cross the placental barrier and distribute into fetal tissues, including brain. Although the neurochemical basis for the behavioral teratogenicity of the phenoxy herbicides is not know, it was recently reported that non-teratogenic doses of a 1:1 mixture of 2,4-D and 2,4,5-T delayed the ontogeny of dopamine and serotonin in the brain of the developing rate. This communication provides further descriptive information about the ontogeny of rat brain nucleic acid, protein, glutamate and ..gamma..-aminobutyrate (GABA) following in utero exposure to non-teratogenic levels of a 1:1 mixture of 2,4-D/2,4,5-T.

  17. Quantitative autoradiographic characterization of GA-BA sub B receptors in mammalian central nervous system

    SciTech Connect

    Chu, D.Chin-Mei.

    1989-01-01

    The inhibitory effects of the amino acid neurotransmitter {gamma}-aminobutyric acid (GABA) within the nervous system appear to be mediated through two distinct classes of receptors: GABA{sub A} and GABA{sub B} receptors. A quantitative autoradiographic method with {sup 3}H-GABA was developed to examine the hypotheses that GABA{sub A} and GABA{sub B} sites have distinct anatomical distributions, pharmacologic properties, and synaptic localizations within the rodent nervous system. The method was also applied to a comparative study of these receptors in postmortem human brain from individuals afflicted with Alzheimer's disease and those without neurologic disease. The results indicated that GABA{sub B} receptors occur in fewer numbers and have a lower affinity for GABA than GABA{sub A} receptors in both rodent and human brain. Within rodent brain, the distribution of these two receptor populations were clearly distinct. GABA{sub B} receptors were enriched in the medial habenula, interpeduncular nucleus, cerebellar molecular layer and olfactory glomerular layer. After selective lesions of postsynaptic neurons of the corticostriatal and perforant pathway, both GABA{sub B} and GABA{sub A} receptors were significantly decreased in number. Lesions of the presynaptic limbs of the perforant but not the corticostriatal pathway resulted in upregulation of both GABA receptors in the area of innervation. GABA{sub B} receptors were also upregulated in CA3 dendritic regions after destruction of dentate granule neurons.

  18. Isoflurane modulates excitability in the mouse thalamus via GABA-dependent and GABA-independent mechanisms.

    PubMed

    Ying, Shui-Wang; Werner, David F; Homanics, Gregg E; Harrison, Neil L; Goldstein, Peter A

    2009-02-01

    GABAergic neurons in the reticular thalamic nucleus (RTN) synapse onto thalamocortical neurons in the ventrobasal (VB) thalamus, and this reticulo-thalamocortical pathway is considered an anatomic target for general anesthetic-induced unconsciousness. A mutant mouse was engineered to harbor two amino acid substitutions (S270H, L277A) in the GABA(A) receptor (GABA(A)-R) alpha1 subunit; this mutation abolished sensitivity to the volatile anesthetic isoflurane in recombinant GABA(A)-Rs, and reduced in vivo sensitivity to isoflurane in the loss-of-righting-reflex assay. We examined the effects of the double mutation on GABA(A)-R-mediated synaptic currents and isoflurane sensitivity by recording from thalamic neurons in brain slices. The double mutation accelerated the decay, and decreased the (1/2) width of, evoked inhibitory postsynaptic currents (eIPSCs) in VB neurons and attenuated isoflurane-induced prolongation of the eIPSC. The hypnotic zolpidem, a selective modulator of GABA(A)-Rs containing the alpha1 subunit, prolonged eIPSC duration regardless of genotype, indicating that mutant mice incorporate alpha1 subunit-containing GABA(A)-Rs into synapses. In RTN neurons, which lack the alpha1 subunit, eIPSC duration was longer than in VB, regardless of genotype. Isoflurane reduced the efficacy of GABAergic transmission from RTN to VB, independent of genotype, suggesting a presynaptic action in RTN neurons. Consistent with this observation, isoflurane inhibited both tonic action potential and rebound burst firing in the presence of GABA(A)-R blockade. The suppressed excitability in RTN neurons is likely mediated by isoflurane-enhanced Ba(2+)-sensitive, but 4-aminopyridine-insenstive, potassium conductances. We conclude that isoflurane enhances inhibition of thalamic neurons in VB via GABA(A)-R-dependent, but in RTN via GABA(A)-R-independent, mechanisms. PMID:18948126

  19. Distribution of 3H-GABA uptake sites in the nematode Ascaris

    SciTech Connect

    Guastella, J.; Stretton, A.O. )

    1991-05-22

    The distribution of uptake sites for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the nematode Ascaris suum was examined by autoradiography of 3H-GABA uptake. Single neural processes in both the ventral and dorsal nerve cords were labeled with 3H-GABA. Serial section analysis identified the cells of origin of these processes as the RMEV-like and RMED-like neurons. These cells belong to a set of four neurons in the nerve ring, all of which are labeled by 3H-GABA. 3H-GABA labeling of at least two other sets of cephalic neurons was seen. One of these pairs consists of medium-sized lateral ganglia neurons, located at the level of the amphid commissure bundle. A second pair is located in the lateral ganglia at the level of the deirid commissure bundle. The position and size of these lateral ganglia cells suggest that they are the GABA-immunoreactive lateral ganglia cells frequently seen in whole-mount immunocytochemical preparations. Four neuronal cell bodies located in the retrovesicular ganglion were also labeled with 3H-GABA. These cells, which are probably cholinergic excitatory motor neurons, do not contain detectable GABA-like immunoreactivity. Heavy labeling of muscle cells was also observed. The ventral and dorsal nerve cord inhibitory motor neurons, which are known to contain GABA-like immunoreactivity, were not labeled above background with 3H-GABA. Together with the experiments reported previously, these results define three classes of GABA-associated neurons in Ascaris: (1) neurons that contain endogenous GABA and possess a GABA uptake system; (2) neurons that contain endogenous GABA, but that either lack a GABA uptake system or possess a GABA uptake system of low activity; (3) neurons that possess a GABA uptake system, but that lack endogenous GABA.

  20. Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition.

    PubMed

    Yoon, Bo-Eun; Woo, Junsung; Chun, Ye-Eun; Chun, Heejung; Jo, Seonmi; Bae, Jin Young; An, Heeyoung; Min, Joo Ok; Oh, Soo-Jin; Han, Kyung-Seok; Kim, Hye Yun; Kim, Taekeun; Kim, Young Soo; Bae, Yong Chul; Lee, C Justin

    2014-11-15

    GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5-10 mM by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca(2+)-induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain. PMID:25239459

  1. Lactic acid bacteria contribution to gut microbiota complexity: lights and shadows

    PubMed Central

    Pessione, Enrica

    2012-01-01

    Lactic Acid Bacteria (LAB) are ancient organisms that cannot biosynthesize functional cytochromes, and cannot get ATP from respiration. Besides sugar fermentation, they evolved electrogenic decarboxylations and ATP-forming deiminations. The right balance between sugar fermentation and decarboxylation/deimination ensures buffered environments thus enabling LAB to survive in human gastric trait and colonize gut. A complex molecular cross-talk between LAB and host exists. LAB moonlight proteins are made in response to gut stimuli and promote bacterial adhesion to mucosa and stimulate immune cells. Similarly, when LAB are present, human enterocytes activate specific gene expression of specific genes only. Furthermore, LAB antagonistic relationships with other microorganisms constitute the basis for their anti-infective role. Histamine and tyramine are LAB bioactive catabolites that act on the CNS, causing hypertension and allergies. Nevertheless, some LAB biosynthesize both gamma-amino-butyrate (GABA), that has relaxing effect on gut smooth muscles, and beta-phenylethylamine, that controls satiety and mood. Since LAB have reduced amino acid biosynthetic abilities, they developed a sophisticated proteolytic system, that is also involved in antihypertensive and opiod peptide generation from milk proteins. Short-chain fatty acids are glycolytic and phosphoketolase end-products, regulating epithelial cell proliferation and differentiation. Nevertheless, they constitute a supplementary energy source for the host, causing weight gain. Human metabolism can also be affected by anabolic LAB products such as conjugated linoleic acids (CLA). Some CLA isomers reduce cancer cell viability and ameliorate insulin resistance, while others lower the HDL/LDL ratio and modify eicosanoid production, with detrimental health effects. A further appreciated LAB feature is the ability to fix selenium into seleno-cysteine. Thus, opening interesting perspectives for their utilization as

  2. Biphasic effects of direct, but not indirect, GABA mimetics and antagonists on haloperidol-induced catalepsy.

    PubMed

    Worms, P; Lloyd, K G

    1980-03-01

    At very low doses the GABA agonists SL 76002 and muscimol diminish haloperidol-induced catalepsy. At somewhat higher doses these compounds potentiate catalepsy. Biphasic effects on DA-receptor mediated functions have previously been noted with bicuculline and picrotoxinin. In contrast, manipulation of GABA levels by enzyme inhibition induced only a monophasic effect on dopamine-mediated behaviour. The potentiation of GABA levels by enzyme inhibition induced only a monophasic effect on dopamine-mediated behaviour. The potentiation of haloperidol-induced catalepsy by GABA mimetics is also observed with dipropylacetate, delta-aminovaleric acid and gamma-acetylenic GABA. This GABA-mimetic potentiation of catakepsy was blocked by the coadministration of bicuculline. These results confirm and extend the hypothesis that GABA-neurons influence DA neuron function. Furthermore they suggest that more than one group of GABA receptors influence directly and/or indirectly DA neuronal function, with different resultant effects. PMID:7189827

  3. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  4. Chronic benzodiazepine treatment and cortical responses to adenosine and GABA.

    PubMed

    Mally, J; Connick, J H; Stone, T W

    1990-10-22

    The effects of chronic treatment of mice with clonazepam have been examined on the responses of neocortical slices to adenosine, 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA). Responses to these agonists were measured as changes in the depolarisation induced by N-methyl-D-aspartate (NMDA). Added to the superfusion medium diazepam blocked responses to adenosine but not 5-HT; this effect was not observed with 2-chloroadenosine or in the presence of 2-hydroxynitrobenzylthioguanosine. GABA was inactive in control slices but chronic treatment with clonazepam induced responses to GABA and enhanced responses to adenosine but not 5-HT. It is suggested that the induction of GABA responses may reflect the up-regulation of GABA receptors, but the increase of adenosine responses by clonazepam implies that there is no simple relationship between adenosine receptor binding and functional responses. PMID:1979931

  5. Neurotoxins from snake venoms and α-conotoxin ImI inhibit functionally active ionotropic γ-aminobutyric acid (GABA) receptors.

    PubMed

    Kudryavtsev, Denis S; Shelukhina, Irina V; Son, Lina V; Ojomoko, Lucy O; Kryukova, Elena V; Lyukmanova, Ekaterina N; Zhmak, Maxim N; Dolgikh, Dmitry A; Ivanov, Igor A; Kasheverov, Igor E; Starkov, Vladislav G; Ramerstorfer, Joachim; Sieghart, Werner; Tsetlin, Victor I; Utkin, Yuri N

    2015-09-11

    Ionotropic receptors of γ-aminobutyric acid (GABAAR) regulate neuronal inhibition and are targeted by benzodiazepines and general anesthetics. We show that a fluorescent derivative of α-cobratoxin (α-Ctx), belonging to the family of three-finger toxins from snake venoms, specifically stained the α1β3γ2 receptor; and at 10 μm α-Ctx completely blocked GABA-induced currents in this receptor expressed in Xenopus oocytes (IC50 = 236 nm) and less potently inhibited α1β2γ2 ≈ α2β2γ2 > α5β2γ2 > α2β3γ2 and α1β3δ GABAARs. The α1β3γ2 receptor was also inhibited by some other three-finger toxins, long α-neurotoxin Ls III and nonconventional toxin WTX. α-Conotoxin ImI displayed inhibitory activity as well. Electrophysiology experiments showed mixed competitive and noncompetitive α-Ctx action. Fluorescent α-Ctx, however, could be displaced by muscimol indicating that most of the α-Ctx-binding sites overlap with the orthosteric sites at the β/α subunit interface. Modeling and molecular dynamic studies indicated that α-Ctx or α-bungarotoxin seem to interact with GABAAR in a way similar to their interaction with the acetylcholine-binding protein or the ligand-binding domain of nicotinic receptors. This was supported by mutagenesis studies and experiments with α-conotoxin ImI and a chimeric Naja oxiana α-neurotoxin indicating that the major role in α-Ctx binding to GABAAR is played by the tip of its central loop II accommodating under loop C of the receptors. PMID:26221036

  6. GABA selectively increases mucin-1 expression in isolated pig jejunum.

    PubMed

    Braun, Hannah-Sophie; Sponder, Gerhard; Pieper, Robert; Aschenbach, Jörg R; Deiner, Carolin

    2015-11-01

    The inhibitory neurotransmitter GABA (γ-aminobutyric acid) is synthesized by glutamic acid decarboxylase, which is expressed in the central nervous system and in various other tissues including the intestine. Moreover, GABA can be ingested in vegetarian diets or produced by bacterial commensals in the gastrointestinal tract. As previous studies in lung have suggested a link between locally increased GABA availability and mucin 5AC production, the present study sought to test whether the presence or lack of GABA (and its precursor glutamine) has an effect on intestinal mucin expression. Porcine jejunum epithelial preparations were incubated with two different amounts of GABA or glutamine on the mucosal side for 4 h, and changes in the relative gene expression of seven different mucins, enzymes involved in mucin shedding, GABA B receptor, enzymes involved in glutamine/GABA metabolism, glutathione peroxidase 2, and interleukin 10 were examined by quantitative PCR (TaqMan(®) assays). Protein expression of mucin-1 (MUC1) was analyzed by Western blot. On the RNA level, only MUC1 was significantly up-regulated by both GABA concentrations compared with the control. Glutamine-treated groups showed the same trend. On the protein level, all treatment groups showed a significantly higher MUC1 expression than the control group. We conclude that GABA selectively increases the expression of MUC1, a cell surface mucin that prevents the adhesion of microorganisms, because of its size and negative charge, and therefore propose that the well-described positive effects of glutamine on enterocytes and intestinal integrity are partly attributable to effects of its metabolite GABA. PMID:26471792

  7. First molecular genotyping of A302S mutation in the gamma aminobutyric acid (GABA) receptor in Aedes albopictus from Malaysia.

    PubMed

    Low, V L; Vinnie-Siow, W Y; Lim Y, A L; Tan, T K; Leong, C S; Chen, C D; Azidah, A A; Sofian-Azirun, M

    2015-09-01

    Given the lack of molecular evidence in altered target-site insecticide resistance mechanism in Aedes albopictus (Skuse) worldwide, the present study aims to detect the presence of A302S mutation in the gene encoding the gamma aminobutyric acid receptor resistant to dieldrin (Rdl) in Ae. albopictus for the first time from its native range of South East Asia, namely Malaysia. World Health Organization (WHO) adult susceptibility bioassay indicated a relatively low level of dieldrin resistance (two-fold) in Ae. albopictus from Petaling Jaya, Selangor. However, PCR-RFLP and direct sequencing methods revealed the presence of the A302S mutation with the predomination of heterozygous genotype (40 out of 82 individuals), followed by the resistant genotype with 11 individuals. This study represents the first field evolved instance of A302S mutation in Malaysian insect species. PMID:26695218

  8. Pharmacodynamic effects and possible therapeutic uses of THIP, a specific GABA-agonist.

    PubMed

    Christensen, A V; Svendsen, O; Krogsgaard-Larsen, P

    1982-10-22

    THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a potent and specific GABA receptor agonist which does not influence the GABA uptake system or GABA metabolizing enzymes. The specificity for the GABA receptor is also demonstrated by lack of action on monoaminergic, cholinergic, histaminergic or opiate receptors. Since in recent years GABA receptor stimulants-among others THIP--have become available many have speculated as to what clinical indication GABA-ergic stimulation might be an important element. The first suggestion was that GABA-ergic drugs by an inhibitory effect on the dopamine neurons would improve the antischizophrenic effect of neuroleptics and improve tardive dyskinesia. Furthermore, studies on brains of deceased Parkinson and Huntington's chorea patients have demonstrated a low level of GABA and its synthesizing enzyme glutamic acid decarboxylase (GAD) in the basal ganglia. Also in epilepsy and diseases with dementia a deficit in the GABA system has been proposed. Therefore a therapeutic strategy for these diseases may be supplementary treatment with drugs which increase GABA receptor activity. Furthermore, recent results in humans have shown that GABA agonists perhaps also could be of benefit in mania and depressions. When considering the neurophysiological elements of nociception and muscle tone it is also reasonable to suggest that GABA-ergic stimulation may reduce pain perception and muscle tone. PMID:6292818

  9. The effects of agonists of ionotropic GABA(A) and metabotropic GABA(B) receptors on learning.

    PubMed

    Zyablitseva, Evgeniya A; Kositsyn, Nikolay S; Shul'gina, Galina I

    2009-05-01

    The research described here investigates the role played by inhibitory processes in the discriminations made by the nervous system of humans and animals between familiar and unfamiliar and significant and nonsignificant events. This research compared the effects of two inhibitory mediators of gamma-aminobutyric acid (GABA): 1) phenibut, a nonselective agonist of ionotropic GABA(A) and metabotropic GABA(B) receptors and 2) gaboxadol a selective agonist of ionotropic GABA(A) receptors on the process of developing active defensive and inhibitory conditioned reflexes in alert non-immobilized rabbits. It was found that phenibut, but not gaboxadol, accelerates the development of defensive reflexes at an early stage of conditioning. Both phenibut and gaboxadol facilitate the development of conditioned inhibition, but the effect of gaboxadol occurs at later stages of conditioning and is less stable than that of phenibut. The earlier and more stable effects of phenibut, as compared to gaboxadol, on storage in memory of the inhibitory significance of a stimulus may occur because GABA(B) receptors play the dominant role in the development of internal inhibition during an early stage of conditioning. On the other hand this may occur because the participation of both GABA(A) and GABA(B) receptors are essential to the process. We discuss the polyfunctionality of GABA receptors as a function of their structure and the positions of the relevant neurons in the brain as this factor can affect regulation of various types of psychological processes. PMID:19476215

  10. Local GABA Concentration Predicts Perceptual Improvements After Repetitive Sensory Stimulation in Humans

    PubMed Central

    Heba, Stefanie; Puts, Nicolaas A. J.; Kalisch, Tobias; Glaubitz, Benjamin; Haag, Lauren M.; Lenz, Melanie; Dinse, Hubert R.; Edden, Richard A. E.; Tegenthoff, Martin; Schmidt-Wilcke, Tobias

    2016-01-01

    Learning mechanisms are based on synaptic plasticity processes. Numerous studies on synaptic plasticity suggest that the regulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a central role maintaining the delicate balance of inhibition and excitation. However, in humans, a link between learning outcome and GABA levels has not been shown so far. Using magnetic resonance spectroscopy of GABA prior to and after repetitive tactile stimulation, we show here that baseline GABA+ levels predict changes in perceptual outcome. Although no net changes in GABA+ are observed, the GABA+ concentration prior to intervention explains almost 60% of the variance in learning outcome. Our data suggest that behavioral effects can be predicted by baseline GABA+ levels, which provide new insights into the role of inhibitory mechanisms during perceptual learning. PMID:26637451

  11. GABA(B) receptor subunit 1 binds to proteins affected in 22q11 deletion syndrome.

    PubMed

    Zunner, Dagmar; Deschermeier, Christina; Kornau, Hans-Christian

    2010-03-01

    GABA(B) receptors mediate slow inhibitory effects of the neurotransmitter gamma-aminobutyric acid (GABA) on synaptic transmission in the central nervous system. They function as heterodimeric G-protein-coupled receptors composed of the seven-transmembrane domain proteins GABA(B1) and GABA(B2), which are linked through a coiled-coil interaction. The ligand-binding subunit GABA(B1) is at first retained in the endoplasmic reticulum and is transported to the cell surface only upon assembly with GABA(B2). Here, we report that GABA(B1), via the coiled-coil domain, can also bind to soluble proteins of unknown function, that are affected in 22q11 deletion/DiGeorge syndrome and are therefore referred to as DiGeorge critical region 6 (DGCR6). In transfected neurons the GABA(B1)-DGCR6 association resulted in a redistribution of both proteins into intracellular clusters. Furthermore, the C-terminus of GABA(B2) interfered with the novel interaction, consistent with heterodimer formation overriding transient DGCR6-binding to GABA(B1). Thus, sequential coiled-coil interactions may direct GABA(B1) into functional receptors. PMID:20036641

  12. Bioactivity-guided isolation of GABA(A) receptor modulating constituents from the rhizomes of Actaea racemosa.

    PubMed

    Cicek, Serhat S; Khom, Sophia; Taferner, Barbara; Hering, Steffen; Stuppner, Hermann

    2010-12-27

    Black cohosh (Actaea racemosa) is a frequently used herbal remedy for the treatment of mild climacteric symptoms. In the present study, the modulation of γ-aminobutryic acid (GABA)-induced chloride currents (I(GABA)) through GABA type A (GABA(A)) receptors by black cohosh extracts and isolated compounds was investigated. GABA(A) receptors, consisting of α(1), β(2), and γ(2S) subunits, were expressed in Xenopus laevis oocytes, and potentiation of I(GABA) was measured using the two-microelectrode voltage clamp technique. In a bioactivity-guided isolation procedure the positive modulation of I(GABA) could be restricted to the plant terpenoid fractions, resulting in the isolation of 11 cycloartane glycosides, of which four significantly (p < 0.05) enhanced I(GABA). The most efficient effect was observed for 23-O-acetylshengmanol 3-O-β-d-xylopyranoside (4, 100 μM), enhancing I(GABA) by 1692 ± 201%, while actein (1), cimigenol 3-O-β-d-xylopyranoside (6), and 25-O-acetylcimigenol 3-O-α-l-arabinopyranoside (8) were significantly less active. In the absence of GABA, only 4 induced small (not exceeding 1% of I(GABA-max)) chloride inward currents through GABA(A) receptors. It is hypothesized that the established positive allosteric modulation of GABA(A) receptors may contribute to beneficial effects of black cohosh extracts in the treatment of climacteric symptoms. PMID:21082802

  13. An Electrostatic Funnel in the GABA-Binding Pathway

    PubMed Central

    Lightstone, Felice C.

    2016-01-01

    The γ-aminobutyric acid type A receptor (GABAA-R) is a major inhibitory neuroreceptor that is activated by the binding of GABA. The structure of the GABAA-R is well characterized, and many of the binding site residues have been identified. However, most of these residues are obscured behind the C-loop that acts as a cover to the binding site. Thus, the mechanism by which the GABA molecule recognizes the binding site, and the pathway it takes to enter the binding site are both unclear. Through the completion and detailed analysis of 100 short, unbiased, independent molecular dynamics simulations, we have investigated this phenomenon of GABA entering the binding site. In each system, GABA was placed quasi-randomly near the binding site of a GABAA-R homology model, and atomistic simulations were carried out to observe the behavior of the GABA molecules. GABA fully entered the binding site in 19 of the 100 simulations. The pathway taken by these molecules was consistent and non-random; the GABA molecules approach the binding site from below, before passing up behind the C-loop and into the binding site. This binding pathway is driven by long-range electrostatic interactions, whereby the electrostatic field acts as a ‘funnel’ that sweeps the GABA molecules towards the binding site, at which point more specific atomic interactions take over. These findings define a nuanced mechanism whereby the GABAA-R uses the general zwitterionic features of the GABA molecule to identify a potential ligand some 2 nm away from the binding site. PMID:27119953

  14. An Electrostatic Funnel in the GABA-Binding Pathway.

    PubMed

    Carpenter, Timothy S; Lightstone, Felice C

    2016-04-01

    The γ-aminobutyric acid type A receptor (GABAA-R) is a major inhibitory neuroreceptor that is activated by the binding of GABA. The structure of the GABAA-R is well characterized, and many of the binding site residues have been identified. However, most of these residues are obscured behind the C-loop that acts as a cover to the binding site. Thus, the mechanism by which the GABA molecule recognizes the binding site, and the pathway it takes to enter the binding site are both unclear. Through the completion and detailed analysis of 100 short, unbiased, independent molecular dynamics simulations, we have investigated this phenomenon of GABA entering the binding site. In each system, GABA was placed quasi-randomly near the binding site of a GABAA-R homology model, and atomistic simulations were carried out to observe the behavior of the GABA molecules. GABA fully entered the binding site in 19 of the 100 simulations. The pathway taken by these molecules was consistent and non-random; the GABA molecules approach the binding site from below, before passing up behind the C-loop and into the binding site. This binding pathway is driven by long-range electrostatic interactions, whereby the electrostatic field acts as a 'funnel' that sweeps the GABA molecules towards the binding site, at which point more specific atomic interactions take over. These findings define a nuanced mechanism whereby the GABAA-R uses the general zwitterionic features of the GABA molecule to identify a potential ligand some 2 nm away from the binding site. PMID:27119953

  15. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation.

    PubMed

    Auteri, Michelangelo; Zizzo, Maria Grazia; Serio, Rosa

    2015-03-01

    Although an extensive body of literature confirmed γ-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine-like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut could not be limited to the maintenance of physiologic intestinal activity. Indeed, a series of interesting studies have suggested a potential key role of GABA in the promising field of neuroimmune interaction, being involved in the modulation of immune cell activity associated with different systemic and enteric inflammatory conditions. Given the urgency of novel therapeutic strategies against chronic immunity-related pathologies, i.e. multiple sclerosis and Inflammatory Bowel Disease, an in-depth comprehension of the enteric GABAergic system in health and disease could provide the basis for new clinical application of nerve-driven immunity. Hence, in the attempt to drive novel researches addressing both the physiological and pathological importance of the GABAergic signalling in the gut, we summarized current evidence on GABA and GABA receptor function in the different parts of the GI tract, with particular focus on the potential involvement in the modulation of GI motility and inflammation. PMID:25526825

  16. Influence of cold stress on contents of soluble sugars, vitamin C and free amino acids including gamma-aminobutyric acid (GABA) in spinach (Spinacia oleracea).

    PubMed

    Yoon, Young-Eun; Kuppusamy, Saranya; Cho, Kye Man; Kim, Pil Joo; Kwack, Yong-Bum; Lee, Yong Bok

    2017-01-15

    The contents of soluble sugars (sucrose, fructose, glucose, maltose and raffinose), vitamin C and free amino acids (34 compounds, essential and non-essential) were quantified in open-field and greenhouse-grown spinaches in response to cold stress using liquid chromatography. In general, greenhouse cultivation produced nutritionally high value spinach in a shorter growing period, where the soluble sugars, vitamin C and total amino acids concentrations, including essential were in larger amounts compared to those grown in open-field scenarios. Further, low temperature exposure of spinach during a shorter growth period resulted in the production of spinach with high sucrose, ascorbate, proline, gamma-aminobutyric acid, valine and leucine content, and these constitute the most important energy/nutrient sources. In conclusion, cultivation of spinach in greenhouse at a low temperature (4-7°C) and exposure for a shorter period (7-21days) before harvest is recommended. This strategy will produce a high quality product that people can eat. PMID:27542466

  17. GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells

    PubMed Central

    Harada, Keita; Matsuoka, Hidetada; Fujihara, Hiroaki; Ueta, Yoichi; Yanagawa, Yuchio; Inoue, Masumi

    2016-01-01

    Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In rat adrenal medullary chromaffin cells only GAD67 is expressed, and GABA is stored in large dense core vesicles (LDCVs), but not synaptic-like microvesicles (SLMVs). The α3β2/3γ2 complex represents the majority of GABAA receptors expressed in rat and guinea pig chromaffin cells, whereas PC12 cells, an immortalized rat chromaffin cell line, express the α1 subunit as well as the α3. The expression of α3, but not α1, in PC12 cells is enhanced by glucocorticoid activity, which may be mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GABA has two actions mediated by GABAA receptors in chromaffin cells: it induces catecholamine secretion by itself and produces an inhibition of synaptically evoked secretion by a shunt effect. Allopregnanolone, a neuroactive steroid which is secreted from the adrenal cortex, produces a marked facilitation of GABAA receptor channel activity. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor in the chromaffin cells. This function of GABA may be facilitated by expression of the immature isoforms of GAD and GABAA receptors and the lack of expression of plasma membrane GABA transporters (GATs). In this review, we will consider how the para/autocrine function of GABA is achieved, focusing on the structural and molecular mechanisms for GABA signaling. PMID:27147972

  18. GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells.

    PubMed

    Harada, Keita; Matsuoka, Hidetada; Fujihara, Hiroaki; Ueta, Yoichi; Yanagawa, Yuchio; Inoue, Masumi

    2016-01-01

    Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In rat adrenal medullary chromaffin cells only GAD67 is expressed, and GABA is stored in large dense core vesicles (LDCVs), but not synaptic-like microvesicles (SLMVs). The α3β2/3γ2 complex represents the majority of GABAA receptors expressed in rat and guinea pig chromaffin cells, whereas PC12 cells, an immortalized rat chromaffin cell line, express the α1 subunit as well as the α3. The expression of α3, but not α1, in PC12 cells is enhanced by glucocorticoid activity, which may be mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GABA has two actions mediated by GABAA receptors in chromaffin cells: it induces catecholamine secretion by itself and produces an inhibition of synaptically evoked secretion by a shunt effect. Allopregnanolone, a neuroactive steroid which is secreted from the adrenal cortex, produces a marked facilitation of GABAA receptor channel activity. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor in the chromaffin cells. This function of GABA may be facilitated by expression of the immature isoforms of GAD and GABAA receptors and the lack of expression of plasma membrane GABA transporters (GATs). In this review, we will consider how the para/autocrine function of GABA is achieved, focusing on the structural and molecular mechanisms for GABA signaling. PMID:27147972

  19. A GABA-activated chloride-conductance not blocked by picrotoxin on spiny lobster neuromuscular preparations.

    PubMed Central

    Albert, J.; Lingle, C. J.; Marder, E.; O'Neil, M. B.

    1986-01-01

    Conductance increases to gamma-aminobutyric acid (GABA) were recorded in the gm6b and opener muscle of the spiny lobsters, Panulirus interruptus and P. argus. GABA-evoked responses were insensitive to picrotoxin at concentrations as high as 5 X 10(-5) M. Some blockade by picrotoxin was observed at higher concentrations. In normal physiological saline, the reversal potential of the Panulirus GABA-induced response was near the resting potential. The reversal potential was unaffected by reductions in sodium and calcium. Reduction of chloride by 50% resulted in a greater than 10 mV shift in the reversal potential of the GABA-induced response. Muscimol was able to mimic the action of GABA while baclofen was without effect. Bicuculline was a weak blocker. Avermectin B1a irreversibly increased the chloride permeability of the gm6b membrane. This conductance increase was blocked by picrotoxin over a range of concentrations similar to those required for blockade of the GABA-induced response. GABA-induced responses of the gm6b muscle of Homarus americanus were blocked almost completely by picrotoxin 10(-6) M. Sensitivity to picrotoxin is not invariably associated with GABA-activated chloride-mediated conductance increases. It is suggested that alteration in the binding-site for picrotoxin on the GABA-activated chloride-ion channel does not change other functional characteristics of the GABA-induced response. PMID:3708210

  20. Extent of colocalization of serotonin and GABA in neurons of the ventral medulla oblongata in rat.

    PubMed

    Millhorn, D E; Hökfelt, T; Seroogy, K; Verhofstad, A A

    1988-09-27

    The colocalization of serotonin (5-hydroxytryptamine; 5-HT) and gamma-aminobutyric acid (GABA) in the ventral aspect of the rat medulla oblongata was studied using antibodies directed against 5-HT and GABA. Although 5-HT- and GABA-immunoreactive cell bodies were observed over the entire rostral-caudal extent of the ventral medulla, the colocalization of these two classical neurotransmitters in single cells was, for the most part, limited to a region that corresponds anatomically to nucleus raphe magnus/nucleus paragigantocellularis. Schematic drawings showing the distribution of 5-HT/GABA cell bodies in the ventral medulla are provided. PMID:3066433

  1. Ionic Mechanisms of Neuronal Excitation by Inhibitory GABA_A Receptors

    NASA Astrophysics Data System (ADS)

    Staley, Kevin J.; Soldo, Brandi L.; Proctor, William R.

    1995-08-01

    Gamma-aminobutyric acid A (GABA_A) receptors are the principal mediators of synaptic inhibition, and yet when intensely activated, dendritic GABA_A receptors excite rather than inhibit neurons. The membrane depolarization mediated by GABA_A receptors is a result of the differential, activity-dependent collapse of the opposing concentration gradients of chloride and bicarbonate, the anions that permeate the GABA_A ionophore. Because this depolarization diminishes the voltage-dependent block of the N-methyl-D-aspartate (NMDA) receptor by magnesium, the activity-dependent depolarization mediated by GABA is sufficient to account for frequency modulation of synaptic NMDA receptor activation. Anionic gradient shifts may represent a mechanism whereby the rate and coherence of synaptic activity determine whether dendritic GABA_A receptor activation is excitatory or inhibitory.

  2. Aldehyde Dehydrogenase 1a1 Mediates a GABA Synthesis Pathway in Midbrain Dopaminergic Neurons

    PubMed Central

    Kim, Jae-Ick; Ganesan, Subhashree; Luo, Sarah X.; Wu, Yu-Wei; Park, Esther; Huang, Eric J.; Chen, Lu; Ding, Jun B.

    2016-01-01

    Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here we show that GABA corelease in dopamine neurons does not utilize the conventional GABA synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol at binge drinking blood alcohol concentrations and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. PMID:26430123

  3. In vivo measurements of glutamate, GABA, and NAAG in schizophrenia.

    PubMed

    Rowland, Laura M; Kontson, Kimberly; West, Jeffrey; Edden, Richard A; Zhu, He; Wijtenburg, S Andrea; Holcomb, Henry H; Barker, Peter B

    2013-09-01

    The major excitatory and inhibitory neurotransmitters, glutamate (Glu) and gamma-aminobutyric acid (GABA), respectively, are implicated in the pathophysiology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide that modulates the Glu system, may also be altered in schizophrenia. This study investigated GABA, Glu + glutamine (Glx), and NAAG levels in younger and older subjects with schizophrenia. Forty-one subjects, 21 with chronic schizophrenia and 20 healthy controls, participated in this study. Proton magnetic resonance spectroscopy ((1)H-MRS) was used to measure GABA, Glx, and NAAG levels in the anterior cingulate (AC) and centrum semiovale (CSO) regions. NAAG in the CSO was higher in younger schizophrenia subjects compared with younger control subjects. The opposite pattern was observed in the older groups. Glx was reduced in the schizophrenia group irrespective of age group and brain region. There was a trend for reduced AC GABA in older schizophrenia subjects compared with older control subjects. Poor attention performance was correlated to lower AC GABA levels in both groups. Higher levels of CSO NAAG were associated with greater negative symptom severity in schizophrenia. These results provide support for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia. The study also highlights the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia. PMID:23081992

  4. A Role for GAT-1 in Presynaptic GABA Homeostasis?

    PubMed Central

    Conti, Fiorenzo; Melone, Marcello; Fattorini, Giorgia; Bragina, Luca; Ciappelloni, Silvia

    2011-01-01

    In monoamine-releasing terminals, neurotransmitter transporters – in addition to terminating synaptic transmission by clearing released transmitters from the extracellular space – are the primary mechanism for replenishing transmitter stores and thus regulate presynaptic homeostasis. Here, we analyze whether GAT-1, the main plasma membrane GABA transporter, plays a similar role in GABAergic terminals. Re-examination of existing literature and recent data gathered in our laboratory show that GABA homeostasis in GABAergic terminals is dominated by the activity of the GABA synthesizing enzyme and that GAT-1-mediated GABA transport contributes to cytosolic GABA levels. However, analysis of GAT-1 KO, besides demonstrating the effects of reduced clearance, reveals the existence of changes compatible with an impaired presynaptic function, as miniature IPSCs frequency is reduced by one-third and glutamic acid decarboxylases and phosphate-activated glutaminase levels are significantly up-regulated. Although the changes observed are less robust than those reported in mice with impaired dopamine, noradrenaline, and serotonin plasma membrane transporters, they suggest that in GABAergic terminals GAT-1 impacts on presynaptic GABA homeostasis, and may contribute to the activity-dependent regulation of inhibitory efficacy. PMID:21503156

  5. Parkinson's Disease and Neurodegeneration: GABA-Collapse Hypothesis

    PubMed Central

    Błaszczyk, Janusz W.

    2016-01-01

    Neurodegenerative diseases constitute a heterogeneous group of age-related disorders that are characterized by a slow but irreversible deterioration of brain functions. Evidence accumulated over more than two decades has implicated calcium-related homeostatic mechanisms, giving rise to the Ca2+ hypothesis of brain aging and, ultimately, cell death. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter within the central (CNS), peripheral and enteric nervous systems. It appears to be involved in a wide variety of physiological functions within and outside the nervous system, that are maintained through a complex interaction between GABA and calcium-dependent neurotransmission and cellular metabolic functions. Within CNS the Ca2+/GABA mechanism stabilizes neuronal activity both at cellular and systemic levels. Decline in the Ca2+/GABA control initiates several cascading processes leading to both weakened protective barriers (in particular the blood-brain barrier) and accumulations of intracellular deposits of calcium and Lewy bodies. Linking such a vital mechanism of synaptic transmission with metabolism (both at cellular and tissue level) by means of a common reciprocal Ca2+/GABA inhibition results in a fragile balance, which is prone to destabilization and auto-destruction. The GABA decline etiology proposed here appears to apply to all human neurodegenerative processes initiated by abnormal intracellular calcium levels. Therefore, the original description of Parkinson's disease (PD) as due to the selective damage of dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder of the nervous system, whose clinical symptoms reflect the localization and progression of the most advanced GABA pathology. A future and more complete therapeutic approach to PD should be aimed first at slowing (or stopping) the progression of Ca2+/GABA functional decline. PMID:27375426

  6. Parkinson's Disease and Neurodegeneration: GABA-Collapse Hypothesis.

    PubMed

    Błaszczyk, Janusz W

    2016-01-01

    Neurodegenerative diseases constitute a heterogeneous group of age-related disorders that are characterized by a slow but irreversible deterioration of brain functions. Evidence accumulated over more than two decades has implicated calcium-related homeostatic mechanisms, giving rise to the Ca(2+) hypothesis of brain aging and, ultimately, cell death. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter within the central (CNS), peripheral and enteric nervous systems. It appears to be involved in a wide variety of physiological functions within and outside the nervous system, that are maintained through a complex interaction between GABA and calcium-dependent neurotransmission and cellular metabolic functions. Within CNS the Ca(2+)/GABA mechanism stabilizes neuronal activity both at cellular and systemic levels. Decline in the Ca(2+)/GABA control initiates several cascading processes leading to both weakened protective barriers (in particular the blood-brain barrier) and accumulations of intracellular deposits of calcium and Lewy bodies. Linking such a vital mechanism of synaptic transmission with metabolism (both at cellular and tissue level) by means of a common reciprocal Ca(2+)/GABA inhibition results in a fragile balance, which is prone to destabilization and auto-destruction. The GABA decline etiology proposed here appears to apply to all human neurodegenerative processes initiated by abnormal intracellular calcium levels. Therefore, the original description of Parkinson's disease (PD) as due to the selective damage of dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder of the nervous system, whose clinical symptoms reflect the localization and progression of the most advanced GABA pathology. A future and more complete therapeutic approach to PD should be aimed first at slowing (or stopping) the progression of Ca(2+)/GABA functional decline. PMID:27375426

  7. GABA shapes the dynamics of bistable perception.

    PubMed

    van Loon, Anouk M; Knapen, Tomas; Scholte, H Steven; St John-Saaltink, Elexa; Donner, Tobias H; Lamme, Victor A F

    2013-05-01

    Sometimes, perception fluctuates spontaneously between two distinct interpretations of a constant sensory input. These bistable perceptual phenomena provide a unique window into the neural mechanisms that create the contents of conscious perception. Models of bistable perception posit that mutual inhibition between stimulus-selective neural populations in visual cortex plays a key role in these spontaneous perceptual fluctuations. However, a direct link between neural inhibition and bistable perception has not yet been established experimentally. Here, we link perceptual dynamics in three distinct bistable visual illusions (binocular rivalry, motion-induced blindness, and structure from motion) to measurements of gamma-aminobutyric acid (GABA) concentrations in human visual cortex (as measured with magnetic resonance spectroscopy) and to pharmacological stimulation of the GABAA receptor by means of lorazepam. As predicted by a model of neural interactions underlying bistability, both higher GABA concentrations in visual cortex and lorazepam administration induced slower perceptual dynamics, as reflected in a reduced number of perceptual switches and a lengthening of percept durations. Thus, we show that GABA, the main inhibitory neurotransmitter, shapes the dynamics of bistable perception. These results pave the way for future studies into the competitive neural interactions across the visual cortical hierarchy that elicit conscious perception. PMID:23602476

  8. Downregulation of GABA[Subscript A] Receptor Protein Subunits a6, ß2, d, e, ?2, ?, and ?2 in Superior Frontal Cortex of Subjects with Autism

    ERIC Educational Resources Information Center

    Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Rustan, Oyvind G.; Rooney, Robert J.; Thuras, Paul D.

    2014-01-01

    We measured protein and mRNA levels for nine gamma-aminobutyric acid A (GABA[subscript A]) receptor subunits in three brain regions (cerebellum, superior frontal cortex, and parietal cortex) in subjects with autism versus matched controls. We observed changes in mRNA for a number of GABA[subscript A] and GABA[subscript B] subunits and overall…

  9. Endogenous gamma-aminobutyric acid (GABA)(A) receptor active neurosteroids and the sedative/hypnotic action of gamma-hydroxybutyric acid (GHB): a study in GHB-S (sensitive) and GHB-R (resistant) rat lines.

    PubMed

    Barbaccia, Maria Luisa; Carai, Mauro A M; Colombo, Giancarlo; Lobina, Carla; Purdy, Robert H; Gessa, Gian Luigi

    2005-07-01

    In the rat brain, gamma-hydroxybutyric-acid (GHB) increases the concentrations of 3alpha-hydroxy,5alpha-pregnan-20-one (allopregnanolone, 3alpha,5alpha-THP) and 3alpha,21-dihydroxy,5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone/3alpha,5alphaTHDOC), two neurosteroids acting as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors. This study was aimed at assessing whether neurosteroids play a role in GHB-induced loss of righting reflex (LORR). Basal and GHB-stimulated brain concentrations of endogenous 3alpha,5alpha-THP and 3alpha,5alpha-THDOC were analyzed in two rat lines, GHB-sensitive (GHB-S) and GHB-resistant (GHB-R), selectively bred for opposite sensitivity to GHB-induced sedation/hypnosis. Basal neurosteroid concentrations were similar in brain cortex of the two rat lines. However, in male GHB-S rats, administration of GHB (1000 mg/kg, i.p., 30 min) increased brain cortical concentrations of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC 7- and 2.5-fold, respectively, whilst male GHB-R animals displayed only a 4- and 2-fold increase, respectively. In GHB-S rats this increase lasted up to 90 min and declined 180 min following GHB administration, a time course that matches LORR onset and duration. In contrast, in GHB-R rats, which failed to show GHB-induced LORR, brain cortical 3alpha,5alpha-THP and 3alpha,5alpha-THDOC had returned to control values within 90 min. At onset of LORR, a similar increase in brain cortical levels of 3alpha,5alpha-THP and 3alpha,5alpha-THDOC (2-3-fold) was observed in GHB-S female rats and in the few female GHB-R rats that lost the righting reflex after GHB administration, but not in female GHB-R rats failing to show LORR. Sub-hypnotic doses (7.5 and 12.5 mg/kg, i.p.) of pregnanolone, administered 10 min before GHB, dose-dependently facilitated the expression of GHB-induced LORR in GHB-R male rats. These results suggest that the GHB-induced increases of brain 3alpha,5alpha-THP and 3alpha,5alpha

  10. Neurotransmitters as food supplements: the effects of GABA on brain and behavior

    PubMed Central

    Boonstra, Evert; de Kleijn, Roy; Colzato, Lorenza S.; Alkemade, Anneke; Forstmann, Birte U.; Nieuwenhuis, Sander

    2015-01-01

    Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. The food supplement version of GABA is widely available online. Although many consumers claim that they experience benefits from the use of these products, it is unclear whether these supplements confer benefits beyond a placebo effect. Currently, the mechanism of action behind these products is unknown. It has long been thought that GABA is unable to cross the blood–brain barrier (BBB), but the studies that have assessed this issue are often contradictory and range widely in their employed methods. Accordingly, future research needs to establish the effects of oral GABA administration on GABA levels in the human brain, for example using magnetic resonance spectroscopy. There is some evidence in favor of a calming effect of GABA food supplements, but most of this evidence was reported by researchers with a potential conflict of interest. We suggest that any veridical effects of GABA food supplements on brain and cognition might be exerted through BBB passage or, more indirectly, via an effect on the enteric nervous system. We conclude that the mechanism of action of GABA food supplements is far from clear, and that further work is needed to establish the behavioral effects of GABA. PMID:26500584

  11. Neurotransmitters as food supplements: the effects of GABA on brain and behavior.

    PubMed

    Boonstra, Evert; de Kleijn, Roy; Colzato, Lorenza S; Alkemade, Anneke; Forstmann, Birte U; Nieuwenhuis, Sander

    2015-01-01

    Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. The food supplement version of GABA is widely available online. Although many consumers claim that they experience benefits from the use of these products, it is unclear whether these supplements confer benefits beyond a placebo effect. Currently, the mechanism of action behind these products is unknown. It has long been thought that GABA is unable to cross the blood-brain barrier (BBB), but the studies that have assessed this issue are often contradictory and range widely in their employed methods. Accordingly, future research needs to establish the effects of oral GABA administration on GABA levels in the human brain, for example using magnetic resonance spectroscopy. There is some evidence in favor of a calming effect of GABA food supplements, but most of this evidence was reported by researchers with a potential conflict of interest. We suggest that any veridical effects of GABA food supplements on brain and cognition might be exerted through BBB passage or, more indirectly, via an effect on the enteric nervous system. We conclude that the mechanism of action of GABA food supplements is far from clear, and that further work is needed to establish the behavioral effects of GABA. PMID:26500584

  12. Comparative Mapping of GABA-Immunoreactive Neurons in the Buccal Ganglia of Nudipleura Molluscs.

    PubMed

    Gunaratne, Charuni A; Katz, Paul S

    2016-04-15

    Phylogenetic comparisons of neurotransmitter distribution are important for understanding the ground plan organization of nervous systems. This study describes the γ-aminobutyric acid (GABA)-immunoreactive (GABA-ir) neurons in the buccal ganglia of six sea slug species (Mollusca, Gastropoda, Euthyneura, Nudipleura). In the nudibranch species, Hermissenda crassicornis, Tritonia diomedea, Tochuina tetraquetra, and Dendronotus iris, the number of GABA-ir neurons was highly consistent. Another nudibranch, Melibe leonina, however, contained approximately half the number of GABA-ir neurons. This may relate to its loss of a radula and its unique feeding behavior. The GABA immunoreactivity in a sister group to the nudibranchs, Pleurobranchaea californica, differed drastically from that of the nudibranchs. Not only did it have significantly more GABA-ir neurons but it also had a unique GABA distribution pattern. Furthermore, unlike the nudibranchs, the Pleurobranchaea GABA distribution was also different from that of other, more distantly related, euopisthobranch and panpulmonate snails and slugs. This suggests that the Pleurobranchaea GABA distribution may be a derived feature, unique to this lineage. The majority of GABA-ir axons and neuropil in the Nudipleura were restricted to the buccal ganglia, commissures, and connectives. However, in Tritonia and Pleurobranchaea, we detected a few GABA-ir fibers in buccal nerves that innervate feeding muscles. Although the specific functions of the GABA-ir neurons in the species in this study are not known, the innervation pattern suggests these neurons may play an integrative or regulatory role in bilaterally coordinated behaviors in the Nudipleura. PMID:26355705

  13. Stimulation of TM3 Leydig cell proliferation via GABAA receptors: A new role for testicular GABA

    PubMed Central

    Geigerseder, Christof; Doepner, Richard FG; Thalhammer, Andrea; Krieger, Annette; Mayerhofer, Artur

    2004-01-01

    The neurotransmitter gamma-aminobutyric acid (GABA) and subtypes of GABA receptors were recently identified in adult testes. Since adult Leydig cells possess both the GABA biosynthetic enzyme glutamate decarboxylase (GAD), as well as GABAA and GABAB receptors, it is possible that GABA may act as auto-/paracrine molecule to regulate Leydig cell function. The present study was aimed to examine effects of GABA, which may include trophic action. This assumption is based on reports pinpointing GABA as regulator of proliferation and differentiation of developing neurons via GABAA receptors. Assuming such a role for the developing testis, we studied whether GABA synthesis and GABA receptors are already present in the postnatal testis, where fetal Leydig cells and, to a much greater extend, cells of the adult Leydig cell lineage proliferate. Immunohistochemistry, RT-PCR, Western blotting and a radioactive enzymatic GAD assay evidenced that fetal Leydig cells of five-six days old rats possess active GAD protein, and that both fetal Leydig cells and cells of the adult Leydig cell lineage possess GABAA receptor subunits. TM3 cells, a proliferating mouse Leydig cell line, which we showed to possess GABAA receptor subunits by RT-PCR, served to study effects of GABA on proliferation. Using a colorimetric proliferation assay and Western Blotting for proliferating cell nuclear antigen (PCNA) we demonstrated that GABA or the GABAA agonist isoguvacine significantly increased TM3 cell number and PCNA content in TM3 cells. These effects were blocked by the GABAA antagonist bicuculline, implying a role for GABAA receptors. In conclusion, GABA increases proliferation of TM3 Leydig cells via GABAA receptor activation and proliferating Leydig cells in the postnatal rodent testis bear a GABAergic system. Thus testicular GABA may play an as yet unrecognized role in the development of Leydig cells during the differentiation of the testicular interstitial compartment. PMID:15040802

  14. GABA transport and calcium dynamics in horizontal cells from the skate retina.

    PubMed Central

    Haugh-Scheidt, L; Malchow, R P; Ripps, H

    1995-01-01

    1. Changes in intracellular calcium concentration [Ca2+]i in response to extracellularly applied gamma-aminobutyric acid (GABA) were studied in isolated horizontal cells from the all-rod skate retina. 2. Calcium measurements were made using fura-2 AM, both with and without whole-cell voltage clamp. Superfusion with GABA, in the absence of voltage clamp, resulted in an increase in [Ca2+]i; the threshold for detection was approximately 50 microM GABA, and a maximal response was elicited by 500 microM GABA. 3. The rise in [Ca2+]i was not mimicked by baclofen nor was it blocked by phaclofen, picrotoxin or bicuculline. However, the GABA-induced [Ca2+]i increase was completely abolished when extracellular sodium was replaced with N-methyl-D-glucamine. 4. With the horizontal cell voltage clamped at -70 mV, GABA evoked a large inward current, but there was no concomitant change in [Ca2+]i. Nifedipine, which blocks L-type voltage-gated Ca2+ channels, suppressed the GABA-induced increase in [Ca2+]i. These findings suggest that the calcium response was initiated by GABA activation of sodium dependent electrogenic transport, and that the resultant depolarization led to the opening of voltage-gated Ca2+ channels, and a rise in [Ca2+]i. 5. The GABA-induced influx of calcium appears not to have been the sole source of the calcium increase. The GABA-induced rise in [Ca2+]i was reduced by dantrolene, indicating that internal Ca2+ stores contributed to the GABA-mediated Ca2+ response. 6. These observations demonstrate that activation of the GABA transporter induces changes in [Ca2+]i which may have important implications for the functional properties of horizontal cells. PMID:8576848

  15. Amiloride and GMQ Allosteric Modulation of the GABA-A ρ1 Receptor: Influences of the Intersubunit Site

    PubMed Central

    Snell, Heather D.

    2015-01-01

    Amiloride, a diuretic used in the treatment of hypertension and congestive heart failure, and 2-guanidine-4-methylquinazoline (GMQ) are guanidine compounds that modulate acid-sensing ion channels. Both compounds have demonstrated affinity for a variety of membrane proteins, including members of the Cys-loop family of ligand-gated ion channels, such as the heteromeric GABA-A αβγ receptors. The actions of these guanidine compounds on the homomeric GABA-A ρ1 receptor remains unclear, especially in light of how many GABA-A αβγ receptor modulators have different effects in the GABA-A ρ1 receptors. We sought to characterize the influence of amiloride and GMQ on the human GABA-A ρ1 receptors using whole-cell patch-clamp electrophysiology. The diuretic amiloride potentiated the human GABA-A ρ1 GABA-mediated current, whereas GMQ antagonized the receptor. Furthermore, a GABA-A second transmembrane domain site, the intersubunit site, responsible for allosteric modulation in the heteromeric GABA-A receptors mediated amiloride’s positive allosteric actions. In contrast, the mutation did not remove GMQ antagonism but only changed the guanidine compound’s potency within the human GABA-A ρ1 receptor. Through modeling and introduction of point mutations, we propose that the GABA-A ρ1 intersubunit site plays a role in mediating the allosteric effects of amiloride and GMQ. PMID:25829529

  16. Potentiation of the ionotropic GABA receptor response by whiskey fragrance.

    PubMed

    Hossain, Sheikh Julfikar; Aoshima, Hitoshi; Koda, Hirofumi; Kiso, Yoshinobu

    2002-11-01

    It is well-known that the target of most mood-defining compounds is an ionotropic gamma-aminobutyric acid receptor (GABA(A) receptor). The potentiation of the response of these inhibitory neurotransmitter receptors induces anxiolytic, sedative, and anesthetic activity in the human brain. To study the effects of whiskey fragrance on the GABA(A) receptor-mediated response, GABA(A) receptors were expressed in Xenopus oocyte by injecting rat whole brain mRNA or cRNA prepared from the cloned cDNA for the alpha(1) and beta(1) subunits of the bovine receptors. Most whiskey components such as phenol, ethoxy, and lactone derivatives potentiated the electrical responses of GABA(A) receptors, especially ethyl phenylpropanoate (EPP), which strongly potentiated the response. When this compound was applied to mice through respiration, the convulsions induced by pentetrazole were delayed, suggesting that EPP was absorbed by the brain, where it could potentiate the GABA(A) receptor responses. The extract of other alcoholic drinks such as wine, sake, brandy, and shochu also potentiated the responses to varying degrees. Although these fragrant components are present in alcoholic drinks at low concentrations (extremely small quantities compared with ethanol), they may also modulate the mood or consciousness of the human through the potentiation of the GABA(A) receptor response after absorption into the brain, because these hydrophobic fragrant compounds are easily absorbed into the brain through the blood-brain barrier and are several thousands times as potent as ethanol in the potentiation of the GABA(A) receptor-mediated response. PMID:12405783

  17. Attenuated inhibition by levofloxacin, l-isomer of ofloxacin, on GABA response in the dissociated rat hippocampal neurons.

    PubMed

    Imanishi, T; Akahane, K; Akaike, N

    1995-06-30

    The effects of ofloxacin (OFLX) and its isomers, levofloxacin (LVFX) and DR-3354, on the gamma-aminobutyric acid (GABA)-induced Cl- current in acutely dissociated rat hippocampal CA1 neurons were investigated using nystatin perforated patch recording configuration under voltage-clamp conditions. At 10(-5) M these 3 compounds themselves did not affect the GABA response. Biphenylacetic acid (BPA) at 10(-5) M also had no effect on the GABA response, but BPA greatly suppressed the GABA response in combination with these 3 compounds without affecting the reversal potential of GABA response. The inhibitory effects of OFLX and DR-3354 on the GABA response were stronger than that of LVFX. LVFX inhibited the response in a competitive and voltage-independent manner. The results suggest that LVFX has lower CNS adverse effects, such as convulsions, compared to OFLX. PMID:7478164

  18. Role of proline and GABA in sexual reproduction of angiosperms.

    PubMed

    Biancucci, Marco; Mattioli, Roberto; Forlani, Giuseppe; Funck, Dietmar; Costantino, Paolo; Trovato, Maurizio

    2015-01-01

    Two glutamate derivatives, proline and γ-aminobutyric acid (GABA), appear to play pivotal roles in different aspects of sexual reproduction in angiosperms, although their precise function in plant reproduction and the molecular basis of their action are not yet fully understood. Proline and GABA have long been regarded as pivotal amino acids in pollen vitality and fertility. Proline may constitute up to 70% of the free amino acid pool in pollen grains and it has been recently shown that Arabidopsis mutants affected in the first and rate-limiting step in proline synthesis produce aberrant and infertile pollen grains, indicating that proline synthesis is required for pollen development and fertility. Concerning GABA, a large body of evidence points to this glutamate derivative as a key determinant of post-pollination fertilization. Intriguingly, proline has also been associated with pollination, another aspect of sexual reproduction, since honeybees were reported to show a strong preference for proline-enriched nectars. In this review, we survey current knowledge on the roles of proline and GABA in plant fertility, and discuss future perspectives potentially capable to improve our understanding on the functions of these amino acids in pollen development, pollination, and pollen tube guidance. PMID:26388884

  19. Role of proline and GABA in sexual reproduction of angiosperms

    PubMed Central

    Biancucci, Marco; Mattioli, Roberto; Forlani, Giuseppe; Funck, Dietmar; Costantino, Paolo; Trovato, Maurizio

    2015-01-01

    Two glutamate derivatives, proline and γ-aminobutyric acid (GABA), appear to play pivotal roles in different aspects of sexual reproduction in angiosperms, although their precise function in plant reproduction and the molecular basis of their action are not yet fully understood. Proline and GABA have long been regarded as pivotal amino acids in pollen vitality and fertility. Proline may constitute up to 70% of the free amino acid pool in pollen grains and it has been recently shown that Arabidopsis mutants affected in the first and rate-limiting step in proline synthesis produce aberrant and infertile pollen grains, indicating that proline synthesis is required for pollen development and fertility. Concerning GABA, a large body of evidence points to this glutamate derivative as a key determinant of post-pollination fertilization. Intriguingly, proline has also been associated with pollination, another aspect of sexual reproduction, since honeybees were reported to show a strong preference for proline-enriched nectars. In this review, we survey current knowledge on the roles of proline and GABA in plant fertility, and discuss future perspectives potentially capable to improve our understanding on the functions of these amino acids in pollen development, pollination, and pollen tube guidance. PMID:26388884

  20. Actions of insecticides on the insect GABA receptor complex

    SciTech Connect

    Bermudez, I.; Hawkins, C.A.; Taylor, A.M.; Beadle, D.J. )

    1991-01-01

    The actions of insecticides on the insect gamma-aminobutyric acid (GABA) receptor were investigated using (35S)t-butylbicyclophosphorothionate (( 35S)TBPS) binding and voltage-clamp techniques. Specific binding of (35S)TBPS to a membrane homogenate derived from the brain of Locusta migratoria locusts is characterised by a Kd value of 79.3 {plus minus} 2.9 nM and a Bmax value of 1770 {plus minus} 40 fmol/mg protein. (35S)TBPS binding is inhibited by mM concentrations of barbiturates and benzodiazepines. In contrast dieldrin, ivermectin, lindane, picrotoxin and TBPS are inhibitors of (35S)TBPS binding at the nanomolar range. Bicuculline, baclofen and pyrethroid insecticides have no effect on (35S)TBPS binding. These results are similar to those obtained in electrophysiological studies of the current elicited by GABA in both Locusta and Periplaneta americana central neurones. Noise analysis of the effects of lindane, TBPS, dieldrin and picrotoxin on the cockroach GABA responses reveals that these compounds decrease the variance of the GABA-induced current but have no effect on its mean open time. All these compounds, with the exception of dieldrin, significantly decrease the conductance of GABA-evoked single current.

  1. Insect Herbivory-Elicited GABA Accumulation in Plants is a Wound-Induced, Direct, Systemic, and Jasmonate-Independent Defense Response

    PubMed Central

    Scholz, Sandra S.; Reichelt, Michael; Mekonnen, Dereje W.; Ludewig, Frank; Mithöfer, Axel

    2015-01-01

    The non-proteinogenic amino acid γ-aminobutyric acid (GABA) is present in all organisms analyzed so far. In invertebrates GABA acts as a neurotransmitter; in plants different functions are under discussion. Among others, its involvement in abiotic stress reactions and as a defensive compound against feeding insects is suggested. GABA is synthesized from glutamate by glutamate decarboxylases and degraded by GABA-transaminases. Here, in Arabidopsis thaliana, gad1/2 double mutants showing reduced GABA concentrations as well as GABA-enriched triple mutants (gad1/2 x pop2-5) were generated and employed for a systematic study of GABA induction, accumulation and related effects in Arabidopsis leaves upon herbivory. The results demonstrate that GABA accumulation is stimulated by insect feeding-like wounding by a robotic caterpillar, MecWorm, as well as by real insect (Spodoptera littoralis) herbivory. Higher GABA levels in both plant tissue and artificial dietary supplements in turn affect the performance of feeding larvae. GABA enrichment occurs not only in the challenged but also in adjacent leaf. This induced response is neither dependent on herbivore defense-related phytohormones, jasmonates, nor is jasmonate induction dependent on the presence of GABA. Thus, in Arabidopsis the rapid accumulation of GABA very likely represents a general, direct and systemic defense reaction against insect herbivores. PMID:26734035

  2. GABA accumulation causes cell elongation defects and a decrease in expression of genes encoding secreted and cell wall-related proteins in Arabidopsis thaliana.

    PubMed

    Renault, Hugues; El Amrani, Abdelhak; Palanivelu, Ravishankar; Updegraff, Emily P; Yu, Agnès; Renou, Jean-Pierre; Preuss, Daphne; Bouchereau, Alain; Deleu, Carole

    2011-05-01

    GABA (γ-aminobutyric acid), a non-protein amino acid, is a signaling factor in many organisms. In plants, GABA is known to accumulate under a variety of stresses. However, the consequence of GABA accumulation, especially in vegetative tissues, remains poorly understood. Moreover, gene expression changes as a consequence of GABA accumulation in plants are largely unknown. The pop2 mutant, which is defective in GABA catabolism and accumulates GABA, is a good model to examine the effects of GABA accumulation on plant development. Here, we show that the pop2 mutants have pollen tube elongation defects in the transmitting tract of pistils. Additionally, we observed growth inhibition of primary root and dark-grown hypocotyl, at least in part due to cell elongation defects, upon exposure to exogenous GABA. Microarray analysis of pop2-1 seedlings grown in GABA-supplemented medium revealed that 60% of genes whose expression decreased encode secreted proteins. Besides, functional classification of genes with decreased expression in the pop2-1 mutant showed that cell wall-related genes were significantly enriched in the microarray data set, consistent with the cell elongation defects observed in pop2 mutants. Our study identifies cell elongation defects caused by GABA accumulation in both reproductive and vegetative tissues. Additionally, our results show that genes that encode secreted and cell wall-related proteins may mediate some of the effects of GABA accumulation. The potential function of GABA as a growth control factor under stressful conditions is discussed. PMID:21471118

  3. GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters

    PubMed Central

    Ramesh, Sunita A.; Tyerman, Stephen D.; Xu, Bo; Bose, Jayakumar; Kaur, Satwinder; Conn, Vanessa; Domingos, Patricia; Ullah, Sana; Wege, Stefanie; Shabala, Sergey; Feijó, José A.; Ryan, Peter R.; Gillham, Matthew

    2015-01-01

    The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms. PMID:26219411

  4. Pharmacological modulation of brain levels of glutamate and GABA in rats exposed to total sleep deprivation

    PubMed Central

    Kamal, Sahar Mohamed

    2010-01-01

    Modulation of gamma-aminobutyric acid (GABA) and glutamate by selected antidepressants and anticonvulsants could play a beneficial role in total sleep deprivation (TSD) caused by depressed mood. In the present study, albino rats were exposed to TSD for five days. On the sixth day, the brains were removed, and GABA and glutamate levels were measured in the prefrontal cortex and thalamus to identify TSD-induced changes in untreated rats and in rats treated with carbamazepine 40 mg/kg intraperitoneally (IP), fluoxetine 20 mg/kg IP, or desipramine 10 mg/kg IP. Carbamazepine and fluoxetine significantly increased GABA and reduced glutamate levels in both brain areas. Desipramine administration did not affect GABA or glutamate concentrations in the tested brain areas; levels were comparable with those induced by TSD without treatment. These results suggest that administration of carbamazepine or fluoxetine could have a beneficial effect by increasing GABA levels during TSD.

  5. Effect of GABA, a bacterial metabolite, on Pseudomonas fluorescens surface properties and cytotoxicity.

    PubMed

    Dagorn, Audrey; Chapalain, Annelise; Mijouin, Lily; Hillion, Mélanie; Duclairoir-Poc, Cécile; Chevalier, Sylvie; Taupin, Laure; Orange, Nicole; Feuilloley, Marc G J

    2013-01-01

    Different bacterial species and, particularly Pseudomonas fluorescens, can produce gamma-aminobutyric acid (GABA) and express GABA-binding proteins. In this study, we investigated the effect of GABA on the virulence and biofilm formation activity of different strains of P. fluorescens. Exposure of a psychotropic strain of P. fluorescens (MF37) to GABA (10-5 M) increased its necrotic-like activity on eukaryotic (glial) cells, but reduced its apoptotic effect. Conversely, muscimol and bicuculline, the selective agonist and antagonist of eukaryote GABAA receptors, respectively, were ineffective. P. fluorescens MF37 did not produce biosurfactants, and its caseinase, esterase, amylase, hemolytic activity or pyoverdine productions were unchanged. In contrast, the effect of GABA was associated to rearrangements of the lipopolysaccharide (LPS) structure, particularly in the lipid A region. The surface hydrophobicity of MF37 was marginally modified, and GABA reduced its biofilm formation activity on PVC, but not on glass, although the initial adhesion was increased. Five other P. fluorescens strains were studied, and only one, MFP05, a strain isolated from human skin, showed structural differences of biofilm maturation after exposure to GABA. These results reveal that GABA can regulate the LPS structure and cytotoxicity of P. fluorescens, but that this property is specific to some strains. PMID:23743829

  6. Effect of GABA, a Bacterial Metabolite, on Pseudomonas fluorescens Surface Properties and Cytotoxicity

    PubMed Central

    Dagorn, Audrey; Chapalain, Annelise; Mijouin, Lily; Hillion, Mélanie; Duclairoir-Poc, Cécile; Chevalier, Sylvie; Taupin, Laure; Orange, Nicole; Feuilloley, Marc G. J.

    2013-01-01

    Different bacterial species and, particularly Pseudomonas fluorescens, can produce gamma-aminobutyric acid (GABA) and express GABA-binding proteins. In this study, we investigated the effect of GABA on the virulence and biofilm formation activity of different strains of P. fluorescens. Exposure of a psychotropic strain of P. fluorescens (MF37) to GABA (10−5 M) increased its necrotic-like activity on eukaryotic (glial) cells, but reduced its apoptotic effect. Conversely, muscimol and bicuculline, the selective agonist and antagonist of eukaryote GABAA receptors, respectively, were ineffective. P. fluorescens MF37 did not produce biosurfactants, and its caseinase, esterase, amylase, hemolytic activity or pyoverdine productions were unchanged. In contrast, the effect of GABA was associated to rearrangements of the lipopolysaccharide (LPS) structure, particularly in the lipid A region. The surface hydrophobicity of MF37 was marginally modified, and GABA reduced its biofilm formation activity on PVC, but not on glass, although the initial adhesion was increased. Five other P. fluorescens strains were studied, and only one, MFP05, a strain isolated from human skin, showed structural differences of biofilm maturation after exposure to GABA. These results reveal that GABA can regulate the LPS structure and cytotoxicity of P. fluorescens, but that this property is specific to some strains. PMID:23743829

  7. Immunocytochemistry of GABA in the brain and suboesophageal ganglion of Manduca sexta.

    PubMed

    Homberg, U; Kingan, T G; Hildebrand, J G

    1987-04-01

    We have used specific antisera against protein-conjugated gamma-aminobutyric acid (GABA) in immunocytochemical preparations to investigate the distribution of putatively GABAergic neurons in the brain and suboesophageal ganglion of the sphinx moth Manduca sexta. About 20,000 neurons per brain hemisphere exhibit GABA-immunoreactivity. Most of these are optic-lobe interneurons, especially morphologically centrifugal neurons of the lamina and tangential neurons that innervate the medulla or the lobula complex. Many GABA-immunoreactive neurons, among them giant fibers of the lobula plate, project into the median protocerebrum. Among prominent GABA-immunoreactive neurons of the median protocerebrum are about 150 putatively negative-feedback fibers of the mushroom body, innervating both the calyces and lobes, and a group of large, fan-shaped neurons of the lower division of the central body. Several commissures in the supra- and suboesophageal ganglion exhibit GABA-like immunoreactivity. In the suboesophageal ganglion, a group of contralaterally descending neurons shows GABA-like immunoreactivity. The frontal ganglion is innervated by immunoreactive processes from the tritocerebrum but does not contain GABA-immunoreactive somata. With few exceptions the brain nerves do not contain GABA-immunoreactive fibers. PMID:3552234

  8. Segregation of Acetylcholine and GABA in the Rat Superior Cervical Ganglia: Functional Correlation.

    PubMed

    Elinos, Diana; Rodríguez, Raúl; Martínez, Luis Andres; Zetina, María Elena; Cifuentes, Fredy; Morales, Miguel Angel

    2016-01-01

    Sympathetic neurons have the capability to segregate their neurotransmitters (NTs) and co-transmitters to separate varicosities of single axons; furthermore, in culture, these neurons can even segregate classical transmitters. In vivo sympathetic neurons employ acetylcholine (ACh) and other classical NTs such as gamma aminobutyric acid (GABA). Herein, we explore whether these neurons in vivo segregate these classical NTs in the superior cervical ganglia of the rat. We determined the topographical distribution of GABAergic varicosities, somatic GABAA receptor, as well as the regional distribution of the segregation of ACh and GABA. We evaluated possible regional differences in efficacy of ganglionic synaptic transmission, in the sensitivity of GABAA receptor to GABA and to the competitive antagonist picrotoxin (PTX). We found that sympathetic preganglionic neurons in vivo do segregate ACh and GABA. GABAergic varicosities and GABAA receptor expression showed a rostro-caudal gradient along ganglia; in contrast, segregation exhibited a caudo-rostral gradient. These uneven regional distributions in expression of GABA, GABAA receptors, and level of segregation correlate with stronger synaptic transmission found in the caudal region. Accordingly, GABAA receptors of rostral region showed larger sensitivity to GABA and PTX. These results suggest the presence of different types of GABAA receptors in each region that result in a different regional levels of endogenous GABA inhibition. Finally, we discuss a possible correlation of these different levels of GABA modulation and the function of the target organs innervated by rostral and caudal ganglionic neurons. PMID:27092054

  9. Segregation of Acetylcholine and GABA in the Rat Superior Cervical Ganglia: Functional Correlation

    PubMed Central

    Elinos, Diana; Rodríguez, Raúl; Martínez, Luis Andres; Zetina, María Elena; Cifuentes, Fredy; Morales, Miguel Angel

    2016-01-01

    Sympathetic neurons have the capability to segregate their neurotransmitters (NTs) and co-transmitters to separate varicosities of single axons; furthermore, in culture, these neurons can even segregate classical transmitters. In vivo sympathetic neurons employ acetylcholine (ACh) and other classical NTs such as gamma aminobutyric acid (GABA). Herein, we explore whether these neurons in vivo segregate these classical NTs in the superior cervical ganglia of the rat. We determined the topographical distribution of GABAergic varicosities, somatic GABAA receptor, as well as the regional distribution of the segregation of ACh and GABA. We evaluated possible regional differences in efficacy of ganglionic synaptic transmission, in the sensitivity of GABAA receptor to GABA and to the competitive antagonist picrotoxin (PTX). We found that sympathetic preganglionic neurons in vivo do segregate ACh and GABA. GABAergic varicosities and GABAA receptor expression showed a rostro-caudal gradient along ganglia; in contrast, segregation exhibited a caudo-rostral gradient. These uneven regional distributions in expression of GABA, GABAA receptors, and level of segregation correlate with stronger synaptic transmission found in the caudal region. Accordingly, GABAA receptors of rostral region showed larger sensitivity to GABA and PTX. These results suggest the presence of different types of GABAA receptors in each region that result in a different regional levels of endogenous GABA inhibition. Finally, we discuss a possible correlation of these different levels of GABA modulation and the function of the target organs innervated by rostral and caudal ganglionic neurons. PMID:27092054

  10. Temperature dependence and GABA modulation of (TH)triazolam binding in the rat brain

    SciTech Connect

    Earle, M.E.; Concas, A.; Wamsley, J.K.; Yamamura, H.I.

    1987-07-27

    The hypnotic triazolam (TZ), a triazolobenzodiazepine displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. The authors major objectives were the direct measurement of the temperature dependence and the gamma-aminobutyric acid (GABA) effect of (TH)TZ binding in the rat brain. Saturation studies showed a shift to lower affinity with increasing temperatures (K/sub d/ = 0.27 +/- 08 nM at 0C; K/sub d/ = 1.96 +/- 0.85 nM at 37C) while the B/sub max/ values remained unchanged (1220 +/- 176 fmoles/mg protein at 0C and 1160 +/- 383 fmoles/mg protein at 37C). Saturation studies of (TH)TZ binding in the presence or absence of GABA (100 M) showed a GABA-shift. At 0C the K/sub d/ values were (K/sub d/ = 0.24 +/- 0.03 nM/-GABA; K/sub d/ = 0.16 +/- 0.04/+GABA) and at 37C the K/sub d/ values were (K/sub d/ = 1.84 +/- 0.44 nM/-GABA; K/sub d/ = 0.95 +/- 0.29 nM/+GABA). In contrast to reported literature, the authors findings show that TZ interacts with benzodiazepine receptors with a temperature dependence and GABA-shift consistent with predicted behavior for benzodiazepine agonists. 20 references, 3 tables.

  11. GABA-shunt enzymes activity in GH3 cells with reduced level of PMCA2 or PMCA3 isoform

    SciTech Connect

    Kowalski, Antoni

    2011-08-12

    Highlights: {yields} Suppression of PMCA2 or PMCA3 slows down proliferation of GH3 cells. {yields} PMCA2 suppression lowers the activity of GABA-shunt enzymes. {yields} PMCA3 suppression increases the expression of glutamate decarboxylase 65. {yields} PMCA2 and PMCA3 function appears to be linked to regulation of GABA metabolism. -- Abstract: GABA ({gamma}-aminobutyric acid) is important neurotransmitter and regulator of endocrine functions. Its metabolism involves three enzymes: glutamate decarboxylase (GAD65 and GAD67), GABA aminotransferase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). As many cellular processes GABA turnover can depend on calcium homeostasis, which is maintained by plasma membrane calcium ATPases (PMCAs). In excitable cells PMCA2 and PMCA3 isoforms are particularly important. In this study we focused on GABA-metabolizing enzymes expression and activity in rat anterior pituitary GH3 cells with suppressed expression of PMCA2 or PMCA3. We observed that PMCA3-reduced cells have increased GAD65 expression. Suppression of PMCA2 caused a decrease in total GAD and GABA-T activity. These results indicate that PMCA2 and PMCA3 presence may be an important regulatory factor in GABA metabolism. Results suggest that PMCA2 and PMCA3 function is rather related to regulation of GABA synthesis and degradation than supplying cells with metabolites, which can be potentially energetic source.

  12. Development of a high-affinity GABA uptake system in embryonic amphibian spinal neurons.

    PubMed

    Lamborghini, J E; Iles, A

    1985-11-01

    High-affinity uptake systems for amino acid neurotransmitter precursors have been highly correlated with the use of the particular amino acid or its derivative as a transmitter. We have found interneurons in the Xenopus embryo spinal cord which accumulate GABA by a high-affinity uptake system. They originate near the end of gastrulation and their ability to accumulate GABA first appears at the early tail bud stage. By position and appearance they are comparable to some of the embryonic interneurons described by A. Roberts and J. D. W. Clarke (1982, Phil. Trans. R. Soc. London Ser. B 296, 195-212). GABA-accumulating neurons also develop in dissociated cell cultures made from the presumptive spinal cord of neural plate stage Xenopus embryos. GABA accumulation in cultured neurons, as in cells in vivo, occurs via a high-affinity uptake system; GABA-accumulating cells have the same time of origin as the cells in vivo, and the ability to accumulate GABA in the population of cultured neurons appears at a time equivalent to that observed in intact sibling embryos. Thus it seems likely that the population of GABA-accumulating neurons developing in cell culture corresponds to the GABA-accumulating interneurons in vivo. The development of these neurons in dissociated cell cultures permits perturbation experiments that would be difficult to perform in vivo. We have examined the development of high-affinity GABA uptake in conditions that permit no electrical impulse activity in the cultures. The onset and extent of development of GABA accumulation in the neuronal population are normal under these conditions. PMID:3932109

  13. A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor

    PubMed Central

    Kaji, Mark D; Kwaka, Ariel; Callanan, Micah K; Nusrat, Humza; Desaulniers, Jean-Paul; Forrester, Sean G

    2015-01-01

    Background and Purpose Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. Experimental Approach We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. Key Results The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(−)-4-amino-3-hydroxybutyric acid [R(−)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(−)- and S(+)-GABOB. Conclusions and Implications The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes. PMID:25850584

  14. A comparative density functional theory study of electronic structure and optical properties of γ-aminobutyric acid and its cocrystals with oxalic and benzoic acid

    NASA Astrophysics Data System (ADS)

    da Silva Filho, J. G.; Freire, V. N.; Caetano, E. W. S.; Ladeira, L. O.; Fulco, U. L.; Albuquerque, E. L.

    2013-11-01

    In this letter, we study the electronic structure and optical properties of the active medicinal component γ-aminobutyric acid (GABA) and its cocrystals with oxalic (OXA) and benzoic (BZA) acid by means of the density functional theory formalism. It is shown that the cocrystallization strongly weakens the zwitterionic character of the GABA molecule leading to striking differences among the electronic band structures and optical absorption spectra of the GABA crystal and GABA:OXA, GABA:BZA cocrystals, originating from distinct sets of hydrogen bonds. Calculated band widths and Δ-sol band gap estimates indicate that both GABA and GABA:OXA, GABA:BZA cocrystals are indirect gap insulators.

  15. GABA Production in Lactococcus lactis Is Enhanced by Arginine and Co-addition of Malate.

    PubMed

    Laroute, Valérie; Yasaro, Chonthicha; Narin, Waranya; Mazzoli, Roberto; Pessione, Enrica; Cocaign-Bousquet, Muriel; Loubière, Pascal

    2016-01-01

    Lactococcus lactis NCDO 2118 was previously selected for its ability to decarboxylate glutamate to γ-aminobutyric acid (GABA), an interesting nutritional supplement able to improve mood and relaxation. Amino acid decarboxylation is generally considered as among the biochemical systems allowing lactic acid bacteria to counteracting acidic stress and obtaining metabolic energy. These strategies also include arginine deiminase pathway and malolactic fermentation but little is known about their possible interactions of with GABA production. In the present study, the effects of glutamate, arginine, and malate (i.e., the substrates of these acid-resistance pathways) on L. lactis NCDO 2118 growth and GABA production performances were analyzed. Both malate and arginine supplementation resulted in an efficient reduction of acidity and improvement of bacterial biomass compared to glutamate supplementation. Glutamate decarboxylation was limited to narrow environmental conditions (pH < 5.1) and physiological state (stationary phase). However, some conditions were able to improve GABA production or activate glutamate decarboxylation system even outside of this compass. Arginine clearly stimulated glutamate decarboxylation: the highest GABA production (8.6 mM) was observed in cultures supplemented with both arginine and glutamate. The simultaneous addition of arginine, malate, and glutamate enabled earlier GABA production (i.e., during exponential growth) at relatively high pH (6.5). As far as we know, no previous study has reported GABA production in such conditions. Although further studies are needed to understand the molecular basis of these phenomena, these results represent important keys suitable of application in GABA production processes. PMID:27458444

  16. GABA Production in Lactococcus lactis Is Enhanced by Arginine and Co-addition of Malate

    PubMed Central

    Laroute, Valérie; Yasaro, Chonthicha; Narin, Waranya; Mazzoli, Roberto; Pessione, Enrica; Cocaign-Bousquet, Muriel; Loubière, Pascal

    2016-01-01

    Lactococcus lactis NCDO 2118 was previously selected for its ability to decarboxylate glutamate to γ-aminobutyric acid (GABA), an interesting nutritional supplement able to improve mood and relaxation. Amino acid decarboxylation is generally considered as among the biochemical systems allowing lactic acid bacteria to counteracting acidic stress and obtaining metabolic energy. These strategies also include arginine deiminase pathway and malolactic fermentation but little is known about their possible interactions of with GABA production. In the present study, the effects of glutamate, arginine, and malate (i.e., the substrates of these acid-resistance pathways) on L. lactis NCDO 2118 growth and GABA production performances were analyzed. Both malate and arginine supplementation resulted in an efficient reduction of acidity and improvement of bacterial biomass compared to glutamate supplementation. Glutamate decarboxylation was limited to narrow environmental conditions (pH < 5.1) and physiological state (stationary phase). However, some conditions were able to improve GABA production or activate glutamate decarboxylation system even outside of this compass. Arginine clearly stimulated glutamate decarboxylation: the highest GABA production (8.6 mM) was observed in cultures supplemented with both arginine and glutamate. The simultaneous addition of arginine, malate, and glutamate enabled earlier GABA production (i.e., during exponential growth) at relatively high pH (6.5). As far as we know, no previous study has reported GABA production in such conditions. Although further studies are needed to understand the molecular basis of these phenomena, these results represent important keys suitable of application in GABA production processes. PMID:27458444

  17. The Memory-Impairing Effects of Septal GABA Receptor Activation Involve GABAergic Septo-Hippocampal Projection Neurons

    ERIC Educational Resources Information Center

    Krebs-Kraft, Desiree L.; Wheeler, Marina G.; Parent, Marise B.

    2007-01-01

    Septal infusions of the [gamma]-aminobutyric acid (GABA)[subscript A] agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA[subscript A] receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are…

  18. Focal Uncaging of GABA Reveals a Temporally Defined Role for GABAergic Inhibition during Appetitive Associative Olfactory Conditioning in Honeybees

    ERIC Educational Resources Information Center

    Raccuglia, Davide; Mueller, Uli

    2013-01-01

    Throughout the animal kingdom, the inhibitory neurotransmitter ?-aminobutyric acid (GABA) is a key modulator of physiological processes including learning. With respect to associative learning, the exact time in which GABA interferes with the molecular events of learning has not yet been clearly defined. To address this issue, we used two…

  19. GABA System in Schizophrenia and Mood Disorders: A Mini Review on Third-Generation Imaging Studies.

    PubMed

    Chiapponi, Chiara; Piras, Federica; Piras, Fabrizio; Caltagirone, Carlo; Spalletta, Gianfranco

    2016-01-01

    Third-generation neuroimaging research has been enriched by advances in magnetic resonance spectroscopy (MRS) measuring the concentration of important neurotrasmitters, such as the inhibitory amino acid GABA. Here, we performed a systematic mini-review on brain MRS studies measuring GABA concentration in patients affected by schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We wondered whether multimodal investigations could overcome intrinsic technical limits of MRS giving a broader view of mental disorders pathogenesis. In SZ, unimodal studies gave mixed results, as increased, decreased, or unaltered GABA levels were reported depending on region, disease phase, and treatment. Conversely, multimodal results showed reduced level of glutamate, but not of GABA, in patients mirrored by in vitro biochemical findings revealing hippocampal reduction in glutamate signaling in SZ, and no deficits in GABA synthesis. Moreover, a mouse model confirmed the unique pathological characteristic of glutamate function in SZ. Unimodal studies in BD revealed again, inconsistent results, while no multimodal investigations including MRS on GABA exist. In MDD, unimodal studies could not differentiate patients from controls nor characterize high-risk subjects and remitted patients. However, a multimodal study combining functional magnetic resonance imaging and MRS revealed that cingulate cortex activity is related to glutamate, N-acetylaspartate levels and anhedonia in patients, and to GABA concentration in healthy subjects, improving the distinction between MDD and physiology. Overall, our results show that unimodal studies do not indicate GABA as a biomarker for the psychiatric disorders considered. Conversely, multimodal studies can widen the understanding of the link between psychopathology, genetics, neuroanatomy, and functional-biochemical brain activity in mental disorders. Although scarce, multimodal approaches seem promising for moving from GABA MRS

  20. GABA System in Schizophrenia and Mood Disorders: A Mini Review on Third-Generation Imaging Studies

    PubMed Central

    Chiapponi, Chiara; Piras, Federica; Piras, Fabrizio; Caltagirone, Carlo; Spalletta, Gianfranco

    2016-01-01

    Third-generation neuroimaging research has been enriched by advances in magnetic resonance spectroscopy (MRS) measuring the concentration of important neurotrasmitters, such as the inhibitory amino acid GABA. Here, we performed a systematic mini-review on brain MRS studies measuring GABA concentration in patients affected by schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We wondered whether multimodal investigations could overcome intrinsic technical limits of MRS giving a broader view of mental disorders pathogenesis. In SZ, unimodal studies gave mixed results, as increased, decreased, or unaltered GABA levels were reported depending on region, disease phase, and treatment. Conversely, multimodal results showed reduced level of glutamate, but not of GABA, in patients mirrored by in vitro biochemical findings revealing hippocampal reduction in glutamate signaling in SZ, and no deficits in GABA synthesis. Moreover, a mouse model confirmed the unique pathological characteristic of glutamate function in SZ. Unimodal studies in BD revealed again, inconsistent results, while no multimodal investigations including MRS on GABA exist. In MDD, unimodal studies could not differentiate patients from controls nor characterize high-risk subjects and remitted patients. However, a multimodal study combining functional magnetic resonance imaging and MRS revealed that cingulate cortex activity is related to glutamate, N-acetylaspartate levels and anhedonia in patients, and to GABA concentration in healthy subjects, improving the distinction between MDD and physiology. Overall, our results show that unimodal studies do not indicate GABA as a biomarker for the psychiatric disorders considered. Conversely, multimodal studies can widen the understanding of the link between psychopathology, genetics, neuroanatomy, and functional–biochemical brain activity in mental disorders. Although scarce, multimodal approaches seem promising for moving from GABA

  1. GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomycescerevisiae

    SciTech Connect

    Kamei, Yuka; Tamura, Takayuki; Yoshida, Ryo; Ohta, Shinji; Fukusaki, Eiichiro; Mukai, Yukio

    2011-04-01

    Highlights: {yields}We demonstrate that two genes in the yeast GABA metabolism pathway affect aging. {yields} Deletion of the UGA1 or GAD1 genes extends replicative lifespan. {yields} Addition of GABA to wild-type cultures has no effect on lifespan. {yields} Intracellular GABA levels do not differ in longevity mutants and wild-type cells. {yields} Levels of tricarboxylic acid cycle intermediates positively correlate with lifespan. -- Abstract: Many of the genes involved in aging have been identified in organisms ranging from yeast to human. Our previous study showed that deletion of the UGA3 gene-which encodes a zinc-finger transcription factor necessary for {gamma}-aminobutyric acid (GABA)-dependent induction of the UGA1 (GABA aminotransferase), UGA2 (succinate semialdehyde dehydrogenase), and UGA4 (GABA permease) genes-extends replicative lifespan in the budding yeast Saccharomycescerevisiae. Here, we found that deletion of UGA1 lengthened the lifespan, as did deletion of UGA3; in contrast, strains with UGA2 or UGA4 deletions exhibited no lifespan extension. The {Delta}uga1 strain cannot deaminate GABA to succinate semialdehyde. Deletion of GAD1, which encodes the glutamate decarboxylase that converts glutamate into GABA, also increased lifespan. Therefore, two genes in the GABA metabolism pathway, UGA1 and GAD1, were identified as aging genes. Unexpectedly, intracellular GABA levels in mutant cells (except for {Delta}uga2 cells) did not differ from those in wild-type cells. Addition of GABA to culture media, which induces transcription of the UGA structural genes, had no effect on replicative lifespan of wild-type cells. Multivariate analysis of {sup 1}H nuclear magnetic resonance spectra for the whole-cell metabolite levels demonstrated a separation between long-lived and normal-lived strains. Gas chromatography-mass spectrometry analysis of identified metabolites showed that levels of tricarboxylic acid cycle intermediates positively correlated with lifespan

  2. Novel functions of GABA signaling in adult neurogenesis.

    PubMed

    Pontes, Adalto; Zhang, Yonggang; Hu, Wenhui

    2013-10-01

    Neurotransmitter gamma-aminobutiric acid (GABA) through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells (NSCs/NPCs). The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na(+)/K(+)/2Cl(-) co-transporter NKCC1 driving Cl(-) influx and neuron-specific K(+)/Cl(-) co-transporter KCC2 driving Cl(-) efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-Schizophrenia 1 (DISC1) and brain-derived neurotrophic factor (BDNF) signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and newborn neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance. PMID:24285940

  3. Novel functions of GABA signaling in adult neurogenesis

    PubMed Central

    PONTES, Adalto; ZHANG, Yonggang; HU, Wenhui

    2013-01-01

    Neurotransmitter gamma-aminobutiric acid (GABA) through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells (NSCs/NPCs). The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na+/K+/2Cl− co-transporter NKCC1 driving Cl− influx and neuron-specific K+/Cl− co-transporter KCC2 driving Cl− efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-Schizophrenia 1 (DISC1) and brain-derived neurotrophic factor (BDNF) signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and newborn neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance. PMID:24285940

  4. Action of tremorgenic mycotoxins on GABA/sub A/ receptor

    SciTech Connect

    Gant, D.B.; Cole, R.J.; Valdes, J.J.; Eldefrawi, M.E.; Eldefrawi, A.T.

    1987-11-09

    The effects of four tremorgenic and one nontremorgenic mycotoxins were studied on ..gamma..-aminobutyric acid (GABA/sub A/) receptor binding and function in rat brain and on binding of a voltage-operated Cl/sup -/ channel in Torpedo electric organ. None of the mycotoxins had significant effect on (/sup 3/H)muscimol or (/sup 3/H)flunitrazepam binding to the GAMA/sup A/ receptor. However, only the four tremorgenic mycotoxins inhibited GABA-induced /sup 36/Cl/sup -/ influx and (/sup 35/S)t-butylbicyclophosphorothionate ((/sup 35/S)TBPS) binding in rate brain membranes, while the nontremorgenic verruculotoxin had no effect. Inhibition of (/sup 35/S)TBPS binding by paspalinine was non-competitive. This suggests that tremorgenic mycotoxins inhibit GABA/sub A/ receptor function by binding close to the receptor's Cl/sup -/ channel. On the voltage-operated Cl/sup -/ channel, only high concentrations of verruculogen and verruculotoxin caused significant inhibition of the channel's binding of (/sup 35/S)TBPS. The data suggest that the tremorgenic action of these mycotoxins may be due in part to their inhibition of GABA/sub A/ receptor function. 21 references, 4 figures, 2 tables.

  5. GABA-mediated inhibition of the anaphylactic response in the guinea-pig trachea.

    PubMed Central

    Gentilini, G.; Franchi-Micheli, S.; Mugnai, S.; Bindi, D.; Zilletti, L.

    1995-01-01

    1. In sensitized guinea-pigs, the effects of gamma-aminobutyric acid (GABA) and GABAmimetic drugs have been investigated on tracheal segments contracted by cumulative application of an allergen (ovoalbumin, OA) and on serosal mast cells. The same drugs have also been tested on activation of alveolar macrophages isolated from unsensitized guinea-pigs. 2. Superfusion with GABA (1-1000 microM) reduced the contraction intensity of tracheal strips. The effect of GABA (100 microM) was not affected by the carrier blockers, nipecotic acid and beta-alanine (300 microM each). It was mimicked by the GABAB agonist (-)-baclofen (100 microM) but not 3-aminopropanephosphinic acid (100 microM, 3-APA). The GABAA agonist, isoguvacine (100 microM) did not exert any effect. GABA (10 microM)-induced inhibition of tracheal contractions was reduced by the GABAB antagonist, 2-hydroxysaclofen (100 microM, 2-HS), but not by the GABAA antagonist, bicuculline (30 microM). 3. The reduction in contraction intensity induced by GABA (100 microM) was prevented by a 40 min preincubation of tracheal strips with capsaicin (10 microM), but not tetrodotoxin (TTX, 0.3 microM). The effect of GABA (1000 microM) was absent after preincubation with indomethacin (2.8 microM) but unmodified when nordihydroguaiaretic acid (NDGA, 3.3 microM) was used. Finally, removal of the epithelium prevented the GABA effect. 4. Anaphylactic histamine release from serosal mast cells isolated from sensitized animals was not affected either by GABA (10-1000 microM) or the selective receptor agonists (-)-baclofen (0.1-1000 microM) and isoguvacine (10-1000 microM).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582447

  6. [The radioprotective effect of GABA-tropic substances, gamma-hydroxybutyrate and piracetam].

    PubMed

    Kulinskiĭ, V I; Klimova, A D

    1993-01-01

    From experiments in mice, it is shown that with a radiation dose of 8 Gy (LD96) the radioprotective effect was exerted by gamma-aminobutyric acid (GABA), substances that increase its concentration in tissues (progabide and valproate), and synthetic agonists of both receptor types, particularly baclofen, a GABA-receptor agonist. The radioprotective effect is also exerted by gamma-hydroxybutyrate, not piracetam. PMID:8469734

  7. GABA(A) receptor downregulation in brains of subjects with autism.

    PubMed

    Fatemi, S Hossein; Reutiman, Teri J; Folsom, Timothy D; Thuras, Paul D

    2009-02-01

    Gamma-aminobutyric acid A (GABA(A)) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABA(A) receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann's Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABA(A) receptor subunit expression in the three brain areas. Our results demonstrate that GABA(A) receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism. PMID:18821008

  8. Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

    PubMed Central

    Wang, Lu; Wang, Yan; Zhou, Shimeng; Yang, Liukun; Shi, Qixin; Li, Yujiao; Zhang, Kun; Yang, Le; Zhao, Minggao; Yang, Qi

    2016-01-01

    Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment. PMID:27517961

  9. Correlation between the enhancement of flunitrazepam binding by GABA and seizure susceptibility in mice

    SciTech Connect

    Marley, R.J.; Wehner, J.M.

    1987-06-08

    Various populations of mice exhibit differential sensitivity to seizure-inducing agents. The relationship of seizure susceptibility to alterations in the GABA receptor complex was investigated in six different populations of mice consisting of four inbred strains (C57BL, DBA, C3H, and BALB) and two selected lines (long sleep and short sleep). Seizure activity was induced by intraperitoneal administration of the GAD inhibitor, 3-mercaptopropionic acid, and latencies to seizure onset and tonus were measured. In naive mice of the same populations, GABA enhancement of TH-flunitrazepam binding was measured in extensively washed whole brain membranes at several GABA concentrations. Both differential seizure sensitivity to 3-mercaptopropionic acid and differential enhancement of TH-flunitrazepam binding by GABA were observed in these six populations of mice. Correlational analyses indicated a positive correlation between the degree of GABA enhancement of TH-flunitrazepam binding and resistance to the seizure-inducing properties of 3-mercaptopropionic acid. These data suggest that genetic differences in sensitivity to seizure-inducing agents that disrupt the GABAergic system may be related to differences in coupling between the various receptors associated with the GABA receptor complex.

  10. Sleep-promoting effects of the GABA/5-HTP mixture in vertebrate models.

    PubMed

    Hong, Ki-Bae; Park, Yooheon; Suh, Hyung Joo

    2016-09-01

    The aim of this study was to investigate the sleep-promoting effect of combined γ-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP) on sleep quality and quantity in vertebrate models. Pentobarbital-induced sleep test and electroencephalogram (EEG) analysis were applied to investigate sleep latency, duration, total sleeping time and sleep quality of two amino acids and GABA/5-HTP mixture. In addition, real-time PCR and HPLC analysis were applied to analyze the signaling pathway. The GABA/5-HTP mixture significantly regulated the sleep latency, duration (p<0.005), and also increased the sleep quality than single administration of the amino acids (p<0.000). Long-term administration increased the transcript levels of GABAA receptor (1.37-fold, p<0.000) and also increased the GABA content compared with the control group 12h after administration (1.43-fold, p<0.000). Our available evidence suggests that the GABA/5-HTP mixture modulates both GABAergic and serotonergic signaling. Moreover, the sleep architecture can be controlled by the regulation of GABAA receptor and GABA content with 5-HTP. PMID:27150227

  11. Comparison of taurine, GABA, Glu, and Asp as scavengers of malondialdehyde in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Deng, Yan; Wang, Wei; Yu, Pingfeng; Xi, Zhijiang; Xu, Lijian; Li, Xiaolong; He, Nongyue

    2013-04-01

    The purpose of this study is to determine if amino acid neurotransmitters such as gamma-aminobutyric acid (GABA), taurine, glutamate (Glu), and aspartate (Asp) can scavenge activated carbonyl toxicants. In vitro, direct reaction between malondialdehyde (MDA) and amino acids was researched using different analytical methods. The results indicated that scavenging activated carbonyl function of taurine and GABA is very strong and that of Glu and Asp is very weak in pathophysiological situations. The results provided perspective into the reaction mechanism of taurine and GABA as targets of activated carbonyl such as MDA in protecting nerve terminals. In vivo, we studied the effect of taurine and GABA as antioxidants by detecting MDA concentration and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. It was shown that MDA concentration was decreased significantly, and the activities of SOD and GSH-Px were increased significantly in the cerebral cortex and hippocampus of acute epileptic state rats, after the administration of taurine and GABA. The results indicated that the peripherally administered taurine and GABA can scavenge free radicals and protect the tissue against activated carbonyl in vivo and in vitro.

  12. Synthesis of new fluorinated analogs of GABA, Pregabalin bioisosteres, and their effects on [(3)H]GABA uptake by rat brain nerve terminals.

    PubMed

    Borisova, T; Pozdnyakova, N; Shaitanova, E; Gerus, I; Dudarenko, M; Mironets, R; Haufe, G; Kukhar, V

    2015-08-01

    Fluorinated analogs of natural substances take an essential place in the design of new biologically active compounds. New fluorinated analogs of γ-aminobutyric acid, that is, β-polyfluoroalkyl-GABAs (FGABAs), were synthesized with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3). FGABAs are bioisosteres of Pregabalin (Lyrica®, Pfizer's blockbuster drug, β-i-Bu-GABA), and have lipophilicity close to this medicine. The effects of synthesized FGABAs on [(3)H]GABA uptake by isolated rat brain nerve terminals (synaptosomes) were assessed and compared with those of Pregabalin. FGABAs 1-3 (100μM) did not influence the initial velocity of [(3)H]GABA uptake when applied acutely, whereas an increase in this parameter was found after preliminary incubation of FGABAs with synaptosomes. Pregabalin after preliminary incubation with synaptosomes caused unidirectional changes in the initial velocity of [(3)H]GABA uptake. Using specific inhibitors of GAT1 and GAT3, NO-711 and SNAP5114, respectively, the ability of FGABAs 1-3 to influence non-GAT1 and non-GAT3 uptake activity of nerve terminals was analyzed, but no specificity was found. Therefore, new synthesized FGABAs are structural but not functional analogs of GABA (because they did not inhibit synaptosomal [(3)H]GABA uptake). Moreover, FGABAs are able to increase the initial velocity of [(3)H]GABA uptake by synaptosomes, and this effect is higher than that of Pregabalin. PMID:26138193

  13. The transporter GAT1 plays an important role in GABA-mediated carbon-nitrogen interactions in Arabidopsis

    PubMed Central

    Batushansky, Albert; Kirma, Menny; Grillich, Nicole; Pham, Phuong A.; Rentsch, Doris; Galili, Gad; Fernie, Alisdair R.; Fait, Aaron

    2015-01-01

    Glutamate derived γ-aminobutyric acid (GABA) is synthetized in the cytosol prior to delivery to the mitochondria where it is catabolized via the TCA cycle. GABA accumulates under various environmental conditions, but an increasing number of studies show its involvement at the crossroad between C and N metabolism. To assess the role of GABA in modulating cellular metabolism, we exposed seedlings of A. thaliana GABA transporter gat1 mutant to full nutrition medium and media deficient in C and N combined with feeding of different concentrations (0.5 and 1 mM) of exogenous GABA. GC-MS based metabolite profiling showed an expected effect of medium composition on the seedlings metabolism of mutant and wild type alike. That being said, a significant interaction between GAT1 deficiency and medium composition was determined with respect to magnitude of change in relative amino acid levels. The effect of exogenous GABA treatment on metabolism was contingent on both the medium and the genotype, leading for instance to a drop in asparagine under full nutrition and low C conditions and glucose under all tested media, but not to changes in GABA content. We additionally assessed the effect of GAT1 deficiency on the expression of glutamate metabolism related genes and genes involved in abiotic stress responses. These results suggest a role for GAT1 in GABA-mediated metabolic alterations in the context of the C-N equilibrium of plant cells. PMID:26483804

  14. Microtransplantation of cellular membranes from squid stellate ganglion reveals ionotropic GABA receptors.

    PubMed

    Conti, Luca; Limon, Agenor; Palma, Eleonora; Miledi, Ricardo

    2013-02-01

    The squid has been the most studied cephalopod, and it has served as a very useful model for investigating the events associated with nerve impulse generation and synaptic transmission. While the physiology of squid giant axons has been extensively studied, very little is known about the distribution and function of the neurotransmitters and receptors that mediate inhibitory transmission at the synapses. In this study we investigated whether γ-aminobutyric acid (GABA) activates neurotransmitter receptors in stellate ganglia membranes. To overcome the low abundance of GABA-like mRNAs in invertebrates and the low expression of GABA in cephalopods, we used a two-electrode voltage clamp technique to determine if Xenopus laevis oocytes injected with cell membranes from squid stellate ganglia responded to GABA. Using this method, membrane patches containing proteins and ion channels from the squid's stellate ganglion were incorporated into the surface of oocytes. We demonstrated that GABA activates membrane receptors in cellular membranes isolated from squid stellate ganglia. Using the same approach, we were able to record native glutamate-evoked currents. The squid's GABA receptors showed an EC(50) of 98 μmol l(-1) to GABA and were inhibited by zinc (IC(50) = 356 μmol l(-1)). Interestingly, GABA receptors from the squid were only partially blocked by bicuculline. These results indicate that the microtransplantation of native cell membranes is useful to identify and characterize scarce membrane proteins. Moreover, our data also support the role of GABA as an ionotropic neurotransmitter in cephalopods, acting through chloride-permeable membrane receptors. PMID:23493508

  15. Aging of whiskey increases the potentiation of GABA(A) receptor response.

    PubMed

    Koda, Hirofumi; Hossain, Sheikh Julfikar; Kiso, Yoshinobu; Aoshima, Hitoshi

    2003-08-27

    It is known that the target of most mood-defining compounds such as ethanol is an ionotropic gamma-aminobutyric acid receptor (GABA(A) receptor). The potentiation of the response of these inhibitory neurotransmitter receptors induces anxiolytic, sedative, and anesthetic activities in the human brain. Because both extracts of whiskey by pentane and fragrant components in whiskey potentiate the GABA(A) receptor-mediated response, GABA(A) receptors were expressed in Xenopus oocyte by injecting cRNAs prepared from the cloned cDNA for the alpha(1) and beta(1) subunits of the bovine receptors in order to study the effects of whiskey itself on the GABA(A) receptor-mediated response. Whiskey itself also potentiated the electrical responses of GABA(A) receptors generally more than ethanol at the same concentration as that of the whiskey. The potentiation of the GABA(A) receptor-mediated response increased with the aging period of the whiskey. Inhalation of whiskey to mice increased the sleeping time induced by pentobarbital more than that of the same concentration of ethanol as the whiskey. These results suggest that not only ethanol but also minor components in whiskey play an important role in the potentiation of GABA(A) receptor-mediated response and possibly the sedative effect of whiskey. Although the minor components are present in extremely small quantities compared with ethanol in alcoholic beverages, they may modulate the mood or consciousness of humans through the potentiation of the GABA(A) receptor response after absorption into the brain, because these hydrophobic compounds are easily absorbed into the brain across the blood-brain barrier and are several thousands times as potent as ethanol in the potentiation of the GABA(A) receptor-mediated response. PMID:12926865

  16. GABA(B) receptors and synaptic modulation.

    PubMed

    Kornau, Hans-Christian

    2006-11-01

    GABA(B) receptors modulate transmitter release and postsynaptic membrane potential at various types of central synapses. They function as heterodimers of two related seven-transmembrane domain receptor subunits. Trafficking, activation and signalling of GABA(B) receptors are regulated both by allosteric interactions between the subunits and by the binding of additional proteins. Recent studies have shed light on the roles of GABA(B) receptors in plasticity processes at excitatory synapses. This review summarizes our knowledge of the localization, structure and function of GABA(B) receptors in the central nervous system and their use as drug targets for neurological and psychiatric disorders. PMID:16932937

  17. GABA and GAD expression in the X-organ sinus gland system of the Procambarus clarkii crayfish: inhibition mediated by GABA between X-organ neurons.

    PubMed

    Pérez-Polanco, Paola; Garduño, Julieta; Cebada, Jorge; Zarco, Natanael; Segovia, José; Lamas, Mónica; García, Ubaldo

    2011-09-01

    In crustaceans, the X-organ-sinus gland (XO-SG) neurosecretory system is formed of distinct populations of neurons that produce two families of neuropeptides: crustacean hyperglycemic hormone and adipokinetic hormone/red pigment-concentrating hormone. On the basis of electrophysiological evidence, it has been proposed that γ-aminobutyric acid (GABA) regulates both electrical and secretory activity of the XO-SG system. In this work we observed that depolarizing current pulses to neurons located in the external rim of the X-organ induced repetitive firing that suppressed the spontaneous firing of previously active X-organ neurons. Picrotoxin reversibly blocked this inhibitory effect suggesting that the GABA released from the stimulated neuron inhibited neighboring cells. Immunoperoxidase in X-organ serial sections showed co-localization of GABA and glutamic acid decarboxylase (GAD) including the aforementioned neurons. Immunofluorescence in whole mount preparations showed that two subpopulations of crustacean hyperglycemic hormone-containing neurons colocalized with GABA. The expression of GAD mRNA was determined in crayfish tissue and X-organ single cells by RT-PCR. Bioinformatics analysis shows, within the amplified region, 90.4% consensus and 41.9% identity at the amino acid level compared with Drosophila melanogaster and Caenorhabditis elegans. We suggest that crustacean hyperglycemic hormone-GABA-containing neurons can regulate the excitability of other X-organ neurons that produce different neurohormones. PMID:21626307

  18. GABA transporters control GABAergic neurotransmission in the mouse subplate.

    PubMed

    Unichenko, P; Kirischuk, S; Luhmann, H J

    2015-09-24

    The subplate is a transient layer between the cortical plate and intermediate zone in the developing cortex. Thalamo-cortical axons form temporary synapses on subplate neurons (SPns) before invading the cortical plate. Neuronal activity within the subplate is of critical importance for the development of neocortical circuits and architecture. Although both glutamatergic and GABAergic inputs on SPns were reported, short-term plasticity of GABAergic transmission has not been investigated yet. GABAergic postsynaptic currents (GPSCs) were recorded from SPns in coronal neocortical slices prepared from postnatal day 3-4 mice using whole-cell patch-clamp technique. Evoked GPSCs (eGPSCs) elicited by electrical paired-pulse stimulation demonstrated paired-pulse depression at all interstimulus intervals tested. Baclofen, a specific GABAB receptor (GABABR) agonist, reduced eGPSC amplitudes and increased paired-pulse ratio (PPR), suggesting presynaptic location of functional GABABRs. Baclofen-induced effects were alleviated by (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid (CGP55845), a selective GABABR blocker. Moreover, CGP55845 increased eGPSC amplitudes and decreased PPR even under control conditions, indicating that GABABRs are tonically activated by ambient GABA. Because extracellular GABA concentration is mainly regulated by GABA transporters (GATs), we asked whether GATs release GABA. 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid (NNC-711) (10μM), a selective GAT-1 blocker, increased eGPSC decay time, decreased eGPSC amplitudes and PPR. The two last effects but not the first one were blocked by CGP55845, indicating that GAT-1 blockade causes an elevation of extracellular GABA concentration and in turn activation of extrasynaptic GABAARs and presynaptic GABABRs. 1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]-(S)-3-piperidinecarboxylic acid (SNAP-5114), a specific GAT-2/3 blocker, failed

  19. Decreased Phosphorylated Protein Kinase B (Akt) in Individuals with Autism Associated with High Epidermal Growth Factor Receptor (EGFR) and Low Gamma-Aminobutyric Acid (GABA)

    PubMed Central

    Russo, Anthony J

    2015-01-01

    Dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway could contribute to the pathogenesis of autism spectrum disorders. In this study, phosphorylated Akt concentration was measured in 37 autistic children and 12, gender and age similar neurotypical, controls using an enzyme-linked immunosorbent assay. Akt levels were compared to biomarkers known to be associated with epidermal growth factor receptor (EGFR) and c-Met (hepatocyte growth factor (HGF) receptor) pathways and severity levels of 19 autism-related symptoms. We found phosphorylated Akt levels significantly lower in autistic children and low Akt levels correlated with high EGFR and HGF and low gamma-aminobutyric acid, but not other biomarkers. Low Akt levels also correlated significantly with increased severity of receptive language, conversational language, hypotonia, rocking and pacing, and stimming, These results suggest a relationship between decreased phosphorylated Akt and selected symptom severity in autistic children and support the suggestion that the AKT pathways may be associated with the etiology of autism. PMID:26508828

  20. mRNA and Protein Levels for GABA[subscript A][alpha]4, [alpha]5, [beta]1 and GABA[subscript B]R1 Receptors are Altered in Brains from Subjects with Autism

    ERIC Educational Resources Information Center

    Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Rooney, Robert J.; Patel, Diven H.; Thuras, Paul D.

    2010-01-01

    We have shown altered expression of gamma-aminobutyric acid A (GABA[subscript A]) and gamma-aminobutyric acid B (GABA[subscript B]) receptors in the brains of subjects with autism. In the current study, we sought to verify our western blotting data for GABBR1 via qRT-PCR and to expand our previous work to measure mRNA and protein levels of 3…

  1. Inhibition of GABA release from slices prepared from several brain regions of rats at various times following a convulsion.

    PubMed Central

    Green, A. R.; Minchin, M. C.; Vincent, N. D.

    1987-01-01

    1 A method is described for the measurement of the K+-evoked release of endogenous gamma-aminobutyric acid (GABA) from slices of rat cortex, hippocampus and striatum. 2 In tissue prepared 30 min following an electroconvulsive shock, K+-evoked GABA release (above basal release) was inhibited by 45% in cortex, 50% in hippocampus and 75% in striatum. A similar inhibition of release was observed with slices prepared from rats in which a convulsion had been induced by flurothyl. There was no change in spontaneous (basal) release following either procedure. 3 An inhibition of K+-evoked endogenous GABA release was also seen in tissue prepared 4 min postictally but not 2 h after the seizure. 4 No difference was observed in the release of [3H]-GABA from preloaded cortical slices prepared from rats given a single electroconvulsive shock. 5 It is proposed that a convulsion results in an inhibition of GABA release and that this inhibition may in turn inhibit GABA synthesis as described in the preceding paper. 6 It is also proposed that changes in the endogenous releasable pool of GABA may not be detected by preloading slices with [3H]-GABA. PMID:3664084

  2. Cortical GABA Levels in Primary Insomnia

    PubMed Central

    Morgan, Peter T.; Pace-Schott, Edward F.; Mason, Graeme F.; Forselius, Erica; Fasula, Madonna; Valentine, Gerald W.; Sanacora, Gerard

    2012-01-01

    Study Objectives: GABA is increasingly recognized as an important neurotransmitter for the initiation and maintenance of sleep. We sought to measure cortical GABA content through proton magnetic resonance spectroscopy (MRS) in persons with and without primary insomnia, and relate brain GABA levels to polysomnographic sleep measures. Design: Two-group comparison study. Setting: Outpatient study at a university research clinic. Participants: Non-medicated persons with primary insomnia (N = 16) and no sleep complaints (N = 17). Interventions: Participants kept sleep diaries and a regular time-in-bed schedule for 9 days, culminating in 2 consecutive nights of ambulatory polysomnography and a single proton MRS session. The main outcome measure was occipital GABA/creatine ratios; secondary measures included sleep measurements and relationship between polysomnographically measured time awake after sleep onset and occipital GABA content. Measurements and Results: The primary insomnia group was distinguished from persons with no sleep complaints on self-reported and polysomnographically measured sleep. The two groups did not differ in age, sex, body mass index, habitual bed- and wake-times, napping, use of caffeine, or use of cigarettes. Mean occipital GABA level was 12% higher in persons with insomnia than in persons without sleep complaints (P < 0.05). In both groups, GABA levels correlated negatively with polysomnographically measured time awake after sleep onset (P < 0.05). Conclusions: Increased GABA levels in persons with insomnia may reflect an allostatic response to chronic hyperarousal. The preserved, negative relationship between GABA and time awake after sleep onset supports this notion, indicating that the possible allostatic response is adaptive. Citation: Morgan PT; Pace-Schott EF; Mason GF; Forselius E; Fasula M; Valentine GW; Sanacora G. Cortical GABA levels in primary insomnia. SLEEP 2012;35(6):807-814. PMID:22654200

  3. Dopaminergic neurons inhibit striatal output via non-canonical release of GABA

    PubMed Central

    Tritsch, Nicolas X.; Ding, Jun B.; Sabatini, Bernardo L.

    2012-01-01

    The substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) contain the two largest populations of dopamine (DA)-releasing neurons in the mammalian brain. These neurons extend elaborate projections in striatum, a large subcortical structure implicated in motor planning and reward-based learning. Phasic activation of dopaminergic neurons in response to salient or reward-predicting stimuli is thought to modulate striatal output via the release of DA to promote and reinforce motor action1–4. Here we show that activation of DA neurons in striatal slices rapidly inhibits action potential firing in both direct-and indirect-pathway striatal projection neurons (SPNs) through vesicular release of the inhibitory transmitter γ-aminobutyric acid (GABA). GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT. Instead GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for DA. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Thus, these findings expand the repertoire of synaptic mechanisms employed by DA neurons to influence basal ganglia circuits, reveal a novel substrate whose transport is dependent on VMAT2, and demonstrate that GABA can function as a bona fide co-transmitter in monoaminergic neurons. PMID:23034651

  4. Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition.

    PubMed

    Lakhani, Ronak; Vogel, Kara R; Till, Andreas; Liu, Jingjing; Burnett, Sarah F; Gibson, K Michael; Subramani, Suresh

    2014-04-01

    In addition to key roles in embryonic neurogenesis and myelinogenesis, γ-aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter. In yeast, we have identified a new role for GABA that augments activity of the pivotal kinase, Tor1. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase, S6K1, leading to oxidative stress, all of which can be mitigated by the Tor1 inhibitor, rapamycin. To confirm these processes in mammals, we examined the succinic semialdehyde dehydrogenase (SSADH)-deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues. Mutant mice displayed increased mitochondrial numbers in the brain and liver, expected with a defect in mitophagy, and morphologically abnormal mitochondria. Administration of rapamycin to these mice reduced mTOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels. These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA. PMID:24578415

  5. Treatment of GABA from Fermented Rice Germ Ameliorates Caffeine-Induced Sleep Disturbance in Mice

    PubMed Central

    Mabunga, Darine Froy N.; Gonzales, Edson Luck T.; Kim, Hee Jin; Choung, Se Young

    2015-01-01

    γ-Aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is involved in sleep physiology. Caffeine is widely used psychoactive substance known to induce wakefulness and insomnia to its consumers. This study was performed to examine whether GABA extracts from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice, without affecting spontaneous locomotor activity and motor coordination. Indeed, caffeine (10 mg/kg, i.p.) delayed sleep onset and reduced sleep duration of mice. Conversely, rice germ ferment extracts-GABA treatment (10, 30, or 100 mg/kg, p.o.), especially at 100 mg/kg, normalized the sleep disturbance induced by caffeine. In locomotor tests, rice germ ferment extracts-GABA slightly but not significantly reduced the caffeine-induced increase in locomotor activity without affecting motor coordination. Additionally, rice germ ferment extracts-GABA per se did not affect the spontaneous locomotor activity and motor coordination of mice. In conclusion, rice germ ferment extracts-GABA supplementation can counter the sleep disturbance induced by caffeine, without affecting the general locomotor activities of mice. PMID:25995826

  6. Treatment of GABA from Fermented Rice Germ Ameliorates Caffeine-Induced Sleep Disturbance in Mice.

    PubMed

    Mabunga, Darine Froy N; Gonzales, Edson Luck T; Kim, Hee Jin; Choung, Se Young

    2015-05-01

    γ-Aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is involved in sleep physiology. Caffeine is widely used psychoactive substance known to induce wakefulness and insomnia to its consumers. This study was performed to examine whether GABA extracts from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice, without affecting spontaneous locomotor activity and motor coordination. Indeed, caffeine (10 mg/kg, i.p.) delayed sleep onset and reduced sleep duration of mice. Conversely, rice germ ferment extracts-GABA treatment (10, 30, or 100 mg/kg, p.o.), especially at 100 mg/kg, normalized the sleep disturbance induced by caffeine. In locomotor tests, rice germ ferment extracts-GABA slightly but not significantly reduced the caffeine-induced increase in locomotor activity without affecting motor coordination. Additionally, rice germ ferment extracts-GABA per se did not affect the spontaneous locomotor activity and motor coordination of mice. In conclusion, rice germ ferment extracts-GABA supplementation can counter the sleep disturbance induced by caffeine, without affecting the general locomotor activities of mice. PMID:25995826

  7. GABA regulates synaptic integration of newly generated neurons in the adult brain

    NASA Astrophysics Data System (ADS)

    Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

    2006-02-01

    Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

  8. Wavelength-Selective One- and Two-Photon Uncaging of GABA

    PubMed Central

    2013-01-01

    We have synthesized photolabile 7-diethylamino coumarin (DEAC) derivatives of γ-aminobutyric acid (GABA). These caged neurotransmitters efficiently release GABA using linear or nonlinear excitation. We used a new DEAC-based caging chromophore that has a vinyl acrylate substituent at the 3-position that shifts the absorption maximum of DEAC to about 450 nm and thus is named “DEAC450”. DEAC450-caged GABA is photolyzed with a quantum yield of 0.39 and is highly soluble and stable in physiological buffer. We found that DEAC450-caged GABA is relatively inactive toward two-photon excitation at 720 nm, so when paired with a nitroaromatic caged glutamate that is efficiently excited at such wavelengths, we could photorelease glutamate and GABA around single spine heads on neurons in brain slices with excellent wavelength selectivity using two- and one-photon photolysis, respectively. Furthermore, we found that DEAC450-caged GABA could be effectively released using two-photon excitation at 900 nm with spatial resolution of about 3 μm. Taken together, our experiments show that the DEAC450 caging chromophore holds great promise for the development of new caged compounds that will enable wavelength-selective, two-color interrogation of neuronal signaling with excellent subcellular resolution. PMID:24304264

  9. Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition

    PubMed Central

    Lakhani, Ronak; Vogel, Kara R; Till, Andreas; Liu, Jingjing; Burnett, Sarah F; Gibson, K Michael; Subramani, Suresh

    2014-01-01

    In addition to key roles in embryonic neurogenesis and myelinogenesis, γ-aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter. In yeast, we have identified a new role for GABA that augments activity of the pivotal kinase, Tor1. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase, S6K1, leading to oxidative stress, all of which can be mitigated by the Tor1 inhibitor, rapamycin. To confirm these processes in mammals, we examined the succinic semialdehyde dehydrogenase (SSADH)-deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues. Mutant mice displayed increased mitochondrial numbers in the brain and liver, expected with a defect in mitophagy, and morphologically abnormal mitochondria. Administration of rapamycin to these mice reduced mTOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels. These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA. PMID:24578415

  10. ACS chemical neuroscience molecule spotlight on STX209 (arbaclofen).

    PubMed

    Hopkins, Corey R

    2011-08-17

    STX209 (arbaclofen) is a γ-amino butyric acid type B (GABA(B)) receptor agonist from Seaside Therapeutics currently in clinical trials for autism spectrum disorders (ASD). The company has initiated a phase 2b study after positive results from a phase 2a trial, announced September 2010 (http://www.seasidetherapeutics.com/sites/default/files/STX209_ASD_P2b Trial_Initiation%206%2021%202011%20Final.pdf). PMID:22860166

  11. {gamma}-aminobutyric acid{sub A} (GABA{sub A}) receptor regulates ERK1/2 phosphorylation in rat hippocampus in high doses of Methyl Tert-Butyl Ether (MTBE)-induced impairment of spatial memory

    SciTech Connect

    Zheng Gang; Zhang Wenbin; Zhang Yun; Chen Yaoming; Liu Mingchao; Yao Ting; Yang Yanxia; Zhao Fang; Li Jingxia; Huang Chuanshu; Luo Wenjing Chen Jingyuan

    2009-04-15

    Experimental and occupational exposure to Methyl Tert-Butyl Ether (MTBE) has been reported to induce neurotoxicological and neurobehavioral effects, such as headache, nausea, dizziness, and disorientation, etc. However, the molecular mechanisms involved in MTBE-induced neurotoxicity are still not well understood. In the present study, we investigated the effects of MTBE on spatial memory and the expression and function of GABA{sub A} receptor in the hippocampus. Our results demonstrated that intraventricular injection of MTBE impaired the performance of the rats in a Morris water maze task, and significantly increased the expression of GABA{sub A} receptor {alpha}1 subunit in the hippocampus. The phosphorylation of ERK1/2 decreased after the MTBE injection. Furthermore, the decreased ability of learning and the reduction of phosphorylated ERK1/2 level of the MTBE-treated rats was partly reversed by bicuculline injected 30 min before the training. These results suggested that MTBE exposure could result in impaired spatial memory. GABA{sub A} receptor may play an important role in the MTBE-induced impairment of learning and memory by regulating the phosphorylation of ERK in the hippocampus.

  12. Comparison between the modes of action of novel meta-diamide and macrocyclic lactone insecticides on the RDL GABA receptor.

    PubMed

    Nakao, Toshifumi; Banba, Shinichi; Hirase, Kangetsu

    2015-05-01

    Macrocyclic lactones, avermectins, and milbemycins are widely used to control arthropods, nematodes, and endo- and ectoparasites in livestock and pets. Their main targets are glutamate-gated chloride channels. Furthermore, macrocyclic lactones reportedly interact with insect RDL γ-aminobutyric acid (GABA) receptors, but their modes of action on insect RDL GABA receptors remain unknown. In this study, we attempted to better understand the modes of action of macrocyclic lactones on RDL GABA receptors. We observed that ivermectin and milbemectin behaved as allosteric agonists of the Drosophila RDL GABA receptor. G336A, G336S, and G336T mutations had profound effects on the activities of ivermectin and milbemectin, and a G336M mutation abolished the allosteric agonist and antagonist activities of these macrocyclic lactones. These results suggest that G336 in TM3 of the Drosophila RDL GABA receptor is important for the binding of macrocyclic lactones. Recently, it has been suggested that a novel RDL GABA receptor antagonist, 3-benzamido-N-(2-bromo-4-perfluoroisopropyl-6-(trifluoromethyl)phenyl)-2-fluorobenzamide (meta-diamide 7), binds to the transmembrane intersubunit pocket near G336 in the Drosophila RDL GABA receptor. Thus, we compared the effects of mutations around G336 and A302 mutations in TM2 on the activities of macrocyclic lactone and meta-diamide 7. The effects of L281C, V340Q, V340N, A302S, and A302N mutations on the activity of meta-diamide 7 differed from those on ivermectin and milbemectin. Molecular modeling studies showed that macrocyclic lactones docked in the intersubunit pocket near G336 in the Drosophila RDL GABA receptor in the open state. In contrast, meta-diamide 7 docked into the Drosophila RDL GABA receptor in the closed state. This suggests that the modes of action of macrocyclic lactone binding to the wild-type Drosophila RDL GABA receptor differ from those of meta-diamide binding. PMID:25987227

  13. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug.

    PubMed

    Lapin, I

    2001-01-01

    Phenibut (beta-phenyl-gamma-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA-mimetic, primarily at GABA(B) and, to some extent, at GABA(A) receptors. It also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut. This article reviews the structure-activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre- or post-operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post-traumatic stress, stuttering and vestibular disorders. PMID:11830761

  14. The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism

    PubMed Central

    Besse, Arnaud; Wu, Ping; Bruni, Francesco; Donti, Taraka; Graham, Brett H.; Craigen, William J.; McFarland, Robert; Moretti, Paolo; Lalani, Seema; Scott, Kenneth L.; Taylor, Robert W.; Bonnen, Penelope E.

    2015-01-01

    Summary ABAT is a key enzyme responsible for catabolism of principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA). We report an essential role for ABAT in a seemingly unrelated pathway, mitochondrial nucleoside salvage, and demonstrate that mutations in this enzyme cause an autosomal recessive neurometabolic disorder and mtDNA depletion syndrome (MDS). We describe a family with encephalomyopathic MDS caused by a homozygous missense mutation in ABAT that results in elevated GABA in subjects’ brains as well as decreased mtDNA levels in subjects’ fibroblasts. Nucleoside rescue and co-IP experiments pinpoint that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Pharmacological inhibition of ABAT through the irreversible inhibitor Vigabatrin caused depletion of mtDNA in photoreceptor cells that was prevented through addition of dNTPs in cell culture media. This work reveals ABAT as a connection between GABA metabolism and nucleoside metabolism and defines a neurometabolic disorder that includes MDS. PMID:25738457

  15. Phenotyping GABA transaminase deficiency: a case description and literature review.

    PubMed

    Louro, Pedro; Ramos, Lina; Robalo, Conceição; Cancelinha, Cândida; Dinis, Alexandra; Veiga, Ricardo; Pina, Raquel; Rebelo, Olinda; Pop, Ana; Diogo, Luísa; Salomons, Gajja S; Garcia, Paula

    2016-09-01

    Gamma-aminobutyric acid transaminase (GABA-T) deficiency is an autosomal recessive disorder reported in only three unrelated families. It is caused by mutations in the ABAT gene, which encodes 4-aminobutyrate transaminase, an enzyme of GABA catabolism and mitochondrial nucleoside salvage. We report the case of a boy, deceased at 12 months of age, with early-onset epileptic encephalopathy, severe psychomotor retardation, hypotonia, lower-limb hyporeflexia, central hypoventilation, and rapid increase in weight and, to a lesser rate, length and head circumference. He presented signs of premature pubarche, thermal instability, and water-electrolyte imbalance. Serum total testosterone was elevated (43.3 ng/dl; normal range <16), as well as serum growth hormone (7.7 ng/ml; normal range <1). Brain magnetic resonance imaging (MRI) showed decreased myelination and generalized brain atrophy, later confirmed by post-mortem examination. ABAT gene sequencing was performed post-mortem, identifying a homozygous variant c.888G > T (p.Gln296His),not previously described. In vitro analysis concluded that this variant is pathogenic. The clinical features of this patient are similar to those reported so far in GABA-T deficiency. However, distinct mutations may have a different effect on enzymatic activity, which potentially could lead to a variable clinical outcome. Clinical investigation aiming for a diagnosis should not end with the patient's death, as it may allow a more precise genetic counselling for the family. PMID:27376954

  16. Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

    PubMed Central

    Yuan, Hongjie; Low, Chian-Ming; Moody, Olivia A.; Jenkins, Andrew

    2015-01-01

    The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases. PMID:25904555

  17. The impact of GABA in harpin-elicited biotic stress responses in Nicotiana tabaccum.

    PubMed

    Dimlioğlu, Gizem; Daş, Zeycan Akcan; Bor, Melike; Özdemir, Filiz; Türkan, İsmail

    2015-09-01

    Harpin is a bacterial elicitor protein that was first isolated from Erwinia amylovora. Infiltration of this elicitor into the leaves of plants activates systemic acquired resistance against a variety of plant pathogens via the salicyclic acid defense pathway. The non-protein amino acid, neurotransmission inhibitor molecule of mammals-GABA- is found in all organisms and is known to be an important component of stress responses in plants. We hypothesized a possible interaction between harpin-induced defense responses and GABA shunt. Therefore, we conducted experiments on harpin-infiltrated tobacco and analyzed the components of GABA shunt in relation to growth, photosynthesis and H2O2 levels. RGR, RWC and photosynthetic efficiency were all affected in harpin-infiltrated tobacco leaves, but the rate of decline was more remarkable on RGR. H2O2 levels showed significant difference on 7 days after harpin infiltration when the necrotic lesions were also visible. GABA accumulation was increased and glutamate levels were decreased parallel to the differences in GDH and GAD enzyme activities, especially on days 5 and 7 of harpin infiltration. Transcript abundance of GDH and GAD encoding genes were differentially regulated in harpin-infiltrated leaves as compared to that of control and mock groups. In the present study, for the first time we showed a relationship between harpin-elicited responses and GABA in tobacco that was not mediated by H2O2 accumulation. Harpin infiltration significantly induced the first components of the GABA shunt such as GDH, GAD, glutamate and GABA in tobacco. PMID:26432406

  18. GABA and glycine in the developing brain.

    PubMed

    Ito, Susumu

    2016-09-01

    GABA and glycine are major inhibitory neurotransmitters in the CNS and act on receptors coupled to chloride channels. During early developmental periods, both GABA and glycine depolarize membrane potentials due to the relatively high intracellular Cl(-) concentration. Therefore, they can act as excitatory neurotransmitters. GABA and glycine are involved in spontaneous neural network activities in the immature CNS such as giant depolarizing potentials (GDPs) in neonatal hippocampal neurons, which are generated by the synchronous activity of GABAergic interneurons and glutamatergic principal neurons. GDPs and GDP-like activities in the developing brains are thought to be important for the activity-dependent functiogenesis through Ca(2+) influx and/or other intracellular signaling pathways activated by depolarization or stimulation of metabotropic receptors. However, if GABA and glycine do not shift from excitatory to inhibitory neurotransmitters at the birth and in maturation, it may result in neural disorders including autism spectrum disorders. PMID:26951057

  19. Unexpected Photo-instability of 2,6-Sulfonamide-Substituted BODIPYs and Its Application to Caged GABA.

    PubMed

    Takeda, Aoi; Komatsu, Toru; Nomura, Hiroshi; Naka, Masamitsu; Matsuki, Norio; Ikegaya, Yuji; Terai, Takuya; Ueno, Tasuku; Hanaoka, Kenjiro; Nagano, Tetsuo; Urano, Yasuteru

    2016-07-01

    Investigation of the unexpected photo-instability of 2,6-sulfonamide-substituted derivatives of the boron dipyrromethene (BODIPY) fluorophore led to the discovery of a photoreaction accompanied by multiple bond scissions. We characterized the photoproducts and utilized the photoreaction to design a caged γ-aminobutyric acid (GABA) derivative that can release GABA upon irradiation in the visible range (>450 nm). This allowed us to stimulate neural cells in mouse brain slices. PMID:27038199

  20. The glutamine-glutamate/GABA cycle: function, regional differences in glutamate and GABA production and effects of interference with GABA metabolism.

    PubMed

    Walls, Anne B; Waagepetersen, Helle S; Bak, Lasse K; Schousboe, Arne; Sonnewald, Ursula

    2015-02-01

    The operation of a glutamine-glutamate/GABA cycle in the brain consisting of the transfer of glutamine from astrocytes to neurons and neurotransmitter glutamate or GABA from neurons to astrocytes is a well-known concept. In neurons, glutamine is not only used for energy production and protein synthesis, as in other cells, but is also an essential precursor for biosynthesis of amino acid neurotransmitters. An excellent tool for the study of glutamine transfer from astrocytes to neurons is [(14)C]acetate or [(13)C]acetate and the glial specific enzyme inhibitors, i.e. the glutamine synthetase inhibitor methionine sulfoximine and the tricarboxylic acid cycle (aconitase) inhibitors fluoro-acetate and -citrate. Acetate is metabolized exclusively by glial cells, and [(13)C]acetate is thus capable when used in combination with magnetic resonance spectroscopy or mass spectrometry, to provide information about glutamine transfer. The present review will give information about glutamine trafficking and the tools used to map it as exemplified by discussions of published work employing brain cell cultures as well as intact animals. It will be documented that considerably more glutamine is transferred from astrocytes to glutamatergic than to GABAergic neurons. However, glutamine does have an important role in GABAergic neurons despite their capability of re-utilizing their neurotransmitter by re-uptake. PMID:25380696

  1. Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels

    PubMed Central

    Ihara, Makoto; Ling, Yun; Yang, Xinling; Kai, Kenji; Hayashi, Hideo; Matsuda, Kazuhiko

    2015-01-01

    Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori) larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA)-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR) RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs. PMID:25902139

  2. Comparative mapping of GABA-immunoreactive neurons in the central nervous systems of nudibranch molluscs.

    PubMed

    Gunaratne, Charuni A; Sakurai, Akira; Katz, Paul S

    2014-03-01

    The relative simplicity of certain invertebrate nervous systems, such as those of gastropod molluscs, allows behaviors to be dissected at the level of small neural circuits composed of individually identifiable neurons. Elucidating the neurotransmitter phenotype of neurons in neural circuits is important for understanding how those neural circuits function. In this study, we examined the distribution of γ-aminobutyric-acid;-immunoreactive (GABA-ir) neurons in four species of sea slugs (Mollusca, Gastropoda, Opisthobranchia, Nudibranchia): Tritonia diomedea, Melibe leonina, Dendronotus iris, and Hermissenda crassicornis. We found consistent patterns of GABA immunoreactivity in the pedal and cerebral-pleural ganglia across species. In particular, there were bilateral clusters in the lateral and medial regions of the dorsal surface of the cerebral ganglia as well as a cluster on the ventral surface of the pedal ganglia. There were also individual GABA-ir neurons that were recognizable across species. The invariant presence of these individual neurons and clusters suggests that they are homologous, although there were interspecies differences in the numbers of neurons in the clusters. The GABAergic system was largely restricted to the central nervous system, with the majority of axons confined to ganglionic connectives and commissures, suggesting a central, integrative role for GABA. GABA was a candidate inhibitory neurotransmitter for neurons in central pattern generator (CPG) circuits underlying swimming behaviors in these species, however none of the known swim CPG neurons were GABA-ir. Although the functions of these GABA-ir neurons are not known, it is clear that their presence has been strongly conserved across nudibranchs. PMID:24638845

  3. Brain regional distribution of GABAA receptors exhibiting atypical GABA agonism: roles of receptor subunits

    PubMed Central

    Halonen, Lauri M.; Sinkkonen, Saku T.; Chandra, Dev; Homanics, Gregg E.; Korpi, Esa R.

    2009-01-01

    The major inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), has only partial efficacy at certain subtypes of GABAA receptors. To characterize these minor receptor populations in rat and mouse brains, we used autoradiographic imaging of t-butylbicyclophosphoro[35S]thionate ([35S]TBPS) binding to GABAA receptors in brain sections and compared the displacing capacities of 10 mM GABA and 1 mM 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a competitive GABA-site agonist. Brains from GABAA receptor α1, α4, δ, and α4 + δ subunit knockout (KO) mouse lines were used to understand the contribution of these particular receptor subunits to “GABA-insensitive” (GIS) [35S]TBPS binding. THIP displaced more [35S]TBPS binding than GABA in several brain regions, indicating that THIP also inhibited GIS-binding. In these regions, GABA prevented the effect of THIP on GIS-binding. GIS-binding was increased in the cerebellar granule cell layer of δ KO and α4 + δ KO mice, being only slightly diminished in that of α1 KO mice. In the thalamus and some other forebrain regions of wild-type mice, a significant amount of GIS-binding was detected. This GIS-binding was higher in α4 KO mice. However, it was fully abolished in α1 KO mice, indicating that the α1 subunit was obligatory for the GIS-binding in the forebrain. Our results suggest that native GABAA receptors in brain sections showing reduced displacing capacity of [35S]TBPS binding by GABA (partial agonism) minimally require the assembly of α1 and β subunits in the forebrain and of α6 and β subunits in the cerebellar granule cell layer. These receptors may function as extrasynaptic GABAA receptors. PMID:19397945

  4. Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels.

    PubMed

    Xu, Yan; Furutani, Shogo; Ihara, Makoto; Ling, Yun; Yang, Xinling; Kai, Kenji; Hayashi, Hideo; Matsuda, Kazuhiko

    2015-01-01

    Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori) larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA)-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR) RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to 10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs. PMID:25902139

  5. Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity

    PubMed Central

    Savtchenko, Leonid; Megalogeni, Maria; Rusakov, Dmitri A.; Walker, Matthew C.; Pavlov, Ivan

    2015-01-01

    GABA transporters control extracellular GABA, which regulates the key aspects of neuronal and network behaviour. A prevailing view is that modest neuronal depolarization results in GABA transporter type-1 (GAT-1) reversal causing non-vesicular GABA release into the extracellular space during intense network activity. This has important implications for GABA uptake-targeting therapies. Here we combined a realistic kinetic model of GAT-1 with experimental measurements of tonic GABAA receptor currents in ex vivo hippocampal slices to examine GAT-1 operation under varying network conditions. Our simulations predict that synaptic GABA release during network activity robustly prevents GAT-1 reversal. We test this in the 0 Mg2+ model of epileptiform discharges using slices from healthy and chronically epileptic rats and find that epileptiform activity is associated with increased synaptic GABA release and is not accompanied by GAT-1 reversal. We conclude that sustained efflux of GABA through GAT-1 is unlikely to occur during physiological or pathological network activity. PMID:25798861

  6. Effect of pressure on (/sup 3/H)GABA release by synaptosomes isolated from cerebral cortex

    SciTech Connect

    Gilman, S.C.; Colton, J.S.; Hallenbeck, J.M.

    1986-12-01

    High hydrostatic pressure has been shown to produce neurological changes in humans which manifest, in part, as tremor, myoclonic jerks, electroencephalographic changes, and convulsions. This clinical pattern has been termed high-pressure nervous syndrome (HPNS). These symptoms may represent an alteration in synaptic transmission in the central nervous system with the inhibitory neural pathways being affected in particular. Since gamma-aminobutyric acid (GABA) transmission has been implicated in other seizure disorders, it was of interest to study GABAergic function at high pressure. Isolated synaptosomes were used to follow GABA release at 67.7 ATA of pressure. The major observation was a 33% depression in total (/sup 3/H)GABA efflux from depolarized cerebrocortical synaptosomes at 67.7 ATA. The Ca2+-dependent component of release was found to be completely blocked during the 1st min of (/sup 3/H)GABA efflux with a slow rise over the subsequent 3 min. These findings lead us to conclude that high pressure interferes with the intraterminal cascade for Ca2+-dependent release of GABA.

  7. GABA/benzodiazepine receptor complex in long-sleep and short-sleep mice

    SciTech Connect

    Marley, R.J.

    1987-01-01

    LS mice are more sensitive to benzodiazepine-induced anesthesia; however, the two lines do not differ in their hypothermic response to flurazepam. SS mice are more resistant to 3-mercaptopropionic acid-induced seizures and more sensitive to the anticonvulsant effects of benzodiazepines. The various correlates of GABA and benzodiazepine actions probably are the results of different mechanisms of action and/or differential regional control. Bicuculline competition for /sup 3/H-GABA binding sites is greater in SS cerebellar tissue and /sup 3/H-flunitrazepam binding is greater in the mid-brain region of LS mice. GABA enhancement of /sup 3/H-flunitrazepma binding is greater in SS mice. Ethanol also enhances /sup 3/H-flunitrazepam binding and increases the levels of /sup 3/H-flunitrazepam binding above those observed for GABA. Using correlational techniques on data from LS and SS mice and several inbred mouse strains, it was demonstrated that a positive relationship exists between the degree of receptor coupling within the GABA receptor complex and the degree of resistance to seizures.

  8. Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease.

    PubMed

    Salminen, Antero; Jouhten, Paula; Sarajärvi, Timo; Haapasalo, Annakaisa; Hiltunen, Mikko

    2016-01-01

    We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis. PMID:26617286

  9. The role of the GABA system in amphetamine-type stimulant use disorders

    PubMed Central

    Jiao, Dongliang; liu, Yao; Li, Xiaohong; liu, Jinggen; Zhao, Min

    2015-01-01

    Abuse of amphetamine-type stimulants (ATS) has become a global public health problem. ATS causes severe neurotoxicity, which could lead to addiction and could induce psychotic disorders or cognitive dysfunctions. However, until now, there has been a lack of effective medicines for treating ATS-related problems. Findings from recent studies indicate that in addition to the traditional dopamine-ergic system, the GABA (gamma-aminobutyric acid)-ergic system plays an important role in ATS abuse. However, the exact mechanisms of the GABA-ergic system in amphetamine-type stimulant use disorders are not fully understood. This review discusses the role of the GABA-ergic system in ATS use disorders, including ATS induced psychotic disorders and cognitive dysfunctions. We conclude that the GABA-ergic system are importantly involved in the development of ATS use disorders through multiple pathways, and that therapies or medicines that target specific members of the GABA-ergic system may be novel effective interventions for the treatment of ATS use disorders. PMID:25999814

  10. Contribution of polyamines metabolism and GABA shunt to chilling tolerance induced by nitric oxide in cold-stored banana fruit.

    PubMed

    Wang, Yansheng; Luo, Zisheng; Mao, Linchun; Ying, Tiejin

    2016-04-15

    Effect of exogenous nitric oxide (NO) on polyamines (PAs) catabolism, γ-aminobutyric acid (GABA) shunt, proline accumulation and chilling injury of banana fruit under cold storage was investigated. Banana fruit treated with NO sustained lower chilling injury index than the control. Notably elevated nitric oxide synthetase activity and endogenous NO level were observed in NO-treated banana fruit. PAs contents in treated fruit were significantly higher than control fruit, due to the elevated activities of arginine decarboxylase and ornithine decarboxylase. NO treatment increased the activities of diamine oxidase, polyamine oxidase and glutamate decarboxylase, while reduced GABA transaminase activity to lower levels compared with control fruit, which resulted the accumulation of GABA. Besides, NO treatment upregulated proline content and significantly enhanced the ornithine aminotransferase activity. These results indicated that the chilling tolerance induced by NO treatment might be ascribed to the enhanced catabolism of PAs, GABA and proline. PMID:26616957