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Gamma-amino-butyric acid derivatives as GABA.sub.B receptor ligands  

US Patent & Trademark Office Database

Gamma-amino-butyric acid derivatives that are GABA.sub.B receptor ligands, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives and pharmaceutical compositions thereof for treating diseases are disclosed.

Xu; Feng (Palo Alto, CA); Gallop; Mark A. (Santa Clara, CA); Peng; Ge (Mountain View, CA); Phan; Thu (Fremont, CA); Dilip; Usha (Sunnyvale, CA); Wustrow; David J. (Saratoga, CA)




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...


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


?-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 17?-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 17?-estradiol production or on mRNA abundance for genes involved in ovarian steroidogenesis (e.g., 11?hsd, 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 teleost fish and addresses the broader topic regarding the peripheral roles of neurotransmitters. PMID:23672824

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



Production of ?-Amino Butyric Acid in Tea Leaves wit Treatment of Lactic Acid Bacteria  

NASA Astrophysics Data System (ADS)

Lactic acid bacteria was searched for producing termented tea that contained a lot of ?-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.

Watanabe, Yuko; Hayakawa, Kiyoshi; Ueno, Hiroshi


Dorso-lateral prefrontal ?-amino butyric acid in men predicts individual differences in rash impulsivity  

PubMed Central

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 ?-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.

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



Functional Expression of ?-Amino Butyric Acid Transporter 2 in Human and Guinea Pig Airway Epithelium and Smooth Muscle  

PubMed Central

??Amino butyric acid (GABA) is a primary inhibitory neurotransmitter in the central nervous system, and is classically released by fusion of synaptic vesicles with the plasma membrane or by egress via GABA transporters (GATs). Recently, a GABAergic system comprised of GABAA and GABAB receptors has been identified on airway epithelial and smooth muscle cells that regulate mucus secretion and contractile tone of airway smooth muscle (ASM). In addition, the enzyme that synthesizes GABA, glutamic acid decarboxylase, has been identified in airway epithelial cells; however, the mechanism(s) by which this synthesized GABA is released from epithelial intracellular stores is unknown. We questioned whether any of the four known isoforms of GATs are functionally expressed in ASM or epithelial cells. We detected mRNA and protein expression of GAT2 and -4, and isoforms of glutamic acid decarboxylase in native and cultured human ASM and epithelial cells. In contrast, mRNA encoding vesicular GAT (VGAT), the neuronal GABA transporter, was not detected. Functional inhibition of 3H-GABA uptake was demonstrated using GAT2 and GAT4/betaine–GABA transporter 1 (BGT1) inhibitors in both human ASM and epithelial cells. These results demonstrate that two isoforms of GATs, but not VGAT, are expressed in both airway epithelial and smooth muscle cells. They also provide a mechanism by which locally synthesized GABA can be released from these cells into the airway to activate GABAA channels and GABAB receptors, with subsequent autocrine and/or paracrine signaling effects on airway epithelium and ASM.

Zaidi, Sarah; Gallos, George; Yim, Peter D.; Xu, Dingbang; Sonett, Joshua R.; Panettieri, Reynold A.; Gerthoffer, William; Emala, Charles W.



Upregulation of Na,Cl(-)-Coupled Betaine/ ?-Amino-Butyric Acid Transporter BGT1 by Tau Tubulin Kinase 2.  


Background/Aims: The serine/threonine kinase Tau-tubulin-kinase 2 (TTBK2) is expressed in various tissues including kidney, liver and brain. Loss of function mutations of TTBK2 lead to autosomal dominant spinocerebellar ataxia type 11 (SCA11). Cell survival is fostered by cellular accumulation of organic osmolytes. Carriers accomplishing cellular accumulation of organic osmolytes include the Na(+), Cl(-)-coupled betaine/?-amino-butyric acid transporter BGT1. The present study explored whether TTBK2 participates in the regulation of BGT1 activity. Methods: Electrogenic transport of GABA was determined in Xenopus oocytes expressing BGT1 with or without wild-type TTBK2, truncated TTBK2[1-450] or kinase inactive mutants TTBK2- KD and TTBK2[1-450]-KD. Results: Coexpression of wild-type TTBK2, but not of TTBK2[1-450], TTBK2-KD or TTBK2[1-450]-KD, increased electrogenic GABA transport. Wildtype TTBK2 increased the maximal transport rate without significantly modifying affinity of the carrier. Coexpression of wild-type TTBK2 significantly delayed the decline of transport following inhibition of carrier insertion with brefeldin A, indicating that wild-type TTBK2 increased carrier stability in the cell membrane. Conclusion: Tau-tubulin-kinase 2 TTBK2 is a powerful stimulator of the osmolyte and GABA transporter BGT1. PMID:23942339

Almilaji, Ahmad; Munoz, Carlos; Hosseinzadeh, Zohreh; Lang, Florian



Elicitation of resistance and defense related proteins by ?-amino butyric acid in sunflower against downy mildew pathogen Plasmopara halstedii  

Microsoft Academic Search

Induction of resistance to downy mildew caused by Plasmopara halstedii in sunflower was studied after treatment with ?-amino butyric acid (BABA). Treatment of sunflower seeds with 50 mM BABA resulted in decreased disease severity and offered 47 and 50% protection under greenhouse and field conditions, respectively. The induction of resistance to P. halstedii by BABA was accompanied by the accumulation of

P. Nandeeshkumar; B. R. Sarosh; K. Ramachandra Kini; H. S. Prakash; H. Shekar Shetty



Isolation of gamma-amino butyric acid from pig hypothalami and demonstration of its prolactin release-inhibiting (PIF) activity in vivo and in vitro.  


A non-retarded fraction with prolactin-release inhibiting factor (PIF) activity obtained by chromatography of a concentrate of porcine hypothalami on carboxymethyl-cellulose was chromatographically distinct from catecholamines. This fraction was purified further by six steps involving chromatography on Sephadex G-25, countercurrent distribution, free-flow electrophoresis, and chromatography on triethylaminoethyl cellulose. The PIF-active substance was isolated and identified as gamma-amino-butyric acid (GABA) by: 1) amino acid analyses using sodium as well as lithium-based buffers for resolution of biological fluids, 2) thin-layer chromatography of underivatized material as well as phenylthiocarbamyl derivatives, and 3) mass spectroscopy. Natural and synthetic GABA inhibited prolactin, but not LH release in vitro from isolated rat pituitary halves at doses as low as 0.1 microgram/ml. The inhibition was proportional to the dose; natural and synthetic GABA possessed identical PIF activity. Synthetic GABA also decreased prolactin release in monolayer cultures of rat pituitary cells and inhibited TRH-stimulated prolactin release. The inhibition of prolactin release in vitro by GABA could not be blocked by perphenazine, which inhibits PIF activity of catecholamines. GABA also suppressed prolactin release in vivo, although large doses were needed. Either rapid iv injection or infusion of GABA in doses of 1 to 100 mg in rats significantly decreased serum prolactin levels, which were previously elevated by pretreatment with monoiodotyrosine perphenazine, chlorpromazine, haloperidol, or sulpiride. beta-hydroxy GABA significantly depressed prolactin release, but beta-(p-chlorophenyl)-GABA (Lioresal, CIBA) and 4 other analogs of GABA were not effective in vivo and/or in vitro. The results indicate that GABA can inhibit prolactin release by a direct action on the pituitary gland, but whether this effect is physiologically meaningful still remains to be determined. PMID:401021

Schally, A V; Redding, T W; Arimura, A; Dupont, A; Linthicum, G L



Ondansetron reverses anti-hypersensitivity from clonidine in rats following peripheral nerve injury: Role of ?-amino butyric acid in ?2-adrenoceptor and 5-HT3 serotonin receptor analgesia  

PubMed Central

Introduction Monoaminergic pathways, impinging an ?2-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 ?-amino butyric acid (GABA) and acetylcholine release, or synaptosome preparation for GABA release. Results Intrathecal administration of the ?2-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 ?2-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 ?2-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 ?2-adrenergic and 5-HT3 receptor agonists in the neuropathic pain state, that cholinergic neuroplasticity after nerve injury is critical for ?2-adrenoceptor-mediated GABA release, and that blockade of spinal 5-HT3 receptors reduces ?2-adrenoceptor-mediated anti-hypersensitivity via reducing total GABA release.

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



Relieving occupational fatigue by consumption of a beverage containing ?-amino butyric acid.  


To elucidate the effect of ?-aminobutyric acid (GABA) on both psychological and physical fatigue and on the performance advances for task solving, we assigned an arithmetic task for the Uchida-Kraepelin Psychodiagnostic Test (UKT) to 30 healthy Japanese subjects, 9 of whom were diagnosed as having chronic fatigue. The subjects were administered 250 mL of a test beverage containing GABA at the dose of 0, 25, and 50 mg before assigning task for the UKT. Psychological fatigue assessed by the Visual Analogue Scale (VAS) was significantly lower in the group administrated the beverage containing 50 mg GABA than in the control group (p<0.05). The results of the Profile of Mood States (POMS) also indicated that psychological fatigue was significantly reduced in the 50-mg-GABA group. The salivary secretion levels of chromogranin A and cortisol-markers of physical fatigue-in both 25-mg and 50-mg-GABA groups were significantly lower than those in the control group. The 50-mg-GABA group also showed higher score on UKT by solving the arithmetic task more accurately than the control group (p<0.01). The results suggest that intake of GABA-containing beverages, especially those containing 50 mg of GABA, may help reduce both psychological and physical fatigue and improve task-solving ability. PMID:21512285

Kanehira, Tsutomu; Nakamura, Yoshiko; Nakamura, Kenji; Horie, Kenji; Horie, Noriko; Furugori, Kaori; Sauchi, Yusuke; Yokogoshi, Hidehiko



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


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

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



Comparative transcriptome analysis of Agrobacterium tumefaciens in response to plant signal salicylic acid, indole-3-acetic acid and gamma-amino butyric acid reveals signalling cross-talk and Agrobacterium--plant co-evolution.  


Agrobacterium has evolved sophisticated strategies to perceive and transduce plant-derived cues. Recent studies have found that numerous plant signals, including salicylic acid (SA), indole-3-acetic acid (IAA) and gamma-amino butyric acid (GABA), profoundly affect Agrobacterium-plant interactions. Here we determine and compare the transcriptome profiles of Agrobacterium in response to these three plant signals. Collectively, the transcription of 103, 115 and 95 genes was significantly altered by SA, IAA and GABA respectively. Both distinct cellular responses and overlapping signalling pathways were elicited by these three plant signals. Interestingly, these three plant compounds function additively to shut off the Agrobacterium virulence programme and activate the quorum-quenching machinery. Moreover, the repression of the virulence programme by SA and IAA and the inactivation of quorum-sensing signals by SA and GABA are regulated through independent pathways. Our data indicate that these plant signals, while cross-talk in plant signalling networks, also act as cross-kingdom signals and play redundant roles in tailoring Agrobacterium regulatory pathways, resulting in intensive signalling cross-talk in Agrobacterium. Our results support the notion that Agrobacterium has evolved the ability to hijack plant signals for its own benefit. The complex signalling interplay between Agrobacterium and its plant hosts reflects an exquisite co-evolutionary balance. PMID:18671824

Yuan, Ze-Chun; Haudecoeur, Elise; Faure, Denis; Kerr, Kathleen F; Nester, Eugene W



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


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

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



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

PubMed Central

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.

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



?-Amino butyric acid-induced resistance in pearl millet to downy mildew is associated with accumulation of defence-related proteins  

Microsoft Academic Search

Earlier studies had indicated that ?-amino butyric acid (BABA) treatment of pearl millet seeds influenced seedling vigor and\\u000a protected seedlings from downy mildew disease caused by the oomycetous biotrophic fungus Sclerospora graminicola. Application of 50mMBABAreduced disease severity and offered protection against S. graminicola of ?74%. The protection induced was durable and operative during the vegetative and reproductive growth periods of

S. Shailasree; K. K. Ramachandra; S. H. Shetty



Identification of GABA (Gamma-Amino-Butyric Acid) Receptor Binding Sites in Insect Ganglia.  

National Technical Information Service (NTIS)

The binding of 3Hmuscimol to membrane fractions from central nervous tissue from fly (Musca domestica) and locust (Schistocerca gregaria) was measured. Specific saturable binding was observed with K sub ds of 10 nM (locust) and 40 nM (fly) and Bmax values...

G. G. Lunt T. N. Robinson T. Miller W. P. Knowles R. W. Olsen



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...


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

PubMed Central

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-treated groups. Conclusion GABA and ORZ from GBR stimulates osteoblastogenesis by upregulation of bone formation genes, possibly via the activation of GABAB receptors and by inhibiting the activity of inflammatory cytokines and reactive oxygen species. Therefore, it could be used effectively in the management of osteoporosis.

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



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

Microsoft Academic Search

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

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



Role of Bicarbonate in the Actions of gamma-aminobutyric acid (Gaba) on Membrane Conductances, Currents, and pH Regulation in Excitable Cells.  

National Technical Information Service (NTIS)

Ion selective microelectrodes and a two or three microelectrode voltage or current clamp were used to examine the effects of inhibitory neurotransmitter Gamma Amino Butyric Acid (GABA) on intracellular pH (pH(i)) extracellular surface pH (pH(s)) intercell...

J. Voipio



Evaluation of the mechanisms by which gamma-amino-butyric acid in association with phosphatidylserine exerts an antiepileptic effect in the rat.  


The i.p. injection in rats of GABA (740 mg/Kg) after sonication with an equal amount of phosphatidylserine (PS) has an antiepileptic effect. The injection of plain GABA has no such an effect. Blood, brain and synaptosomal accumulation of exogenous labeled GABA under the two circumstances are evaluated. In the case of GABA/PS injection there is a higher passage of the exogenous labeled neurotransmitter into the blood and brain nerve endings (synaptosomes). A higher synaptosomal accumulation of the exogenous labeled neurotransmitter is found even when GABA and PS are injected separately. Since these accumulation increases occur at a time when there is the antiepileptic effect, they seem relevant to it. Our interpretation of the chain of the events resulting in the antiepileptic action is that the phospholipid facilitates from the beginning the first passage of the exogenous neurotransmitter form the peritoneum to the blood. Then a higher passage to the brain tissue and eventually to the GABA-ergic nerve endings ensues. The brisker accumulation of the exogenous neurotransmitter in the nerve endings could be at the basis of a more efficient GABA-ergic inhibitory control in the brain. PMID:1461369

Benassi, E; Besio, G; Cupello, A; Mainardi, P; Patrone, A; Rapallino, M V; Vignolo, L; Loeb, C W



Pollen Tube Growth and Guidance Is Regulated by POP2, an Arabidopsis Gene that Controls GABA Levels  

Microsoft Academic Search

During angiosperm reproduction, pollen grains form a tube that navigates through female tissues to the micropyle, delivering sperm to the egg; the signals that mediate this process are poorly understood. Here, we describe a role for ?-amino butyric acid (GABA) in pollen tube growth and guidance. In vitro, GABA stimulates pollen tube growth, although vast excesses are inhibitory. The Arabidopsis

Ravishankar Palanivelu; Laura Brass; Anna F. Edlund; Daphne Preuss



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


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) (?-aminobutyric acid) ?5 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 "?5 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 (?-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 ?5 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) ?5 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

Gabriella, Guerrini; Giovanna, Ciciani



Quantitation of Edited GABA Signals in Magnetic Resonance Spectroscopy  

Microsoft Academic Search

Amino butyric acid (GABA) is an inhibitory neurotransmitter that plays an important role in several brain disorders. Reliable detection of GABA in vivo, us- ing 1H Magnetic Resonance Spectroscopy is difficult and faces various challenges. Spectral-Editing sequences based on multiple quantum filtering techniques enable remov- ing overlapping signals. However, advanced signal pro- cessing accommodating sequence-dependence of the edited signals are

B. Tchong Len; H. Ratiney; C. Cudalbu; B. Fenet; A. R. Allouche; M. Aubert-Frecon; D. van Ormondt; D. Graveron-Demilly


GABA concentration in schizophrenia patients and the effects of antipsychotic medication: A proton magnetic resonance spectroscopy study  

Microsoft Academic Search

Gamma-amino butyric acid (GABA) is thought to play a role in the pathophysiology of schizophrenia. High magnetic field proton magnetic resonance spectroscopy (1H-MRS) provides a reliable measurement of GABA in specific regions of the brain. This study measured GABA concentration in the anterior cingulate cortex (ACC) and in the left basal ganglia (ltBG) in 38 patients with chronic schizophrenia and

Shin'Ya Tayoshi; Masahito Nakataki; Satsuki Sumitani; Kyoko Taniguchi; Sumiko Shibuya-Tayoshi; Shusuke Numata; Jun-ichi Iga; Shu-ichi Ueno; Masafumi Harada; Tetsuro Ohmori



Increases in GABA concentrations during cerebral ischaemia: a microdialysis study of extracellular amino acids  

PubMed Central

Objectives: Increases in the extracellular concentration of the excitatory amino acids glutamate and aspartate during cerebral ischaemia in patients are well recognised. Less emphasis has been placed on the concentrations of the inhibitory amino acid neurotransmitters, notably ?-amino-butyric acid (GABA), despite evidence from animal studies that GABA may act as a neuroprotectant in models of ischaemia. The objective of this study was to investigate the concentrations of various excitatory, inhibitory and non-transmitter amino acids under basal conditions and during periods of cerebral ischaemia in patients with head injury or a subarachnoid haemorrhage. Methods: Cerebral microdialysis was established in 12 patients with head injury (n=7) or subarachnoid haemorrhage (n=5). Analysis was performed using high performance liquid chromatography for a total of 19 (excitatory, inhibitory and non-transmitter) amino acids. Patients were monitored in neurointensive care or during aneurysm clipping. Results: During stable periods of monitoring the concentrations of amino acids were relatively constant enabling basal values to be established. In six patients, cerebral ischaemia was associated with increases (up to 1350 fold) in the concentration of GABA, in addition to the glutamate and aspartate. Parallel increases in the concentration of glutamate and GABA were found (r=0.71, p<0.005). Conclusions: The results suggest that, in the human brain, acute cerebral ischaemia is not accompanied by an imbalance between excitatory and inhibitory amino acids, but by an increase in all neurotransmitter amino acids. These findings concur with the animal models of ischaemia and raise the possibility of an endogenous GABA mediated neuroprotective mechanism in humans.

Hutchinson, P; O'Connell, M; Al-Rawi, P; Kett-White, C; Gupta, A; Maskell, L; Pickard, J; Kirkpatrick, P



Glutamic Acid Decarboxylase (GAD) as a Biomarker of GABAergic Activity in Autism: Impact on Cerebellar Circuitry and Function  

Microsoft Academic Search

\\u000a Basic circuits in the brain involve excitatory and inhibitory mechanisms. Inhibition in the brain is primarily sustained by\\u000a the inhibitory neurotransmitter, gamma-amino-butyric acid (GABA). Neurons that use GABA as their neurotransmitter selectively\\u000a express the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). This review focuses on recent studies showing abnormalities\\u000a in the expression of two GAD isoforms, GAD65 and GAD67, by cerebellar

Gene J. Blatt; Jean-Jacques Soghomonian; Jane Yip


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

PubMed Central

Aside from traditional neurotransmission and regulation of secretion, ?-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.

Young, Stephanie Z.; Bordey, Angelique



Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments  

Microsoft Academic Search

Glutamate and ?-amino butyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate glutamate receptor function. Drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects. Recent studies employing magnetic resonance spectroscopy also suggest that

J H Krystal; G Sanacora; H Blumberg; A Anand; D S Charney; G Marek; C N Epperson; A Goddard; G F Mason



The evaluation of effect of alpha-lipoic acid and vitamin E on the lipid peroxidation, gamma-amino butyric acid and serotonin level in the brain of mice ( Mus musculus) acutely intoxicated with lindane  

Microsoft Academic Search

The objective of the present study was to evaluate the neurotoxic effects of lindane, in mice and the protective potential of two antioxidants alpha-lipoic acid (ALA) and vitamin E, against the observed lindane induced toxicity. 7–8 weeks old healthy Swiss mice were administered acute doses of lindane (40 mg\\/kg b.w.) or antioxidants or both subcutaneously and analyzed 18 h later. ALA and vitamin

Renu Bist; Devendra Kumar Bhatt



Production of gaba (? - Aminobutyric acid) by microorganisms: a review  

PubMed Central

GABA (?-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.

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



5HT1 and 5HT2 receptor agonists blunt (^)-a-amino-3- hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-stimulated GH secretion in prepubertal male rats  

Microsoft Academic Search

Objective: Excitatory amino acids, g-amino butyric acid (GABA), serotonin and catecholamines are involved in the control of GH secretion. The actions of these neurotransmitters are interconnected, and recently we showed that the stimulatory effect of GABA was blocked by MK-801, an antagonist of N-methyl-D-aspartate receptors. The present experiments were carried out to analyze the interrelationships between (^)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors

Leonor Pinilla; Lucas C Gonzalez; Manuel Tena-Sempere; Enrique Aguilar


GABA release by hippocampal astrocytes  

PubMed Central

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 (?-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.

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



GABA(A) receptor modulators from the Chinese herbal drug Junci Medulla--the pith of Juncus effusus.  


The gamma-amino butyric acid (GABA) type A (GABA(A)) receptor represents a crucial target for clinical agents in the treatment of anxiety and insomnia. Using the two-microelectrode voltage clamp technique on recombinant ?????(2S) GABA (A) receptors, effusol (1) and dehydroeffusol (2) were isolated in a bioactivity-guided approach from the pith of Juncus effusus L. Both compounds concentration-dependently enhanced GABA induced chloride currents (I(GABA)) by a maximum 188 ± 20 (1) and 239 ± 18 % (2), independent of the benzodiazepine (BZ) binding site. This activity on the GABA (A) receptor may explain the traditional use of J. effusus as a sedative and anxiolytic agent in Chinese medicine. PMID:22271080

Singhuber, Judith; Baburin, Igor; Khom, Sophia; Zehl, Martin; Urban, Ernst; Hering, Steffen; Kopp, Brigitte



Effects of glutamate decarboxylase and gamma-aminobutyric acid (GABA) transporter on the bioconversion of GABA in engineered Escherichia coli.  


Gamma-aminobutyric acid (GABA) is a non-essential amino acid and a precursor of pyrrolidone, a monomer of nylon 4. GABA can be biosynthesized through the decarboxylation of L: -glutamate by glutamate decarboxylase. In this study, the effects of glutamate decarboxylase (gadA, gadB), glutamate/GABA antiporter (gadC) and GABA aminotransferase (gabT) on GABA production were investigated in Escherichia coli. Glutamate decarboxylase was overexpressed alone or with the glutamate/GABA antiporter to enhance GABA synthesis. GABA aminotransferase, which redirects GABA into the TCA cycle, was knock-out mutated. When gadB and gadC were co-overexpressed in the gabT mutant strain, a final GABA concentration of 5.46 g/l was obtained from 10 g/l of monosodium glutamate (MSG), which corresponded to a GABA yield of 89.5%. PMID:21971608

Le Vo, Tam Dinh; Kim, Tae Wan; Hong, Soon Ho



GABA-related drugs modulate the behavioral effects of lorazepam  

Microsoft Academic Search

The behavioral effects of the GABA-related drugs SL 75102 (4-{[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)-methylene]amino}butyric acid) and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyrindin-3-ol) were studied alone and in combination with lorazepam. Two groups of squirrel monkeys responded under a fixed-interval schedule of food presentation. In one group, responding was suppressed by superimposing a fixed-ratio schedule of response-produced electric shock; responding was not suppressed in the second group. Dose-response curves

Joseph G. Wettstein; Roger D. Spealman



Suppression of ?-aminobutyric acid (GABA) transaminases induces prominent GABA accumulation, dwarfism and infertility in the tomato (Solanum lycopersicum L.).  


Tomatoes accumulate ?-aminobutyric acid (GABA) at high levels in the immature fruits. GABA is rapidly converted to succinate during fruit ripening through the activities of GABA transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSADH). Although three genes encoding GABA-T and both pyruvate- and ?-ketoglutarate-dependent GABA-T activities have been detected in tomato fruits, the mechanism underlying the GABA-T-mediated conversion of GABA has not been fully understood. In this work, we conducted loss-of-function analyses utilizing RNA interference (RNAi) transgenic plants with suppressed pyruvate- and glyoxylate-dependent GABA-T gene expression to clarify which GABA-T isoforms are essential for its function. The RNAi plants with suppressed SlGABA-T gene expression, particularly SlGABA-T1, showed severe dwarfism and infertility. SlGABA-T1 expression was inversely associated with GABA levels in the fruit at the red ripe stage. The GABA contents in 35S::SlGABA-T1(RNAi) lines were 1.3-2.0 times and 6.8-9.2 times higher in mature green and red ripe fruits, respectively, than the contents in wild-type fruits. In addition, SlGABA-T1 expression was strongly suppressed in the GABA-accumulating lines. These results indicate that pyruvate- and glyoxylate-dependent GABA-T is the essential isoform for GABA metabolism in tomato plants and that GABA-T1 primarily contributes to GABA reduction in the ripening fruits. PMID:23435575

Koike, Satoshi; Matsukura, Chiaki; Takayama, Mariko; Asamizu, Erika; Ezura, Hiroshi



"Intracellular" GABA affects the equilibrium distribution of Cl- across the plasma membrane of a GABA acceptive neuron.  


The permeability of Cl- ions through single microdissected plasma membrane from Deiters' neurons was studied by a microtechnique. In particular, the time course of the passage of 36Cl- ions from a microchamber, M1, to another one, M2, across the membrane was followed. This study was performed with or without gamma-amino-butyric acid (GABA) in the two microchambers. The results suggest that in basal conditions the high intracellular concentration normally present in these neurons, 3.3 mM (1), causes a higher permeability of Cl- in the direction inside----outside in the respect of the plasma membrane. "Extracellular" GABA, 0.1 mM, is able to abolish this imbalance in Cl- permeability in the two opposite directions. This event appears to be the basis for GABA induced hyperpolarization of these neurons. PMID:3362293

Hydén, H; Cupello, A; Palm, A



Collaborative Regulation of Escherichia coli Glutamate-Dependent Acid Resistance by Two AraC-Like Regulators, GadX and GadW (YhiW)  

Microsoft Academic Search

An important feature of Escherichia coli pathogenesis is an ability to withstand extremely acidic environ- ments of pH 2 or lower. This acid resistance property contributes to the low infectious dose of pathogenic E. coli species. One very efficient E. coli acid resistance system encompasses two isoforms of glutamate decarboxylase (gadA and gadB) and a putative glutamate:-amino butyric acid (GABA)

Zhuo Ma; Hope Richard; Don L. Tucker; Tyrrell Conway; John W. Foster



Microbial production and degradation of ?-aminobutyric acid (GABA) in the abalone larval settlement habitat  

Microsoft Academic Search

By producing or degrading gamma-aminobutyric acid (GABA), microbes may affect the settlement of abalone (Haliotis) larvae. GABA was not detectable in extracts of crustose red algae (CRA) which are the preferred settlement substratum for Haliotis larvae. The CRA surfaces and their associated biofilms did not produce GABA from glutamate, and GABA production from putrescine required gabaculine (transaminase inhibitor). The GABA-degrading

H. F. Kaspar; D. O. Mountfort



Peripherally Delivered Glutamic Acid Decarboxylase Gene Therapy for Spinal Cord Injury Pain  

Microsoft Academic Search

Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of ?-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons

Jun Liu; Darren Wolfe; Shuanglin Hao; Shaohua Huang; Joseph C. Glorioso; Marina Mata; David J. Fink



Activation of GABA B receptors reverses spontaneous gating deficits in juvenile DBA\\/2J mice  

Microsoft Academic Search

Rationale  Gamma-amino-butyric acid (GABA)B receptors play a key role in the pathophysiology of psychotic disorders. We previously reported that baclofen, the prototypical\\u000a GABAB agonist, elicits antipsychotic-like effects in the rat paradigm of prepulse inhibition (PPI) of the startle, a highly validated\\u000a animal model of schizophrenia.\\u000a \\u000a \\u000a \\u000a Objectives  We studied the role of GABAB receptors in the spontaneous PPI deficits displayed by DBA\\/2J mice.

Marco Bortolato; Roberto Frau; Marco Orrù; A. Paola Piras; Mauro Fà; Antonella Tuveri; Monica Puligheddu; Gian Luigi Gessa; M. Paola Castelli; Giampaolo Mereu; Francesco Marrosu



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


Tonic ?-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

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



Ultrasound-induced enhancement of ACh, AChE and GABA in fetal brain tissue of mouse.  


Pregnant mice were exposed to continuous-wave (CW) ultrasound of 875 kHz frequency at 1 W/cm2 for 300 and 400 s, spread over five days, starting from the sixth day of pregnancy. The neurotransmitters, acetylcholine (ACh) and gamma amino butyric acid (GABA), and the associated enzyme acetylcholinesterase (AChE) levels, were estimated in the exposed fetal brains. Enhanced levels, significant at p < 0.001, were observed in the brains excised on day 10, day 15 and day 20 of gestation compared to sham-exposed and cage-control brains. PMID:8356785

Suneetha, N; Kumar, R P



Allosteric modulation of retinal GABA receptors by ascorbic acid  

PubMed Central

Summary Ionotropic ?-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 ?1 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 ?1 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.

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



GABA sub A (gamma-aminobutyric acid) type binding sites on membranes of spermatozoa  

SciTech Connect

The binding of ({sup 3}H) gamma-aminobutyric acid (GABA) to seminal membranes of swines and rams was examined. Specific, GABA binding was demonstrated in both species, which showed the features of GABA{sub A} type receptors. The affinity of binding was similar in both species, whereas the density of seminal GABA binding sites was 5 times higher in swine. Our findings suggest that GABA may have a direct effect on spermatozoa.

Erdoe, S.L. (Georg-August Univ., Goettingen (West Germany)); Wekerle, L. (Research Institute for Animal Husbandry, Herceghalom (Hungary))



The mechanism by which intracellular GABA increases Cl- outward permeability across Deiters' neurone plasma membranes.  


The present experiments aimed to clarify how the interaction of gamma-amino-butyric acid (GABA) with its receptors on the cytoplasmic side of the Deiters' neurone plasma membrane causes Cl- permeability to be higher in the in----out than in the opposite direction. To this end, the rate of 36Cl- in----out passage was studied in basal conditions, with GABA on the cytoplasmic side and in the presence of both GABA and an increased ionic strength buffer on that side. The results show that an increase in ionic strength reverses the GABA effect of 36Cl- permeability. The reversion being caused by changes in the buffer on the intracellular but not on the extracellular side. Our interpretation of this result is that the interaction of GABA with its cytoplasmic side receptors induces an exposure of positive charges only at the intracellular mouth of the intraneuronal GABA gated Cl- channels. This asymmetry would be the basis of the reported higher Cl- permeability in the in----out direction. PMID:2469663

Rapallino, M V; Cupello, A; Hydén, H



Tolerance to allopregnanolone with focus on the GABA-A receptor  

PubMed Central

Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the ?-amino butyric acid –A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor ?4 subunit and the expression of the ?4 subunit mRNA in the ventral-posteriomedial nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.

Turkmen, Sahruh; Backstrom, Torbjorn; Wahlstrom, Goran; Andreen, Lotta; Johansson, Inga-Maj



Distinct development of GABA system in the ventral and dorsal horns in the embryonic mouse spinal cord.  


In the adult brain, ?-amino butyric acid (GABA) is an inhibitory neurotransmitter, whereas it acts as an excitatory transmitter in the immature brain, and may be involved in morphogenesis. In the present study, we immunohistochemically examined the developmental changes in GABA signaling in the embryonic mouse cervical spinal cord. Glutamic acid decarboxylase and GABA were markers for GABA neurons. Vesicular GABA transporter was a marker for GABAergic and glycinergic terminals. Potassium chloride cotransporter 2 was a marker for GABAergic inhibition. We found five points: (1) In the ventral part, GABA neurons were divided into three groups. The first differentiated group sent commissural axons after embryonic day 11 (E11), but disappeared or changed their transmitter by E15. The second and third differentiated groups were localized in the ventral horn after E12, and sent axons to the ipsilateral marginal zone. There was a distal-to-proximal gradient in varicosity formation in GABAergic axons and a superficial-to-deep gradient in GABAergic synapse formation in the ventral horn; (2) In the dorsal horn, GABA neurons were localized after E13, and synapses were diffusely formed after E15; (3) GABA may be excitatory for several days before synapses formation; (4) There was a ventral-to-dorsal gradient in the development of GABA signaling. The GABAergic inhibitory network may develop in the ventral horn between E15 and E17, and GABA may transiently play crucial roles in inhibitory regulation of the motor system in the mouse fetus; (5) GABA signaling continued to develop after birth, and GABAergic system diminished in the ventral horn. PMID:23044470

Kosaka, Yoshinori; Kin, Hidemichi; Tatetsu, Masaharu; Uema, Itsuki; Takayama, Chitoshi



Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A  

PubMed Central

Abstact Background Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. Methods In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. Results Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAA?1, GABAA?, GABAA?, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAA?5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. Conclusions Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management.



Antiepileptic activity of lobeline isolated from the leaf of Lobelia nicotianaefolia and its effect on brain GABA level in mice  

PubMed Central

Objective To investigate the anticonvulsant activity of the lobeline isolated from the Lobelia nicotianaefolia in chemoconvulsant-induced seizures and its biochemical mechanism by investigating relationship between seizure activities and altered gamma amino butyric acid (GABA) in brain of mice in Pentylenetetrazol (PTZ) seizure models. Methods The anticonvulsant activity of the isolated lobeline (5, 10, 20 and 30 mg/kg, i.p.) was investigated in PTZ and strychnine induced seizures in mice and the effect of isolated lobeline on brain GABA level in seizures induced by PTZ. Diazepam was used as reference anticonvulsant drugs for comparison. Results Isolated lobeline (10, 20 and 30 mg/kg, i.p.) significantly delayed and antagonized (P < 0.050–0.001) the onset of PTZ-induced seizures. It also antagonized strychnine induced seizures. The mortality was also prevented in the test group of animals. In biochemical evaluation, isolated lobeline (5, 10 and 20 mg/kg, i.p.) significantly increased the brain GABA level. And at dose of 30 mg/kg GABA level showed slight decrease in PTZ model. Conclusions In our findings, isolated lobeline (20mg/kg) exhibited potent anticonvulsant activity against PTZ induced seizures. Also a biochemical evaluation suggested significant increase in barain GABA level at 20 mg/kg i.p. of isolated lobeline. Hence, we may propose that lobeline reduces epileptic seizures by enhancing the GABA release supporting the GABAergic mechanism.

Tamboli, Abrar M; Rub, Rukhsana A; Ghosh, Pinaki; Bodhankar, SL



Effects of Chlorotrifluoroethylene Oligomer Fatty Acids on Recombinant GABA Receptors Expressed in Xenopus Oocytes  

Microsoft Academic Search

.   GABA-activated Cl? current was expressed in Xenopus oocytes after injecting cRNA that had been transcribed in vitro from complementary DNA (cDNA) coding for a single GABA ?i-subunit cloned from human retina. The expressed current was insensitive to 100 ?m bicuculline, but was activated by the GABA analogue trans-4-aminocrontonic acid (TACA). Anion-selective permeability of the\\u000a expressed ?1-subunit was determined by

N. J. DelRaso; Y. Huang; L. Lu



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

Microsoft Academic Search

Several transmitter candidates including serotonin (5-HT), ATP, and norepinephrine (NE) have been identified in taste buds. Recently, ?-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

Yijen A. Huang; Elizabeth Pereira; Stephen D. Roper; Hiroaki Matsunami



Detection of ?-Aminobutyric Acid (GABA) by Longitudinal Scalar Order Difference Editing  

Microsoft Academic Search

Two novel spectral editing techniques for the in vivo detection of ?-aminobutyric acid (GABA) are presented. The techniques rely on the generation of longitudinal scalar order (LSO) coherences, which in combination with J-difference editing results in the selective detection of GABA. The utilization of LSO coherences makes the editing sequences insensitive to phase and frequency instabilities. Furthermore, the spectral editing

Robin A. de Graaf; Douglas L. Rothman



Detection of gamma-Aminobutyric Acid (GABA) by Longitudinal Scalar Order Difference Editing  

Microsoft Academic Search

Two novel spectral editing techniques for the in vivo detection of gamma-aminobutyric acid (GABA) are presented. The techniques rely on the generation of longitudinal scalar order (LSO) coherences, which in combination with J-difference editing results in the selective detection of GABA. The utilization of LSO coherences makes the editing sequences insensitive to phase and frequency instabilities. Furthermore, the spectral editing

Robin A. de Graaf; Douglas L. Rothman



Gamma-aminobutyric acid (GABA)-C receptor stimulation increases prolactin (PRL) secretion in cultured rat anterior pituitary cells.  


Gamma-aminobutyric acid (GABA) reportedly inhibits secretion of anterior pituitary hormones by directly acting on GABA-A and GABA-B receptors on anterior pituitary cells, but the roles of GABA-C receptors are little known. In this study, involvement of GABA-C receptors in the secretion of prolactin (PRL) was examined using cultured rat anterior pituitary cells. GABA-C receptor agonist, cis-4-aminocrotonic acid (CACA, 0.1-1 mM) increased PRL secretion dose-dependently, while GABA-A receptor agonist, 100 microM muscimol, but not GABA-B receptor agonist, 100 microM baclofen, decreased the secretion. GABA-C receptor antagonist, 15 microM (1,2,5,6-tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA), and GABA-A receptor antagonist, 100 microM bicuculline, not only reversed such an agonist-induced increase or decrease in PRL secretion, but also suppressed or enhanced spontaneous PRL secretion, raising a possibility of GABA-C or GABA-A receptor stimulation by intrinsic pituitary-derived GABA. GABA-C receptor subunits (rho1, rho2, rho3) and GABA synthesizing enzymes (GAD 65 and GAD 67) were shown to be expressed as assayed by RT-PCR, and GABA-C receptor stimulation by CACA obviously increased intracellular Ca2+ concentration in the anterior pituitary cells. Thus, PRL secretion from anterior pituitary cells appears to be enhanced via direct GABA-C receptor stimulation by GABA originating from the anterior pituitary cells besides well-known hypothalamic GABA. PMID:16677614

Nakayama, Yasuhisa; Hattori, Naoki; Otani, Hitomi; Inagaki, Chiyoko



Sex-specific differences in GABA(A) -benzodiazepine receptor availability: relationship with sensitivity to pain and tobacco smoking craving.  


Sex differences exist in tobacco smoking behaviors. Nicotine, the primary addictive ingredient in tobacco smoke, indirectly affects ?-amino butyric acid (GABA) function. Previous studies reported sex-by-smoking interactions in brain GABA levels. The goal of the present study was to evaluate if there is a sex-by-smoking interaction at the GABA(A)-benzodiazepine receptors (GABA(A)-BZRs), as well as relationships between GABA(A)-BZR availability and behavioral variables before and after 1 week of smoking cessation. Twenty-six women (8 non-smokers, age 36.0 ± 13.4 years; 19 smokers, age 34.6 ± 8.9 years) and 25 men (8 non-smokers, age 37.9 ± 13.8 years; 17 smokers, 34.1 ± 12.4 years) were imaged using [123I]iomazenil and single-photon emission computed tomography. Smokers were imaged at baseline 7 hours after the last cigarette. A significantly great number of men were able to abstain from smoking for 1 week (P = 0.003). There were no significant differences in nicotine dependence and cigarette craving, mood or pain sensitivity between male and female smokers. There was a significant effect of gender across all brain regions (frontal, parietal, anterior cingulate, temporal and occipital cortices, and cerebellum; P < 0.05), with all women (smokers and non-smokers combined) having a higher GABA(A)-BZR availability than all men. There was a negative correlation between GABA(A)-BZR availability and craving (P ? 0.02) and pain sensitivity (P = 0.04) in female smokers but not male smokers. This study provides further evidence of a sex-specific regulation of GABA(A)-BZR availability in humans and demonstrates the potential for GABA(A)-BZRs to mediate tobacco smoking craving and pain symptoms differentially in female and male smokers. PMID:22353491

Esterlis, Irina; McKee, Sherry A; Kirk, Kathryne; Lee, Dianne; Bois, Frederic; Stiklus, Stephanie M; Seibyl, John P; Krishnan-Sarin, Suchitra; O'Malley, Stephanie S; Staley, Julie K; Cosgrove, Kelly P



Two-dimensional, J-resolved spectroscopic imaging of GABA at 4 Tesla in the human brain.  


A method for measuring brain gamma-amino butyric acid (GABA) levels is presented that combines 2D J-resolved magnetic resonance spectroscopy (J-MRS) techniques with chemical-shift imaging (2D-JMRSI) at 4 Tesla (T). The results of phantom and in vivo experiments agree well in demonstrating that the (2)CH(2) GABA resonance situated at 2.97 ppm can be resolved from the neighboring creatine (Cr) resonance at 3.03 ppm and quantified. Single-voxel, J-resolved standard and metabolite-nulled in vivo experiments on six healthy subjects reveal a broad component from the underlying macromolecules (MM) that resonates at and around 3.00 ppm, which is estimated to contribute approximately 15% to the J-resolved GABA resonance in this large voxel at a repetition time (TR) of 4.5 s. With our 2D-JMSRI at 1.25 s TR, the macromolecule resonance contribution to our GABA measurements is approximated to be 12%. Six healthy human subjects underwent scanning at 4T with this sequence, yielding a global brain GABA concentration of 0.76 +/- 0.20 mM after correction for 12% macromolecule contribution. PMID:16155894

Jensen, J Eric; Frederick, Blaise Deb; Wang, Liqun; Brown, John; Renshaw, Perry F



Induction of the GABA cell phenotype: an in vitro model for studying neurodevelopmental disorders.  


Recent studies of the hippocampus have suggested that a network of genes is associated with the regulation of the GAD?? (GAD1) expression and may play a role in ?-amino butyric acid (GABA) dysfunction in schizophrenia (SZ) and bipolar disorder (BD). To obtain a more detailed understanding of how GAD?? regulation may result in GABAergic dysfunction, we have developed an in vitro model in which GABA cells are differentiated from the hippocampal precursor cell line, HiB5. Growth factors, such as PDGF, and BDNF, regulate the GABA phenotype by inducing the expression of GAD?? and stimulating the growth of cellular processes, many with growth cones that form appositions with the cell bodies and processes of other GAD??-positive cells. These changes are associated with increased expression of acetylated tubulin, microtubule-associated protein 2 (MAP2) and the post-synaptic density protein 95 (PSD95). The addition of BDNF, together with PDGF, increases the levels of mRNA and protein for GAD??, as well as the high affinity GABA uptake protein, GAT1. These changes are associated with increased concentrations of GABA in the cytoplasm of "differentiated" HiB5 neurons. In the presence of Ca²? and K?, newly synthesized GABA is released extracellularly. When the HiB5 cells appear to be fully differentiated, they also express GAD??, parvalbumin and calbindin, and GluR subtypes as well as HDAC1, DAXX, PAX5, Runx2, associated with GAD?? regulation. Overall, these results suggest that the HiB5 cells can differentiate into functionally mature GABA neurons in the presence of gene products that are associated with GAD?? regulation in the adult hippocampus. PMID:22457755

Subburaju, Sivan; Benes, Francine M



??????????????????????- ??????????????????????????????????????????????????????? Accumulation of gamma-aminobutyric acid (GABA) in non-waxy and waxy rice germ during water soaking ????? ?????????? ?????? ??????????? ???? ?????????????? ???????? ????????????  

Microsoft Academic Search

Rice germ contains protein, vitamins, minerals, dietary fiber and gamma- aminobutyric acid (GABA). GABA has been proved to be effective for lowering the blood pressure of human being. It has neurotransmission functions and tranquilizer effects. Determination of GABA in rice germ and brown rice were investigated by using low- amylose, high-amylose and waxy rice cultivars. Percentage of germ weight showed

Patcharee Tungtrakul; Vipa Surojanametakul; Ladda Wattanasiritham


Molecular and physiological evidence for functional gamma-aminobutyric acid (GABA)-C receptors in growth hormone-secreting cells.  


The neurotransmitter gamma-aminobutyric acid (GABA), released by hypothalamic neurons as well as by growth hormone- (GH) and adrenocorticotropin-producing cells, is a regulator of pituitary endocrine functions. Different classes of GABA receptors may be involved. In this study, we report that GH cells, isolated by laser microdissection from rat pituitary slices, possess the GABA-C receptor subunit rho2. We also demonstrate that in the GH adenoma cell line, GH3, GABA-C receptor subunits are not only expressed but also form functional channels. GABA-induced Cl- currents were recorded using the whole cell patch clamp technique; these currents were insensitive to bicuculline (a GABA-A antagonist) but could be induced by the GABA-C agonist cis-4-aminocrotonic acid. In contrast to typical GABA-C mediated currents in neurons, they quickly desensitized. Ca2+i recordings were also performed on GH3 cells. The application of either GABA or cis-4-aminocrotonic acid led to Ca2+ transients of similar amplitude, indicating that the activation of GABA-C receptors in GH3 cells may cause membrane depolarization, opening of voltage-gated Ca2+ channels, and a subsequent Ca2+ influx. Our results point at a role for GABA in pituitary GH cells and disclose an additional pathway to the one known via GABA-B receptors. PMID:12660236

Gamel-Didelon, Katia; Kunz, Lars; Fohr, Karl Josef; Gratzl, Manfred; Mayerhofer, Artur



The standardized extract of Loeselia mexicana possesses anxiolytic activity through the ?-amino butyric acid mechanism  

Microsoft Academic Search

Ethnopharmacological relevanceLoeselia mexicana (Lam.) Brand has been used in Mexican Traditional Medicine to treat “espanto” or “susto” (fear), which is a culturally affiliated syndrome whose symptomatology comprises loss of appetite, difficulty in sleeping, and also nausea and fatigue, with a sensation of fear or risk – real or imagined – to external stimuli.

Maribel Herrera-Ruiz; Adolfo González-Carranza; Alejandro Zamilpa; Enrique Jiménez-Ferrer; Maira Huerta-Reyes; Víctor M. Navarro-García


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

PubMed Central

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 ?-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.

Ciranna, L



Expression of the -Aminobutyric Acid (GABA) Plasma Membrane Transporter1 in Monkey and Human Retina  

Microsoft Academic Search

PURPOSE. To determine the expression pattern of the predom- inant -aminobutyric acid (GABA) plasma membrane trans- porter 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 con- focal microscopy. Double-labeling studies were performed with the GAT-1 antibody using antibodies to GABA, vasoactive intestinal polypeptide (VIP),

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



Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins.  


There is accumulating evidence that most beta-lactam antibiotics (i.e., cephalosporins and penicillins) have some degree of convulsive activity, both in laboratory animals as well as in clinical settings. The proposed mechanism is suppression of inhibitory postsynaptic responses, mainly mediated by gamma-amino butyric acid (GABA)(A)-receptors (GABA(A)-R). However, comprehensive studies on the convulsive activities of various beta-lactam antibiotics in vivo and in vitro have not been performed. We have therefore examined the convulsive activities of seven different cephalosporins using both in vivo and in vitro models: intracerebroventricular (ICV) administration in mouse; [(3)H]muscimol binding assay (BA) in mouse brain synaptosome; and inhibition of recombinant mouse alpha1beta2gamma2s GABA(A)-Rs in Xenopus oocyte (GR). The rank orders of convulsive activities in mouse (cefazolin>cefoselis>cefotiam>cefpirome>cefepime>ceftazidime>cefozopran) correlated with those of inhibitory potencies on [(3)H]muscimol binding and GABA-induced currents of GABA(A)-R in vitro, with correlation coefficients of ICV:GR, ICV:BA and BA:GR of 0.882, 0.821 and 0.832, respectively. In contrast, none of the antibiotics had affinities for N-methyl-D-aspartate (NMDA) receptors nor facilitatory actions on NMDA receptor-mediated current in oocytes. These results clearly demonstrate that the mechanism of cephalosporin-induced convulsions is mediated predominantly through the inhibition of GABA(A)-R function and not through NMDA receptor modulation. PMID:12871648

Sugimoto, Masahiro; Uchida, Ichiro; Mashimo, Takashi; Yamazaki, Shunji; Hatano, Kazuo; Ikeda, Fumiaki; Mochizuki, Yoshitaka; Terai, Takao; Matsuoka, Nobuya



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


?-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

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



Behavioral and Neural Analysis of GABA in the Acquisition, Consolidation, Reconsolidation, and Extinction of Fear Memory  

PubMed Central

The current review systematically documents the role of ?-amino-butyric acid (GABA) in different aspects of fear memory—acquisition and consolidation, reconsolidation, and extinction, and attempts to resolve apparent contradictions in the data in order to identify the function of GABAA receptors in fear memory. First, numerous studies have shown that pre- and post-training administration of drugs that facilitate GABAergic transmission disrupt the initial formation of fear memories, indicating a role for GABAA receptors, possibly within the amygdala and hippocampus, in the acquisition and consolidation of fear memories. Similarly, recent evidence indicates that these drugs are also detrimental to the restorage of fear memories after their reactivation. This suggests a role for GABAA receptors in the reconsolidation of fear memories, although the precise neural circuits are yet to be identified. Finally, research regarding the role of GABA in extinction has shown that GABAergic transmission is also disruptive to the formation of newly acquired extinction memories. We argue that contradictions to these patterns are the result of variations in (a) the location of drug infusion, (b) the dosage of the drug and/or (c) the time point of drug administration. The question of whether these GABA-induced memory deficits reflect deficits in retrieval is discussed. Overall, the evidence implies that the processes mediating memory stability consequent to initial fear learning, memory reactivation, and extinction training are dependent on a common mechanism of reduced GABAergic neurotransmission.

Makkar, Steve R; Zhang, Shirley Q; Cranney, Jacquelyn



Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice.  


Degeneration of medium spiny GABA neurons in the basal ganglia underlies motor dysfunction in Huntington's disease (HD), which presently lacks effective therapy. In this study, we have successfully directed human embryonic stem cells (hESCs) to enriched populations of DARPP32-expressing forebrain GABA neurons. Transplantation of these human forebrain GABA neurons and their progenitors, but not spinal GABA cells, into the striatum of quinolinic acid-lesioned mice results in generation of large populations of DARPP32(+) GABA neurons, which project to the substantia nigra as well as receiving glutamatergic and dopaminergic inputs, corresponding to correction of motor deficits. This finding raises hopes for cell therapy for HD. PMID:22424902

Ma, Lixiang; Hu, Baoyang; Liu, Yan; Vermilyea, Scott Christopher; Liu, Huisheng; Gao, Lu; Sun, Yan; Zhang, Xiaoqing; Zhang, Su-Chun



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

SciTech Connect

Type A {gamma}-aminobutyric acid (GABA{sub A}) 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. The authors 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 is 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABA{sub A} 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}{sub 1}, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family.

Cutting, G.R.; Lu, Luo; Kasch, L.M.; Montrose-Rafizadeh, C.; Antonarakis, S.E.; Guggino, W.B.; Kazazian, H.H. Jr. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)); O'Hara, B.F.; Donovan, D.M.; Shimada, Shoichi (National Inst. on Drug Abuse, Baltimore, MD (United States)); Uhl, G.R. (National Inst. on Drug Abuse, Baltimore, MD (United States) Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States))



(3-Aminocyclopentyl)methylphosphinic acids: novel GABA(C) receptor antagonists.  


Our understanding of the role GABA(C) receptors play in the central nervous system is limited due to a lack of specific ligands. Here we describe the pharmacological effects of (+/-)-cis-3- and (+/-)-trans-3-(aminocyclopentyl)methylphosphinic acids ((+/-)-cis- and (+/-)-trans-3-ACPMPA) as novel ligands for the GABA(C) receptor showing little activity at GABA(A) or GABA(B) receptors. (+/-)-cis-3-ACPMPA has similar potency to (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at human recombinant rho1 (K(B)=1.0+/-0.2microM) and rat rho3 (K(B)=5.4+/-0.8microM) but is 15 times more potent than TPMPA on human recombinant rho2 (K(B)=1.0+/-0.3microM) GABA(C) receptors expressed in Xenopus oocytes. (+/-)-cis- and (+/-)-trans-3-ACPMPA are novel lead compounds for developing into more potent and selective GABA(C) receptor antagonists with increased lipophilicity for in vivo studies. PMID:17098260

Chebib, Mary; Hanrahan, Jane R; Kumar, Rohan J; Mewett, Kenneth N; Morriss, Gwendolyn; Wooller, Soraya; Johnston, Graham A R



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


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

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



Utilization of Barley or Wheat Bran to Bioconvert Glutamate to ?-Aminobutyric Acid (GABA).  


This study deals with the utilization of agro-industrial wastes created by barley and wheat bran in the production of a value-added product, ?-aminobutyric acid (GABA). The simple and eco-friendly reaction requires no pretreatment or microbial fermentation steps but uses barley or wheat bran as an enzyme source, glutamate as a substrate, and pyridoxal 5'-phosphate (PLP) as a cofactor. The optimal reaction conditions were determined on the basis of the temperatures and times used for the decarboxylation reactions and the initial concentrations of barley or wheat bran, glutamate, and PLP. The optimal reactions produced 9.2 mM of GABA from 10 mM glutamate, yielding a 92% GABA conversion rate, when barley bran was used and 6.0 mM of GABA from 10 mM glutamate, yielding a 60% GABA conversion rate, when wheat bran was used. The results imply that barley bran is more efficient than wheat bran in the production of GABA. PMID:24024689

Jin, Wen-Jie; Kim, Min-Ju; Kim, Keun-Sung



?-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic ?-Cells  

PubMed Central

OBJECTIVE Paracrine signaling via ?-aminobutyric acid (GABA) and GABAA receptors (GABAARs) has been documented in rodent islets. Here we have studied the importance of GABAergic signaling in human pancreatic islets. RESEARCH DESIGN AND METHODS Expression of GABAARs in islet cells was investigated by quantitative PCR, immunohistochemistry, and patch-clamp experiments. Hormone release was measured from intact islets. GABA release was monitored by whole-cell patch-clamp measurements after adenoviral expression of ?1?1 GABAAR subunits. The subcellular localization of GABA was explored by electron microscopy. The effects of GABA on electrical activity were determined by perforated patch whole-cell recordings. RESULTS PCR analysis detected relatively high levels of the mRNAs encoding GABAAR ?2, ?3, ?2, and ? subunits in human islets. Patch-clamp experiments revealed expression of GABAAR Cl? channels in 52% of ?-cells (current density 9 pA/pF), 91% of ?-cells (current density 148 pA/pF), and 6% of ?-cells (current density 2 pA/pF). Expression of GABAAR subunits in islet cells was confirmed by immunohistochemistry. ?-Cells secreted GABA both by glucose-dependent exocytosis of insulin-containing granules and by a glucose-independent mechanism. The GABAAR antagonist SR95531 inhibited insulin secretion elicited by 6 mmol/l glucose. Application of GABA depolarized ?-cells and stimulated action potential firing in ?-cells exposed to glucose. CONCLUSIONS Signaling via GABA and GABAAR constitutes an autocrine positive feedback loop in human ?-cells. The presence of GABAAR in non–?-cells suggests that GABA may also be involved in the regulation of somatostatin and glucagon secretion.

Braun, Matthias; Ramracheya, Reshma; Bengtsson, Martin; Clark, Anne; Walker, Jonathan N.; Johnson, Paul R.; Rorsman, Patrik



Up-regulation of the betaine/GABA transporter BGT1 by JAK2.  


Janus-activated kinase-2 JAK2 is activated by hyperosmotic shock and modifies the activity of several Na(+) coupled transporters. Carriers up-regulated by osmotic shock include the Na(+) coupled osmolyte transporter BGT1 (betaine/GABA transporter 1), which accomplishes the concentrative cellular uptake of ?-amino-butyric acid (GABA). The present study thus explored whether JAK2 participates in the regulation of BGT1 activity. To this end, cRNA encoding BGT1 was injected into Xenopus oocytes with or without cRNA encoding wild type JAK2, constitutively active (V617F)JAK2 or inactive (K882E)JAK2, and electrogenic GABA transport determined by dual electrode voltage clamp. In oocytes injected with cRNA encoding BGT1 but not in oocytes injected with water or with cRNA encoding JAK2 alone, the addition of 1mM GABA to the extracellular fluid generated an inward current (I(BGT)). In BGT1 expressing oocytes I(BGT) was significantly increased by coexpression of JAK2 or (V617F)JAK2, but not by coexpression of (K882E)JAK2. According to kinetic analysis coexpression of JAK2 increased the maximal I(BGT) without significantly modifying the concentration required for halfmaximal I(BGT) (K(M)). In oocytes expressing BGT1 and (V617F)JAK2 I(BGT) was gradually decreased by JAK2 inhibitor AG490 (40 ?M). The decline of I(BGT) following disruption of carrier insertion with brefeldin A (5 ?M) was similar in the absence and presence of the JAK2 inhibitor AG490 (40 ?M). In conclusion, JAK2 is a novel regulator of the GABA transporter BGT1. The kinase up-regulates the carrier presumably by enhancing the insertion of carrier protein into the cell membrane. PMID:22405821

Hosseinzadeh, Zohreh; Shojaiefard, Manzar; Bhavsar, Shefalee K; Lang, Florian



The GABA-B antagonist 2-hydroxysaclofen reverses the effects of baclofen on the discriminative stimulus effects of D-amphetamine in the conditioned taste aversion procedure.  


Some of the behavioral effects of d-amphetamine (d-AMPH) are mediated by an increase in dopamine neurotransmission in the nucleus accumbens. However, there is evidence that gamma-amino-butyric-acid-B (GABA-B) receptors are involved in some behavioral effects of D-AMPH and cocaine. Here, we examined the effects of baclofen on the discriminative stimulus properties of D-AMPH, using conditioned taste aversion (CTA) as the drug discrimination procedure. Male Wistar rats were deprived of water and trained in the CTA procedure. They received D-AMPH (1 mg/kg, i.p.) before gaining access to saccharin, which was followed by an injection of LiCl. On alternate days, the subjects received saline before and after the access to saccharin. After the rats learned the D-AMPH-saline discrimination, the standard dose of D-AMPH was replaced by different doses of D-AMPH, baclofen (a GABA-B receptor agonist), 2-hydroxysaclofen (a GABA-B receptor antagonist), a combination of baclofen+D-AMPH, or a combination of 2-hydroxysaclofen+baclofen+D-AMPH. Baclofen did not substitute for D-AMPH, but, when combined with D-AMPH, it produced a small but significant decrease in the discriminative stimulus effects of D-AMPH. This effect was reversed by administration of 2-hydroxysaclofen. These data suggest that GABA-B receptors play a regulatory role in the discriminative stimulus effects of D-AMPH. PMID:19361543

Miranda, Florencio; Jiménez, Juan C; Cedillo, Laura N; Sandoval-Sánchez, Alma; Millán-Mejía, Patricia; Sánchez-Castillo, Hugo; Velázquez-Martínez, David N



A single amino acid in the second transmembrane domain of GABA rho receptors regulates channel conductance.  


GABAC receptors, expressed predominately in vertebrate retina, are thought to be formed mainly by GABA rho subunits, each of which exhibits distinct physiological and pharmacological properties. In this study, the receptors formed by perch GABA rho subunits were expressed in HEK cells, and their single channel conductances were determined using noise analysis techniques. The receptors formed by the perch rho1A subunit gate a channel with a conductance of 0.2 pS, whereas the receptors formed by GABA rho2 subunits exhibit much higher channel conductances, i.e., 3.2 and 3.5 pS for perch rho2A and rho2B receptors, respectively. A comparison of the amino acid sequences of the channel-forming TMII regions of the various subunits suggested that a single amino acid at position 2' was a potential site for the large differential in conductance. We found that switching the serine residue at that site in the GABA rho2 subunit to the proline residue present in the rho1 subunit reduced the channel conductance to a level similar to that of the wild type rho1 receptor. Conversely, mutating proline to serine in the amino acid sequence of the rho1 receptor significantly increased its unitary conductance. These results indicate that a single amino acid in the TMII region plays an important role in determining the single channel conductance of the GABAC receptors. PMID:17398006

Zhu, Yujie; Ripps, Harris; Qian, Haohua



Correlation Between Hepatocyte Growth Factor (HGF) and Gamma-Aminobutyric Acid (GABA) Plasma Levels in Autistic Children  

PubMed Central

There is much support for the role of Gamma-Aminobutyric acid (GABA) in the etiology of autism. Recent research has shown that hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility. This study was designed to determine and correlate plasma levels of HGF, GABA, as well as symptom severity, in autistic children and neurotypical controls. Plasma from 48 autistic children and 29 neurotypical controls was assessed for HGF and GABA concentration using ELISAs. Symptom severity was assessed in these autistic individuals and compared to HGF and GABA concentrations. We previously reported that autistic children had significantly decreased levels of HGF. In this study, the same autistic children had significantly increased plasma levels of GABA (P = 0.002) and decreased HGF levels correlated with these increased GABA levels (r = 0.3; P = 0.05). High GABA levels correlated with increasing hyperactivity (r = 0.6; P = 0.0007) and impulsivity severity (r = 0.5; P = 0.007), tip toeing severity (r = 0.35; P = 0.03), light sensitivity (r = 0.4; P = 0.02), and tactile sensitivity (r = 0.4; P = 0.01). HGF levels did not correlate significantly with any symptom severity. These results suggest an association between HGF and GABA levels and suggest that plasma GABA levels are related to symptom severity in autistic children.

Russo, Anthony J.



Vigabatrin, a GABA Transaminase Inhibitor, Reversibly Eliminates Tinnitus in an Animal Model  

PubMed Central

Animal models have facilitated basic neuroscience research investigating the pathophysiology of tinnitus. It has been hypothesized that partial deafferentation produces a loss of tonic inhibition in the auditory system that may lead to inappropriate neuroplastic changes eventually expressed as tinnitus. The pathological down-regulation of ?-amino butyric acid (GABA) provides a potential mechanism for this loss of inhibition. Using an animal model previously demonstrated to be sensitive to treatments that either induce or attenuate tinnitus, the present study examined the effect of the specific GABA agonist vigabatrin on chronic tinnitus. It was hypothesized that vigabatrin would decrease the evidence of tinnitus by restoring central inhibitory function through increased GABA availability. Vigabatrin has been demonstrated to elevate central GABA levels (Mattson et al. 1995). Tinnitus was induced in rats using a single 1-h unilateral exposure to band-limited noise, which preserved normal hearing in one ear. Psychophysical evidence of tinnitus was obtained using a free-operant conditioned-suppression method: Rats lever-pressed for food pellets and were trained to discriminate between the presence and absence of sound by punishing lever pressing with a mild foot shock (0.5 mA; 1 s) at the conclusion of randomly introduced silent periods (60 s) inserted into background low-level noise. Additional random insertion of pure tone and noise periods of variable intensity enabled the derivation of psychophysical functions that reflected the presence of tinnitus with features similar to 20-kHz tones. Vigabatrin was chronically administered via drinking water at 30 and 81 mg kg?1 day?1, with each dose level tested over 2 weeks, followed by a 0-mg washout test. Vigabatrin completely and reversibly eliminated the psychophysical evidence of tinnitus at both doses. Although vigabatrin has serious negative side effects that have prevented its clinical use in the USA, it is nevertheless a potentially useful tool in unraveling tinnitus pathophysiology.

Spires, T. JosephD.; Bauer, Carol A.



J-difference editing of gamma-aminobutyric acid (GABA): Simulated and experimental multiplet patterns.  


Purpose: To investigate factors that influence the multiplet pattern observed in J-difference editing of gamma-aminobutyric acid (GABA). Methods: Density matrix simulations were applied to investigate the shape of the 3 ppm GABA multiplet as a function of the editing sequence's slice-selective refocusing pulse properties, in particular bandwidth, transition width, and flip angle. For comparison to the calculations, experimental measurements were also made at 3 T on a 10 mM GABA solution using the MEGA-PRESS sequence at various refocusing pulse flip angles. Results: Good agreement was found between experiments and simulations. The edited multiplet consists of two outer lines of slightly unequal intensity due to strong coupling, and a smaller central line, the result of the unequal J-couplings between the C4 and C3 protons. The size of the center peak increases with increasing slice-selective refocusing pulse transition width, and deviation of the flip angle from 180°. Conclusion: The 3 ppm GABA multiplet pattern observed in the MEGA-PRESS experiment depends quite strongly on the properties of the slice-selective refocusing pulses used. Under some circumstance, the central peak can be quite large; this does not necessarily indicate inefficient editing, or a subtraction artifact, but should be recognized as a property of the pulse sequence itself. Magn Reson Med 70:1183-1191, 2013. © 2012 Wiley Periodicals, Inc. PMID:23213033

Near, Jamie; Evans, C John; Puts, Nicolaas A J; Barker, Peter B; Edden, Richard A E



Conductance Properties of GABA (Gamma-Aminobutyric Acid)-Activated Chloride Currents Recorded from Cultured Hippocampal Neurons,  

National Technical Information Service (NTIS)

The conductance characteristics of gamma aminobutyric acid-activated single channel currents from cultured hippocampal neurons were examined using patch clamp techniques. GABA-activated currents had amplitudes which were linearly correlated to the membran...

C. N. Allen E. X. Albuquerque



Calcium dependent release of gamma-aminobutyric acid (GABA) from human cerebral cortex.  


The release of the amino acids GABA, taurine, glycine, glutamine and leucine from human neocortex was investigated in vitro by utilizing brain tissue removed during 8 standard temporal lobectomies for epilepsy or tumor. Slices (0.5 mm thick) were cut from each biopsy and randomly placed in three different chambers. After 90 min preincubation, the three sets of slices were incubated for 60 s in wells containing, respectively, (A) regular ACSF (control), (B) ACSF with 50 mM K+ (to depolarize the cell membrane) and (C) ACSF with 50 mM K+, 0 mM Ca2+ and 4 mM Mg2+ (depolarization during blocked synaptic transmission). The content of amino acids in the wells was determined by high-performance liquid chromatography after pre-column derivatization of the amino acids with o-phthalaldehyde. Membrane depolarization (well B) increased the GABA release to 650% (620 pmol/mg) of control (well A, 95 pmol/mg). Blocking synaptic transmission (well C) reduced the evoked release by 50% (360 pmol/mg). The release of glycine, taurine, glutamine and leucine during membrane depolarization was not significantly different from the control values. The data provide evidence for a Ca(2+)-dependent release of GABA, supporting a possible role of this amino acid as a neurotransmitter in human neocortex. PMID:1508401

Haugstad, T S; Hegstad, E; Langmoen, I A



In vivo photorelease of GABA in the mouse cortex.  


Electrical stimulation has been used for more than 100 years in neuroscientific and biomedical research as a powerful tool for controlled perturbations of neural activity. Despite quickly driving neuronal activity, this technique presents some important limitations, such as the impossibility to activate or deactivate specific neuronal populations within a single stimulation site. This problem can be avoided by pharmacological methods based on the administration of receptor ligands able to cause specific changes in neuronal activity. However, intracerebral injections of neuroactive molecules inherently confound the dynamics of drug diffusion with receptor activation. Caged compounds have been proposed to circumvent this problem, for spatially and temporally controlled release of molecules. Caged compounds consist of a protecting group and a ligand made inactive by the bond between the two parts. By breaking this bond with light of an appropriate wavelength, the ligand recovers its activity within milliseconds. To test these compounds in vivo, we recorded local field potentials (LFPs) from the cerebral cortex of anesthetized female mice (CF1, 60-70 days, 20-30 g) before and after infusion with caged ?-amino-butyric-acid (GABA). After 30 min, we irradiated the cortical surface with pulses of blue light in order to photorelease the caged GABA and measure its effect on global brain activity. Laser pulses significantly and consistently decreased LFP power in four different frequency bands with a precision of few milliseconds (P < 0.000001); however, the inhibitory effects lasted several minutes (P < 0.0043). The technical difficulties and limitations of neurotransmitter photorelease are presented, and perspectives for future in vivo applications of the method are discussed. PMID:21755263

Lopes-dos-Santos, V; Campi, J; Filevich, O; Ribeiro, S; Etchenique, R



Calpain Cleavage of Brain Glutamic Acid Decarboxylase 65 Is Pathological and Impairs GABA Neurotransmission  

PubMed Central

Previously, we have shown that the GABA synthesizing enzyme, L-glutamic acid decarboxylase 65 (GAD65) is cleaved to form its truncated form (tGAD65) which is 2–3 times more active than the full length form (fGAD65). The enzyme responsible for cleavage was later identified as calpain. Calpain is known to cleave its substrates either under a transient physiological stimulus or upon a sustained pathological insult. However, the precise role of calpain cleavage of fGAD65 is poorly understood. In this communication, we examined the cleavage of fGAD65 under diverse pathological conditions including rats under ischemia/reperfusion insult as well as rat brain synaptosomes and primary neuronal cultures subjected to excessive stimulation with high concentration of KCl. We have shown that the formation of tGAD65 progressively increases with increasing stimulus concentration both in rat brain synaptosomes and primary rat embryo cultures. More importantly, direct cleavage of synaptic vesicle - associated fGAD65 by calpain was demonstrated and the resulting tGAD65 bearing the active site of the enzyme was detached from the synaptic vesicles. Vesicular GABA transport of the newly synthesized GABA was found to be reduced in calpain treated SVs. Furthermore, we also observed that the levels of tGAD65 in the focal cerebral ischemic rat brain tissue increased corresponding to the elevation of local glutamate as indicated by microdialysis. Moreover, the levels of tGAD65 was also proportional to the degree of cell death when the primary neuronal cultures were exposed to high KCl. Based on these observations, we conclude that calpain-mediated cleavage of fGAD65 is pathological, presumably due to decrease in the activity of synaptic vesicle - associated fGAD65 resulting in a decrease in the GABA synthesis - packaging coupling process leading to reduced GABA neurotransmission.

Buddhala, Chandana; Suarez, Marjorie; Modi, Jigar; Prentice, Howard; Ma, Zhiyuan; Tao, Rui; Wu, Jang Yen



Detection of ?-Aminobutyric Acid (GABA) by Longitudinal Scalar Order Difference Editing  

NASA Astrophysics Data System (ADS)

Two novel spectral editing techniques for the in vivo detection of ?-aminobutyric acid (GABA) are presented. The techniques rely on the generation of longitudinal scalar order (LSO) coherences, which in combination with J-difference editing results in the selective detection of GABA. The utilization of LSO coherences makes the editing sequences insensitive to phase and frequency instabilities. Furthermore, the spectral editing selectivity can be increased independent of the echo time, thereby opening the echo time for state-of-the-art water suppression and/or spatial localization techniques. The performance of the LSO editing techniques is theoretically demonstrated with product operator calculations and density matrix simulations and experimentally evaluated on phantoms in vitro and on human brain in vivo.

de Graaf, Robin A.; Rothman, Douglas L.



Systematic analysis of ?-aminobutyric acid (GABA) metabolism and function in the social amoeba Dictyostelium discoideum.  


While GABA has been suggested to regulate spore encapsulation in the social amoeba Dictyostelium discoideum, the metabolic profile and other potential functions of GABA during development remain unclear. In this study, we investigated the homeostasis of GABA metabolism by disrupting genes related to GABA metabolism and signaling. Extracellular levels of GABA are tightly regulated during early development, and GABA is generated by the glutamate decarboxylase, GadB, during growth and in early development. However, overexpression of the prespore-specific homologue, GadA, in the presence of GadB reduces production of extracellular GABA. Perturbation of extracellular GABA levels delays the process of aggregation. Cytosolic GABA is degraded by the GABA transaminase, GabT, in the mitochondria. Disruption of a putative vesicular GABA transporter (vGAT) homologue DdvGAT reduces secreted GABA. We identified the GABAB receptor-like family member GrlB as the major GABA receptor during early development, and either disruption or overexpression of GrlB delays aggregation. This delay is likely the result of an abolished pre-starvation response and late expression of several "early" developmental genes. Distinct genes are employed for GABA generation during sporulation. During sporulation, GadA alone is required for generating GABA and DdvGAT is likely responsible for GABA secretion. GrlE but not GrlB is the GABA receptor during late development. PMID:23548898

Wu, Yuantai; Janetopoulos, Chris



Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides  

SciTech Connect

Lithium trialkylborohydrides were found to effect rapid monodealkylation of phosphonic diesters, and this reaction was applied to the synthesis of alkylphosphonic acid 2-aminoethyl esters [H2N(CH2)2OP(OH)R, 4], a little-explored class of analogs of the inhibitory neurotransmitter ?-aminobutyric acid (GABA). Compound 4a (R = Me) proved to be a potent antagonist at human ?1 GABAC receptors (expressed in Xenopus laevis oocytes), with an IC50 of 11.1 M, but is inactive at ?1?2?2 GABAA receptors.

Chowdhury, Sarwat [University of Illinois, Chicago; Muni, Niraj J. [University of Illinois, Chicago; Greenwood, Nicholas P. [University of Illinois, Chicago; Pepperberg, Dr. David R. [University of Illinois, Chicago; Standaert, Robert F [ORNL



Isolation, characterization, and utilization of ?-aminobutyric acid (GABA)-producing lactic acid bacteria from Myanmar fishery products fermented with boiled rice  

Microsoft Academic Search

?-Aminobutyric acid (GABA)-producing lactic acid bacteria (LAB) were isolated from four types of Myanmar traditional fermented\\u000a fishery products with boiled rice. All of them belonged to the genus Lactobacillus, and comparison of the effects of these representatives on GABA accumulation in fermented fishery products with boiled rice\\u000a revealed that Lactobacillus farciminis D323 is the most effective strain as a starter

Su Myo Thwe; Takeshi Kobayashi; Tianyao Luan; Takaaki Shirai; Munenaka Onodera; Naoko Hamada-Sato; Chiaki Imada



Effects of the gamma-aminobutyrate transaminase inhibitors gabaculine and gamma-vinyl GABA on gamma-aminobutyric acid release from slices of rat cerebral cortex  

SciTech Connect

The release of (/sup 3/H)gamma-aminobutyric acid (GABA) from pre-loaded slices of rat cerebral cortex was investigated in the presence and absence of the GABA-transaminase inhibitors gabaculine and gamma-vinyl GABA. In the experiments carried out without an inhibitor, an ion-exchange column chromatographic technique was used to separate (/sup 3/H)GABA from tritiated metabolites released with it into the superfusate. The presence of gabaculine (5 microM) substantially reduced the Ca2+-dependence of the release of (/sup 3/H)GABA evoked by a 4 min 30 mM K+ pulse, whereas this was not appreciably reduced by the presence of gamma-vinyl GABA (2 mM or 10 mM). Nevertheless, the characteristics of (/sup 3/H)GABA release were not identical in the presence and absence of either inhibitor.

Bedwani, J.R.; Mehta, A.



Synthesis of novel gamma-aminobutyric acid (GABA) uptake inhibitors. 5.(1) Preparation and structure-activity studies of tricyclic analogues of known GABA uptake inhibitors.  


On the basis of the SAR of a series of known gamma-aminobutyric acid (GABA) uptake inhibitors, including 4 (SKF 89976), new tricyclic analogues have been prepared. These novel compounds are derivatives of nipecotic acid, guvacine, and homo-beta-proline, substituted at the nitrogen of these amino acids by various lipophilic moieties such as (10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)alkoxyalkyl or (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)alkoxyalkyl. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound in this new series, and it was found that several of the novel compounds showed a high potency comparable with that of the reference compounds 4, 5 (tiagabine), and 6 (CI-966). Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). One compound, (R)-1-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid (23), was selected for further biological investigations and showed a protective index comparable to or slightly better than that of the recently launched anticonvulsant product 5 ((R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid). PMID:11405652

Andersen, K E; Sørensen, J L; Lau, J; Lundt, B F; Petersen, H; Huusfeldt, P O; Suzdak, P D; Swedberg, M D



Modulation of the ?-aminobutyric acid (GABA) system by Passiflora incarnata L.  


Passiflora incarnata L. (Passifloraceae) is important in herbal medicine for treating anxiety or nervousness, Generalized Anxiety Disorder (GAD), symptoms of opiate withdrawal, insomnia, neuralgia, convulsion, spasmodic asthma, ADHD, palpitations, cardiac rhythm abnormalities, hypertension, sexual dysfunction and menopause. However, the mechanism of action is still under discussion. Despite gaps in our understanding of neurophysiological processes, it is increasingly being recognized that dysfunction of the GABA system is implicated in many neuropsychiatric conditions, including anxiety and depressive disorders. Therefore, the in vitro effects of a dry extract of Passiflora incarnata (sole active ingredient in Pascoflair® 425 mg) on the GABA system were investigated. The extract inhibited [(3) H]-GABA uptake into rat cortical synaptosomes but had no effect on GABA release and GABA transaminase activity. Passiflora incarnata inhibited concentration dependently the binding of [(3) H]- SR95531 to GABA(A) -receptors and of [(3) H]-CGP 54626 to GABA(B) -receptors. Using the [(35) S]-GTP?S binding assay Passiflora could be classified as an antagonist of the GABA(B) receptor. In contrast, the ethanol- and the benzodiazepine-site of the GABA(A) -receptor were not affected by this extract. In conclusion, the first evidence was shown that numerous pharmacological effects of Passiflora incarnata are mediated via modulation of the GABA system including affinity to GABA(A) and GABA(B) receptors, and effects on GABA uptake. PMID:21089181

Appel, Kurt; Rose, Thorsten; Fiebich, Bernd; Kammler, Thomas; Hoffmann, Christine; Weiss, Gabriele



Regulation of native GABA A receptors by PKC and protein phosphatase activity  

Microsoft Academic Search

Rationale and objective: Protein kinase C (PKC) modulation of ionotropic receptors is a common mechanism for regulation of channel function. The effects of PKC and phosphatase activation on native gamma-amino- butyric acid (GABAA) receptors in adult brain are unknown. Previous studies of recombinant GABAA receptors have provided evidence that PKC activation inhibits receptor function, whereas other studies suggest that PKC

Sandeep Kumar; Rahul T. Khisti; A. Leslie Morrow



Efficient gamma-aminobutyric acid bioconversion by employing synthetic complex between glutamate decarboxylase and glutamate/GABA antiporter in engineered Escherichia coli.  


Gamma-aminobutyric acid (GABA) is a precursor of one of the most promising heat-resistant biopolymers, Nylon-4, and can be produced by the decarboxylation of monosodium glutamate (MSG). In this study, a synthetic protein complex was applied to improve the GABA conversion in engineered Escherichia coli. Complexes were constructed by assembling a single protein-protein interaction domain SH3 to the glutamate decarboxylase (GadA and GadB) and attaching a cognate peptide ligand to the glutamate/GABA antiporter (GadC) at the N-terminus, C-terminus, and the 233rd amino acid residue. When GadA and GadC were co-overexpressed via the C-terminus complex, a GABA concentration of 5.65 g/l was obtained from 10 g/l MSG, which corresponds to a GABA yield of 93 %. A significant increase of the GABA productivity was also observed where the GABA productivity increased 2.5-fold in the early culture period due to the introduction of the synthetic protein complex. The GABA pathway efficiency and GABA productivity were enhanced by the introduction of the complex between Gad and glutamate/GABA antiporter. PMID:23729191

Le Vo, Tam Dinh; Ko, Ji-seun; Park, Si Jae; Lee, Seung Hwan; Hong, Soon Ho



Distribution and effects of PACAP, VIP, nitric oxide and GABA in the gut of the African clawed frog Xenopus laevis.  


The distribution and possible effects on gastrointestinal motility of pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), nitric oxide and gamma-amino-butyric acid (GABA) were investigated in the African clawed frog (Xenopus laevis) using immunohistochemistry and in vitro strip preparations. PACAP- and VIP-immunoreactive nerve fibres were common in the myenteric plexus as well as in the longitudinal and circular muscle layers all along the gastrointestinal tract. Double labelling demonstrated a close correlation between PACAP and VIP immunoreactivities, indicating that the two neurotransmitters are colocalised within the enteric nervous system. Occasionally, PACAP- and VIP-positive nerve cell bodies were seen in the myenteric or submucous plexa. In addition, VIP immunoreactivity coexisted with helospectin immunoreactivity. Nitric oxide synthase (NOS)-immunoreactive nerve cells were found in the myenteric plexus at an average density for the whole gastrointestinal tract of 4584 +/- 540 cells cm(-2). The NOS-immunoreactive nerve cells were usually multipolar with an average size of 11.3 +/- 3.7 x 23.2 +/- 6.6 microm. Some NOS-immunoreactive nerve fibres were VIP-immunoreactive but not all VIP-positive fibres showed NOS immunoreactivity. GABA immunoreactivity was found in nerve fibres and nerve cells in the myenteric plexus of all regions of the gut. Few GABA-immunoreactive nerve fibres were VIP-immunoreactive. PACAP 27, VIP, sodium nitroprusside (a nitric oxide donor; NaNP) and GABA caused similar responses on spontaneously contracting circular preparations of the cardiac stomach of X. laevis. The mean force developed was decreased, mainly by a reduction in resting tension, while the amplitude of contractions was not necessarily affected. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) increased the mean force developed, indicating a nitrergic tone in the preparations. In contrast, PACAP 27, VIP, NaNP, GABA and L-NAME had no significant effect on longitudinal strip preparations from the duodenum. These results indicate that PACAP, VIP, nitric oxide and GABA, which are known to be important inhibitory neurotransmitters in other vertebrates, are widely spread in the enteric nervous system of Xenopus laevis and may be involved in the inhibitory control of gastric motility. Although no effect of PACAP, VIP, nitric oxide or GABA on the longitudinal strips of the duodenum was seen in this study, this does not rule out the possibility that they might play an important role in controlling intestinal motility as well. PMID:11919271

Olsson, Catharina



GABA (Gamma Aminobutyric Acid) Involvement in the Action of Anti-Anxiety Drugs.  

National Technical Information Service (NTIS)

GABA involvement in the action of anti-anxiety drugs were studied. Because GABA is contained exclusively within Glial cells in the rat superior cervical ganglion and pineal gland, they were chosen as the models in determining the role of glial GABA in syn...

A. Suria



Treatment of self-injurious behaviour with a GABA (gamma-aminobutyric acid) analogue.  


Self-injurious behaviour (SIB) is not uncommon in the severely subnormal. Corbett (1975) found the incidence in several reported series to vary between 3.5 per cent and almost 40 per cent, and Van Velzen (1973), in a survey of ten institutions in the Netherlands, found it present in 584 patients out of almost 2,000 (30.3 per cent). Treatment is notoriously difficult and many kinds have been tried including physical restraint, drug regimes, and electric shock aversion therapy. An account is given here of a drug trial using baclofen, a gamma-aminobutyric acid (GABA) analogue that crosses the blood brain barrier. GABA, in addition to being a muscle relaxant, is also a major inhibitor in many areas of the brain, including the cortex and basal ganglia (Callingham, 1972) andit was presumed by the author that some severely subnormal defectives have damage in these areas and hence might be deficient in this inhibitor. The trial commenced with a preliminary period during which the reactions of patients to the drug at different dose levels were observed. This was followed by a double-blind cross-over trial in patients who had already shown improvement. PMID:390158

Primrose, D A



gamma-Aminobutyric acidA (GABAA) receptors modulate [3H]GABA release from isolated neuronal growth cones in the rat.  


Potassium-induced release of gamma-[3H]aminobutyric acid [( 3H]GABA) from a growth cone-enriched fraction isolated from neonatal rat forebrain was inhibited by the GABA mimetic muscimol in a dose-dependent manner (IC50 15 nM). The GABA antagonist bicuculline completely reversed the effect of muscimol. Bicuculline alone slightly potentiated the K+-induced release of [3H]GABA. Baclofen, a proposed selective agonist for a bicuculline-insensitive GABAB receptor, was found to cause only a slight reduction in the K+-induced release of [3H]GABA. These results are compatible with the presence of a negative feedback mechanism mediated by GABAA receptors for controlling [3H]GABA release from growth cones of the developing rat forebrain. PMID:2989732

Lockerbie, R O; Gordon-Weeks, P R



Synthesis of novel GABA uptake inhibitors. Part 6: preparation and evaluation of N-Omega asymmetrically substituted nipecotic acid derivatives.  


In a previous series of potent GABA uptake inhibitors published from this laboratory, we noticed that asymmetry in the substitution pattern of the bis-aromatic moiety in known GABA uptake inhibitors such as 4 [1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid] and 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid] was beneficial for high affinity. This led us to investigate asymmetric analogues of known symmetric GABA uptake inhibitors in which one of the aryl groups has been exchanged with an alkyl, alkylene or cycloalkylene moiety as well as other modifications in the lipophilic part. The in vitro values for inhibition of [(3)H]-GABA uptake in rat synaptosomes was determined for each compound, and it was found that several of the novel compounds inhibit GABA uptake as potently as their known symmetrical reference analogues. Several of the novel compounds were also evaluated for their ability to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in vivo. Some of the compounds, for example 18 [(R)-1-(2-(((1,2-bis(2-fluorophenyl)ethylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid], show a high in vivo potency and protective index comparable with that of our recently launched anticonvulsant product, 5 [(R)-1-(4,4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid], and may therefore serve as second-generation drug candidates. PMID:11597457

Andersen, K E; Lau, J; Lundt, B F; Petersen, H; Huusfeldt, P O; Suzdak, P D; Swedberg, M D



Enhancement of ?-aminobutyric acid (GABA) in Nham (Thai fermented pork sausage) using starter cultures of Lactobacillus namurensis NH2 and Pediococcus pentosaceus HN8.  


The aim was to produce Nham that was enriched with ?-aminobutyric acid (GABA); therefore two GABA producing lactic acid bacteria (Pediococcus pentosaceus HN8 and Lactobacillus namurensis NH2) were used as starter cultures. By using the central composite design (CCD) we showed that addition of 0.5% monosodium glutamate (MSG) together with an inoculum size of roughly 6logCFU/g of each of the two strains produced a maximal amounts of GABA (4051mg/kg) in the 'GABA Nham' product. This was higher than any current popular commercial Nham product by roughly 8 times. 'GABA Nham' with the additions of both starters and MSG (TSM) supported maximum populations of lactic acid bacteria (LAB) with a minimum of yeasts and no staphylococci or molds when compared to the controls that had no addition of any starters or MSG (TNN), or only the addition of MSG (TNM), or with only the starter (TSN). Based on proximate analysis among the Nham sets, 'GABA Nham' was low in fat, carbohydrate and energy although its texture and color were slightly different from the control (TNN). However, sensory evaluations of 'GABA Nham' were more acceptable than the controls and commercial Nham products for all tested parameters. Hence, a unique novel 'GABA Nham' fermented pork sausage was successfully developed. PMID:24135673

Ratanaburee, Anussara; Kantachote, Duangporn; Charernjiratrakul, Wilawan; Sukhoom, Ampaitip



(?)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-ene Carboxylic Acid. A Potent GABA Aminotransferase Inactivator that Irreversibly Inhibits through an Elimination-Aromatization Pathway†  

PubMed Central

Inhibition of ?-aminobutyric acid aminotransferase (GABA-AT) raises the concentration of GABA, an inhibitory neurotransmitter in human brain, which could have therapeutic applications for a variety of neurological diseases including epilepsy. Based on studies of several previously synthesized conformationally-restricted GABA-AT inhibitors, (±)- (1S,2R,5S)-5-amino-2-fluorocyclohex-3-ene carboxylic acid (12) was designed as a mechanismbased inactivator. This compound was shown to irreversibly inhibit GABA-AT; substrate protects the enzyme from inactivation. Mechanistic experiments demonstrated the loss of one fluoride ion per active site during inactivation and the formation of N-m-carboxyphenylpyridoxamine 5?-phosphate (26), the same product generated by inactivation of GABA-AT by gabaculine (8). An elimination-aromatization mechanism is proposed to account for these results.

Wang, Zhiyong; Yuan, Hai; Nikolic, Dejan; Van Breemen, Richard B.; Silverman, Richard B.



Neocortical hyperexcitability after GABA withdrawal in vitro  

Microsoft Academic Search

The sharp interruption of the intracortical instillation of exogenous ?-aminobutyric acid (GABA), generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal last several days or weeks. The present work reports that GABA withdrawal-induced hyperexcitability can be produced in vitro: a sudden withdrawal of GABA (5 mM; 120 min) or benzodiazepine (60 ?M flunitrazepam) from the superfusion, induced a

E Calixto; A. M López-Colomé; C Casasola; T Montiel; J Bargas; S Brailowsky



The GABA Receptors  

Microsoft Academic Search

?-Aminobutyric acid (GABA), an amino acid neurotransmitter, is widely distributed throughout the neuraxis. Two pharmacologically\\u000a and molecularly distinct GABA receptors have been identified, GABAA and GABAB. GABAA receptors are pentameric ligand-gated chloride-ion channels, whereas GABAB receptors are heterodimeric G protein-coupled sites. Although GABAA receptor subtypes can display pharmacological differences, the two molecularly distinct GABAB receptors have similar substrate specificities, limiting

S. J. Enna


The GABA postsynaptic membrane receptor-ionophore complex  

Microsoft Academic Search

Summary The function of the inhibitory neurotransmitter, ?-aminobutyric acid (GABA), has been implicated in the mode of action of many drugs which excite or depress the central nervous system. Many convulsant agents appear to block GABA action whereas anticonvulsants enhance GABA action. Some of these drug effects involve altered GABA-mediated synaptic transmission at the level of GABA biosynthesis, release from

Richard W. Olsen



GABA and mood disorders: a brief review and hypothesis  

Microsoft Academic Search

Considerable evidence implicates the neurotransmitter ?-aminobutyric acid (GABA) in the biochemical pathophysiology of mood disorders. Animal models of depression show regional brain GABA deficits and GABA agonists have antidepressant activity in these models. Somatic treatments for depression and mania upregulate the GABAB receptor, similar to the effect of GABA agonists. Clinical data indicate that decreased GABA function accompanies depressed or

Frederick Petty



Presumed case of "stiff-horse syndrome" caused by decreased gamma-aminobutyric acid (GABA) production in an American Paint mare.  


Glutamic acid decarboxylase (GAD) converts glutamic acid into the inhibitory neurotransmitter ?-aminobutyric acid (GABA). Increased serum GAD (auto) antibody concentrations were found in a mare with increased postural musculature tone resulting in stiffness and recumbence. The mare was treated with dexamethasone which resulted in resolution of clinical signs and decreased GAD antibody concentrations. PMID:22753968

Purcell, Tawna Backman; Sellers, Ann Davidson; Goehring, Lutz S



Presumed case of "stiff-horse syndrome" caused by decreased gamma-aminobutyric acid (GABA) production in an American Paint mare  

PubMed Central

Glutamic acid decarboxylase (GAD) converts glutamic acid into the inhibitory neurotransmitter ?-aminobutyric acid (GABA). Increased serum GAD (auto) antibody concentrations were found in a mare with increased postural musculature tone resulting in stiffness and recumbence. The mare was treated with dexamethasone which resulted in resolution of clinical signs and decreased GAD antibody concentrations.

Purcell, Tawna Backman; Sellers, Ann Davidson; Goehring, Lutz S.



Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase  

PubMed Central

Two principal neurotransmitters are involved in the regulation of mammalian neuronal activity, namely, ?-aminobutyric acid (GABA), an inhibitory neurotransmitter, and L-glutamic acid, an excitatory neurotransmitter. Low GABA levels in the brain have been implicated in epilepsy and several other neurological diseases. Because of GABA’s poor ability to cross the blood-brain barrier (BBB), a successful strategy to raise brain GABA concentrations is the use of a compound that does cross the BBB and inhibits or inactivates GABA aminotransferase (GABA-AT), the enzyme responsible for GABA catabolism. Vigabatrin, a mechanism-based inactivator of GABA-AT, is currently a successful therapeutic for epilepsy, but has harmful side effects, leaving a need for improved GABA-AT inactivators. Here, we report the synthesis and evaluation of a series of heteroaromatic GABA analogues as substrates of GABA-AT, which will be used as the basis for the design of novel enzyme inactivators.

Hawker, Dustin D.; Silverman, Richard B.



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 ...


Gamma-aminobutyric acid (GABA) receptor rho (GABRR) polymorphisms and risk for essential tremor.  


Some clinical and experimental data suggest a possible role of gamma-aminobutyrate (GABA)-ergic mechanisms in the pathophysiology of essential tremor (ET), such as the improvement of ET with some GABAergic drugs and the development of an experimental model of ET in GABA A receptor alpha-1 knockout mice (postural and kinetic tremor and motor incoordination similar to human ET). To investigate the possible association between the GABA receptor subtype rho1, rho2, and rho3 (GABRR1, GABRR2, and GABRR3) genotypes and allelic variants of the single nucleotide polymorphisms GABRR1-M26V (Met26Val, rs12200969), GABRR1-H27R (His26Arg, rs1186902), GABRR2-T455M (Thr55Met, rs282129), and GABRR3-Y205X (Tyr205X, rs832032), and the risk for ET, we studied the frequency of the previously mentioned GABRR genotypes and allelic variants in 200 patients with ET and 250 healthy controls using TaqMan genotyping. The frequencies of the GABBR1 genotypes and allelic variants of the studied polymorphisms did not differ significantly between patients with ET and controls, and were unrelated with the age at onset of tremor, gender, localization of tremor, and response of tremor to ethanol. These data suggest that the single nucleotide polymorphisms studied in the GABBR genes are not related to the risk for ET. PMID:20820800

García-Martín, Elena; Martínez, Carmen; Alonso-Navarro, Hortensia; Benito-León, Julián; Lorenzo-Betancor, Oswaldo; Pastor, Pau; Puertas, Inmaculada; Rubio, Lluisa; López-Alburquerque, Tomás; Agúndez, José A G; Jiménez-Jiménez, Félix Javier



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

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 ?-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.

Brozoski, Thomas; Odintsov, Boris; Bauer, Carol



Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase.  


Two principal neurotransmitters are involved in the regulation of mammalian neuronal activity, namely, ?-aminobutyric acid (GABA), an inhibitory neurotransmitter, and L-glutamic acid, an excitatory neurotransmitter. Low GABA levels in the brain have been implicated in epilepsy and several other neurological diseases. Because of GABA's poor ability to cross the blood-brain barrier (BBB), a successful strategy to raise brain GABA concentrations is the use of a compound that does cross the BBB and inhibits or inactivates GABA aminotransferase (GABA-AT), the enzyme responsible for GABA catabolism. Vigabatrin, a mechanism-based inactivator of GABA-AT, is currently a successful therapeutic for epilepsy, but has harmful side effects, leaving a need for improved GABA-AT inactivators. Here, we report the synthesis and evaluation of a series of heteroaromatic GABA analogues as substrates of GABA-AT, which will be used as the basis for the design of novel enzyme inactivators. PMID:22944334

Hawker, Dustin D; Silverman, Richard B



Influence of a Gamma Amino Acid on the Structures and Reactivity of Peptide a3 Ions  

PubMed Central

Collision-induced dissociation of protonated AGabaAIG (where Gaba is gamma-amino butyric acid, NH2-(CH2)3-COOH) leads to an unusually stable a3 ion. Tandem mass spectrometry and theory are used here to probe the enhanced stability of this fragment, whose counterpart is not usually observed in CID of protonated peptides containing only alpha amino acids. Experiments are carried out on the unlabelled and 15N-Ala labeled AGabaAIG (labeled separately at residue one or three) probing the b3, a3, a3-NH3 (a3*), and b2 fragments while theory is used to characterize the most stable b3, a3, and b2 structures and the formation and dissociation of the a3 ion. Our results indicate the AGabaA oxazolone b3 isomer undergoes head-to-tail macrocyclization and subsequent ring opening to form the GabaAA sequence isomer while this chemistry is energetically disfavored for the AAA sequence. The AGabaA a3 fragment also undergoes macrocyclization and rearrangement to form the rearranged imine-amide isomer while this reaction is energetically disfavored for the AAA sequence. The barriers to dissociation of the AGabaA a3 ion via the a3?b2 and a3?a3* channels are higher than the literature values reported for the AAA sequence. These two effects provide a clear explanation for the enhanced stability of the AGabaA a3 ion.

Bernier, Matthew C.; Paizs, Bela; Wysocki, Vicki H.



Genetic variability in glutamic acid decarboxylase genes: associations with post-traumatic seizures after severe TBI.  


Post traumatic seizures (PTS) occur frequently after traumatic brain injury (TBI). Since gamma-amino butyric acid (GABA) neurotransmission is central to excitotoxicity and seizure development across multiple models, we investigated how genetic variability for glutamic acid decarboxylase (GAD) influences risk for PTS. Using both a tagging and functional single nucleotide polymorphism (SNP) approach, we genotyped the GAD1 and GAD2 genes and linked them with PTS data, regarding time to first seizure, obtained for 257 adult subjects with severe TBI. No significant associations were found for GAD2. In the GAD1 gene, the tagging SNP (tSNP) rs3828275 was associated with an increased risk for PTS occurring <1 wk. The tSNP rs769391 and the functional SNP rs3791878 in the GAD1 gene were associated with increased PTS risk occurring 1 wk-6 mo post-injury. Both risk variants conferred an increased susceptibility to PTS compared to subjects with 0-1 risk variant. Also, those with haplotypes having both risk variants had a higher PTS risk 1 wk-6 mo post-injury than those without these haplotypes. Similarly, diplotype analysis showed those with 2 copies of the haplotype containing both risk alleles were at the highest PTS risk. These results implicate genetic variability within the GABA system in modulating the development of PTS. PMID:22840783

Darrah, Shaun D; Miller, Megan A; Ren, Dianxu; Hoh, Nichole Z; Scanlon, Joelle M; Conley, Yvette P; Wagner, Amy K



Effects of poly-?-glutamic acid on serum and brain concentrations of glutamate and GABA in diet-induced obese rats  

PubMed Central

Poly-gamma-glutamic acid (?-PGA) is a mucilaginous and biodegradable compound produced by Bacillus subtilis from fermented soybeans, and is found in the traditional Korean soy product, cheongkukjang. This study was carried out to evaluate the effects of ?-PGA from a food source on the concentration of the neurotransmitter GABA and its metabolic precursor glutamate in diet-induced obese rats. Eight-week old male Sprague-Dawley rats (n=60) were used. The rats were divided into two groups and obesity was induced by providing either a 10% control fat or 45% high fat diet for 5 weeks. The rats were then blocked into 6 groups and supplemented with a 0.1% ?-PGA diet for 4 weeks. After sacrifice, brain and serum GABA and glutamate concentrations were analyzed by high performance liquid chromatography with fluorometric detection. The rats fed the high fat diet had significantly increased body weights. ?-PGA supplementation significantly increased serum concentrations of glutamate and GABA in the control fat diet groups while this effect was not found in the high fat groups. In the brain, glutamate concentrations were significantly higher in the ?-PGA supplemented groups both in rats fed the normal and high fat diets than in the no ?-PGA controls. GABA concentrations showed the same tendency. The results indicated that ?-PGA intake increased GABA concentrations in the serum and brain. However, the effects were not shown in obese rats.

Lee, Hyesung; Chang, Moon-Jeong



Effect of Acceleration on Brain Metabolites Einfluss der Beschleunigung Auf Stoffwechselmetaboliten des Gehirns.  

National Technical Information Service (NTIS)

Acceleration effects (+Gz) were investigated. The fast glutamate depression can be explained only partly by the accompanying gamma amino butyric acid (GABA) increase, the concentration of which depends mainly on enzyme activity converting glutamate into G...

G. Schaefer



Detection of amino acids in human nasal mucosa using microdialysis technique: increased glutamate in allergic rhinitis.  


Amino acids, the smaller basic biochemical units of neuropeptides, have not been evaluated in the nasal cavity. The purpose of this study was to measure the concentration of neurotransmitting amino acids of the central nervous system, glutamate, aspartate, serine, taurine (2-aminoethane sulfonic acid; a conditionally essential amino acids), and GABA (gamma-amino-butyric acid; an amino acid produced in the brain), in nasal mucosa of allergic rhinitis patients and normal controls using a microdialysis technique. A microdialysis probe appropriate for use on human nasal mucosa was developed using Cuprophan hollow fiber. Glutamate concentration in allergy group was significantly higher (p = 0.004) than in control group, while the concentrations of the other four amino acids showed no significant difference between the two groups. Our findings and review of the literature suggest that glutamate is one of the most potent neurotransmitters associated with the parasympathetic nerve in the nasal cavity, and that the microdialysis technique is useful in studying the pharmacokinetics in situ and local organ chemistry of the nasal cavity. PMID:16572741

Lee, Hyun-Sun; Goh, Eui-kyung; Wang, Soo-Geun; Chon, Kyong-Myong; Kim, Hae-Kyu; Roh, Hwan-Jung



Gamma hydroxybutyrate is not a GABA agonist.  


Gamma hydroxybutyrate (GHB) is primarily known and used as a relatively specific inhibitor of central DA release. However, it is also widely assumed to be an agonist or prodrug of gamma-aminobutyric acid (GABA) and its central activity has been attributed to an action exerted at GABA receptors. Nevertheless, there is compelling evidence that: (1) GHB formation may occur independently of GABA; (2) GHB is behaviorally, biochemically and physiologically distinct from GABA in many ways, and does not consistently effect GABAA or GABAB agonist induced responses; (3) GHB has little effect on either GABAA or GABAB receptors at less than millimolar concentrations. Consequently, GHB does not appear to be either a GABA prodrug or a GABA agonist. However, the GHB metabolite gamma butyrolactone (GBL) may possess some limited GABA agonist activity. PMID:8931105

Feigenbaum, J J; Howard, S G



trans-4-Amino-2-methylbut-2-enoic acid (2-MeTACA) and (+/-)-trans-2-aminomethylcyclopropanecarboxylic acid ((+/-)-TAMP) can differentiate rat rho3 from human rho1 and rho2 recombinant GABA(C) receptors.  


1. This study investigated the effects of a number of GABA analogues on rat rho3 GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. 2. The potency order of agonists was muscimol (EC(50)=1.9 +/- 0.1 microM) (+)-trans-3-aminocyclopentanecarboxylic acids ((+)-TACP; EC(50)=2.7 +/- 0.9 microM) trans-4-aminocrotonic acid (TACA; EC(50)=3.8 +/-0.3 microM) GABA (EC(50)=4.0 +/- 0.3 microM) > thiomuscimol (EC(50)=24.8 +/- 2.6 microM) > (+/-)-cis-2-aminomethylcyclopropane-carboxylic acid ((+/-)-CAMP; EC(50)=52.6 +/-8.7 microM) > cis-4-aminocrotonic acid (CACA; EC(50)=139.4 +/- 5.2 microM). 3. The potency order of antagonists was (+/-)-trans-2-aminomethylcyclopropanecarboxylic acid ((+/-)-TAMP; K(B)=4.8+/-1.8 microM) (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA; K(B)=4.8 +/-0.8 microM) > (piperidin-4-yl)methylphosphinic acid (P4MPA; K(B)=10.2+/-2.3 microM) 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; K(B)=10.2+/-0.3 microM) imidazole-4-acetic acid (I4AA; K(B)=12.6+/-2.7 microM) > 3-aminopropylphosphonic acid (3-APA; K(B)=35.8+/-13.5 microM). 4. trans-4-Amino-2-methylbut-2-enoic acid (2-MeTACA; 300 microM) had no effect as an agonist or an antagonist indicating that the C2 methyl substituent is sterically interacting with the ligand-binding site of rat rho3 GABA(C) receptors. 5. 2-MeTACA affects rho1 and rho2 but not rho3 GABA(C) receptors. In contrast, (plus minus)-TAMP is a partial agonist at rho1 and rho2 GABA(C) receptors, while at rat rho3 GABA(C) receptors it is an antagonist. Thus, 2-MeTACA and (+/-)-TAMP could be important pharmacological tools because they may functionally differentiate between rho1, rho2 and rho3 GABA(C) receptors in vitro. PMID:11861315

Vien, Jimmy; Duke, Rujee K; Mewett, Kenneth N; Johnston, Graham A R; Shingai, Ryuzo; Chebib, Mary



GABA interaction with lipids in organic medium  

SciTech Connect

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.

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



GABA Neurotransmitter  

NSDL National Science Digital Library

GABA occurs in 30-40% of all synapses-only glutamate is more widely distributed. Neurons in every region of the brain use GABA to fine-tune neurotransmission. Increasing GABA at the neuronal synapse inhibits the generation of the action potential of the neuron, thereby making it less likely to excite nearby neurons. A single neuron may have thousands of other neurons synapsing onto it. Some of these release activating (or depolarizing) neurotransmitters; others release inhibitory (or hyperpolarizing) neurotransmitters. GABA is the primary inhibitory neurotransmitter, which means it decreases the neuron's action potential. When the action potential drops below a certain level, known as the threshold potential, the neuron will not generate action potentials and thus not excite nearby neurons. The nucleus of a neuron is located in the cell body. Extending out from the cell body are dendrites and axons. Dendrites conduct impulses toward the cell body, Axons conducting impulses away from the cell body. A recording electrode has been attached to a voltmeter to record the charge across the cell membrane, the thin layer that controls movement in and out of the neuron. The resting potential in excitable neurons is usually around -65 to -70 millivolts (mV), which can be seen on the voltmeter. Excitatory synapses reduce the membrane potential: The synapses labeled A, B, and C are excitatory (e.g. glutamate ACH). These synapses release activating neurotransmitters, which reduce the resting potential of the neuron. If the voltage reaches the threshold potential, typically around -50 mv, an action potential is generated, which will travel down the axon, where it will communicate with a nearby cell. The strength of the stimuli that produce an action potential is important only insomuch as it reaches threshold potential. The resultant action potential is always the same, whether it was created by relatively strong or relatively weak stimuli. action potential is a constant. Decreasing the action potential: GABA is the primary inhibitory neurotransmitter, which means it decreases the neuronâÃÂÃÂs action potential. When the action potential drops below the threshold potential, the neuron will not excite nearby neurons. Exitatory PostSynaptic Potential (EPSP): The Exitatory PostSynaptic Potential (EPSP) of a single excitatory synapse is not sufficient to reach the threshold of the neuron. Rather, when a number of EPSPs are created in quick succession, their charges sum together. It is the combined sum of these EPSPs that creates an action potential Activation of inhibitory synapses such as GABA, on the other hand, makes resting potential more negative. This hyperpolarization is called an inhibitory postsynaptic potential (IPSP). Activation of inhibitory synapses (D and E) makes the resting potential of the neuron more negative. The resulting IPSP may also prevent what would otherwise have been effective EPSPs from triggering an action potential. It is the total summation of the EPSPs and IPSPs that determines whether a neuronâÃÂÃÂs charge is sufficient to cross the potential threshold.



Amino Acids and Sugars in the Gas Phase: Microwave Data for Astrochemistry  

NASA Astrophysics Data System (ADS)

Microwave spectroscopy, considered the most definitive gas phase structural probe, can distinguish between different conformational structures since they have unique spectroscopic constants and give separate rotational spectra. However it has been limited to molecular specimens having an appreciable vapor pressure. In general, molecules of biological importance have low vapor pressures and tend to undergo degradation upon heating. The combination of laser ablation with Fourier transform microwave spectroscopy in supersonic jets (LA-MB-FTMW) which overcomes the problems of thermal decomposition has rendered accessible the gas phase structural studies of these molecules. To date different ?-, ?- and ?-amino acids have been studied using this technique. Even in conformationally challenging systems the preferred conformations can be identified by rotational spectroscopy, as has been illustrated with the assignment of seven low-energy conformers in serine and threonine, six in cysteine and aspartic acid , and nine in ?-amino butyric (gaba). This technique has been successfully applied to the study of monosaccarides. Three conformers of the prototypes ?-D-glucose and ?-D-glucose have been characterized for the first time in the gas phase. After the first experimental observation of the monohydrated cluster of glycine, complexes between amino acids and nitrogen bases with water have also been investigated to obtain information on the changes induced in the conformational or tautomeric preferences by the addition of solvent molecules. The information given here is relevant for the unambiguous identification of these amino acids and sugars in the interstellar medium.

Mata, S.; Cabezas, C.; Varela, M.; Peña, I.; Perez, C.; Blanco, S.; Sanz, M. E.; Lopez, J. C.; Alonso, J. L.



In intact islets interstitial GABA activates GABA(A) receptors that generate tonic currents in ?-cells.  


In the rat islets ?-aminobutyric acid (GABA) is produced by the ?-cells and, at least, the ?-cells express the GABA(A) receptors (GABA(A) channels). In this study, we examined in intact islets if the interstitial GABA activated the GABA(A) receptors. We used the patch-clamp technique to record whole-cell and single-channel currents and single-cell RT-PCR to identify the cell-type we recorded from, in the intact rat islets. We further identified which GABA(A) receptor subunits were expressed. We determined the cell-type of 43 cells we recorded from and of these 49%, 28% and 7% were ?, ? and ?-cells, respectively. In the remaining 16% of the cells, mRNA transcripts of more than one hormone gene were detected. The results show that in rat islets interstitial GABA activates tonic current in the ?-cells but not in the ?-cells. Seventeen different GABA(A) receptor subunits are expressed with high expression of ?1, ?2, ?4, ?6, ?3, ?1, ?, ?1, ?2 and ?3 subunits whereas no expression was detected for ?5 or ? subunits. The abundance of the GABA(A) receptor subunits detected suggests that a number of GABA(A) receptor subtypes are formed in the islets. The single-channel and tonic currents were enhanced by pentobarbital and inhibited by the GABA(A) receptor antagonist SR-95531. The single-channel conductance ranged from 24 to 105 pS. Whether the single-channel conductance is related to subtypes of the GABA(A) receptor or variable interstitial GABA concentrations remains to be determined. Our results reveal that GABA is an extracellular signaling molecule in rat pancreatic islets and reaches concentration levels that activate GABA(A) receptors on the glucagon-releasing ?-cells. PMID:23826240

Jin, Yang; Korol, Sergiy V; Jin, Zhe; Barg, Sebastian; Birnir, Bryndis



Vertebrate GABA receptors  

Microsoft Academic Search

Physiologic-pharmacologic studies in vivo and with tissue cultures have revealed that synaptic GABA receptors exist in the vertebrate CNS. The GABA antagonist, bicuculline, can be used to detect synaptic GABA receptors in both the presence and absence of Na+, even though GABA binding to cerebral subcellular fractions occurs mainly to transport (uptake) receptors in the presence of Na+.

Francis V. DeFeudis



GABA-transaminase and glutamic acid decarboxylase changes in the brain of rats treated with pyrithiamine  

Microsoft Academic Search

Pyrithiamine, a thiamine phosphokinase inhibitor, was fed to rats on a thiamine-deficient diet, producing weight loss, ataxia and loss of righting reflex in 10 days. Some rats were then sacrificed; others were returned to a normal diet, to be sacrificed only when their weight had returned to pre-experimental levels. Rats were sacrificed for assay of glutamic acid decarboxylase (GAD) and

Sharlene G. Thompson; Edith G. McGeer



Selective Susceptibility to Inhibitors of GABA Synthesis and Antagonists of GABA A Receptor in Rats with Genetic Absence Epilepsy  

Microsoft Academic Search

Thalamocortical spike-and-wave discharges characterize the nonconvulsive absence seizures that occur spontaneously in genetic absence epilepsy rats from Strasbourg (GAERS), a selected strain of Wistar rats. GABA is crucial in the generation of absence seizures. The susceptibility to convulsions induced by threshold doses of various GABA receptor antagonists and inhibitors of GABA synthesis, kainic acid and strychnine, was compared in GAERS

Marguerite Vergnes; Any Boehrer; Sophie Reibel; Simone Simler; Christian Marescaux



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

ERIC Educational Resources Information Center

|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…

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



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

ERIC Educational Resources Information Center

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…

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



Comparison of bioactive components in GABA tea and green tea produced in Taiwan  

Microsoft Academic Search

The aim of this study is to investigate the bioactive components of GABA (?-aminobutyric acid) tea as compared with green tea produced in Taiwan. Using in total 56 tea samples (28 green tea and 28 GABA tea), moisture content, Hunter L, a and b values, phenolic compounds, amino acids including GABA, fatty acids and ascorbic acid were determined. The results

Hsueh Fang Wang; Yung Sheng Tsai; Mu Lien Lin; Andi Shau-mei Ou



The Plasticizer Di(2-ethylhexyl) Phthalate Modulates ??-Aminobutyric Acid Type A and Glycine Receptor Function  

Microsoft Academic Search

INTRODUCTION: Intravenous (IV) fluid bags made of polyvinyl chloride (PVC) often contain the plasticizer di(2-ethylhexyl) phthalate (DEHP) to make the PVC flexible. Phthalate esters have been reported to inhibit neuronal nicotinic acetylcholine receptors, which are sensitive to many inhaled anesthetics. This raises the possi- bility that DEHP might modulate the function of other cys-loop receptors, such as -amino butyric acid

Liya Yang; Pavle S. Milutinovic; Robert J. Brosnan; Edmond I Eger; James M. Sonner



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


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

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



Glutamate, GABA and epilepsy.  


The nature and value of various animal models of epilepsy for the study and understanding of the human epilepsies are reviewed, with special reference to the ILAE classification of seizures. Kindling as a model of complex-partial seizures with secondary generalisation is treated in detail, dwelling principally on the evidence that the neurotransmitters glutamate and GABA are centrally involved in the kindling process. Kindling in the entorhinal cortex-hippocampus system and its relationship to LTP are analysed in detail. Changes in amino acid content in animal and human brain tissue following onset of the epileptic state are reviewed with special reference to glutamate and GABA. Studies of changes in the extent of basal and stimulus-evoked release of glutamate and GABA both in vivo (microdialysis) and in vitro (brain slices) are evaluated. This includes both kindling and other models of epilepsy, and microdialysis of human patients with epilepsy. Experiments which study the influence of pre-synaptic metabotropic glutamate receptors on glutamate release, and consequently on the extent of electrical kindling, are described. This pre-synaptic control of glutamate release can be studied using synaptosomes. The significance of the ability of focal intracerebrally injected glutamate and NMDA to cause (chemical) kindling and the strong sensitivity of this process to pre-treatment with NMDA receptor antagonists is analysed. Electrical and chemical kindling effects are additive, indicating the existence of mechanisms in common. They are both sensitive to NMDA antagonists and the common mechanism is probably NMDA receptor activation due to the presence of exogenous (chemical) or endogenous (electrically-released) extracellular glutamate. The participation of the NMDA receptor in the generation of the spontaneous hyperactivity which characterises the chronic epileptic state is reviewed. This includes the entry of Ca2+ to stimulate various post-synaptic phosphorylation processes, and possible modulation of NMDA receptor population size and sensitivity. The question of whether neurotransmitter glutamate is involved in initiation and/or spread of seizures is discussed. PMID:8787032

Bradford, H F



Functional milk beverage fortified with phenolic compounds extracted from olive vegetation water, and fermented with functional lactic acid bacteria.  


Functional milk beverages (FMB100 and FMB200) fortified with phenolic compounds (100 and 200mg/l) extracted from olive vegetable water, and fermented with ?-amino butyric acid (GABA)-producing (Lactobacillus plantarum C48) and autochthonous human gastro-intestinal (Lactobacillus paracasei 15N) lactic acid bacteria were manufactured. A milk beverage (MB), without addition of phenolic compounds, was used as the control. Except for a longer latency phase of FMB200, the three beverages showed an almost similar kinetic of acidification, consumption of lactose and synthesis of lactic acid. Apart from the beverage, Lb. plantarum C48 showed a decrease of ca. Log 2.52-2.24 cfu/ml during storage. The cell density of functional Lb. paracasei 15N remained always above the value of Log 8.0 cfu/ml. During fermentation, the total concentration of free amino acids markedly increased without significant (P > 0.05) differences between beverages. The concentration of GABA increased during fermentation and further storage (63.0 ± 0.6-67.0 ± 2.1mg/l) without significant (P > 0.05) differences between beverages. After fermentation, FMB100 and FMB200 showed the same phenolic composition of the phenol extract from olive vegetable water but a different ratio between 3,4-DHPEA and 3,4-DHPEA-EDA. During storage, the concentrations of 3,4-DHPEA-EDA, p-HPEA and verbascoside of both FMB100 and FMB200 decreased. Only the concentration of 3,4-DHPEA increased. As shown by SPME-GC-MS analysis, diactetyl, acetoin and, especially, acetaldehyde were the main volatile compounds found. The concentration of phenolic compounds does not interfere with the volatile composition. Sensory analyses based on triangle and paired comparison tests showed that phenolic compounds at the concentrations of 100 or 200mg/l were suitable for addition to functional milk beverages. PMID:21458095

Servili, M; Rizzello, C G; Taticchi, A; Esposto, S; Urbani, S; Mazzacane, F; Di Maio, I; Selvaggini, R; Gobbetti, M; Di Cagno, R



GABA synthesis in brain slices is dependent on glutamine produced in astrocytes  

Microsoft Academic Search

The rate of ?-aminobutyric acid (GABA) synthesis in rat-brain slices was determined by inhibiting GABA transaminase with 20-µM gabaculine and measuring the increase of GABA. Added 500-µM glutamine increased the rate of GABA synthesis by 50%, indicating that glutamate decarboxylase is not saturated in brain slices. The stimulation of GABA synthesis with added glutamine in brain slices was much less

Gino Battaglioli; David L. Martin



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


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

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



Channel-mediated tonic GABA release from glia.  


Synaptic inhibition is based on both tonic and phasic release of the inhibitory transmitter ?-aminobutyric acid (GABA). Although phasic GABA release arises from Ca(2+)-dependent exocytosis from neurons, the mechanism of tonic GABA release is unclear. Here we report that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation through the Bestrophin 1 (Best1) anion channel. We demonstrate that GABA directly permeates through Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Our results identify a molecular mechanism for tonic inhibition and establish a role for interactions between glia and neurons in mediating tonic inhibition. PMID:20929730

Lee, Soojung; Yoon, Bo-Eun; Berglund, Ken; Oh, Soo-Jin; Park, Hyungju; Shin, Hee-Sup; Augustine, George J; Lee, C Justin



Medicinal chemistry and molecular pharmacology of GABA(C) receptors.  


GABA(C) receptors belong to the nicotinicoid superfamily of ionotropic receptors that include nicotinic acetylcholine receptors, bicuculline-sensitive GABA(A) receptors, strychnine-sensitive glycine receptors and 5HT3 serotonin receptors. The GABA(C) receptor concept arose from medicinal chemical studies of a conformationally restricted analog of GABA. Receptors matching the predicted properties of GABA(C) receptors were cloned from the retina. Post cloning studies revealed the unique physiology and pharmacology of these relatively simple homomeric receptors. Three subtypes of GABA(C) receptors have been cloned from mammalian sources and pharmacological differences between the rho1, rho2 and rho3 GABA(C) receptors have been described. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and the gut and their involvement in vision, aspects of memory and sleep-waking behaviour. This review concentrates on the medicinal chemistry and molecular pharmacology of GABA(C) receptor subtypes emphasising possible new investigational tools with which to investigate further GABA(C) receptor function. The most useful currently available ligands that show some GABA(C) receptor subtype selectivity are TPMPA, P4PMA, imidazole-4-acetic acid, 2-methyl-TACA and (+/-)-TAMP. PMID:12171579

Johnston, Graham A R



The GABA A receptor subunits heterologously expressed in Xenopus oocytes.  


The ?-aminobutyric acid (GABA) A receptor is composed of a variety of subunits and combinations and shows a characteristic distribution in the CNS. To date, 20 subunits of the GABA A receptor have been cloned: ?1-6, ?1-4, ?1-3, ?, ?, ? , ?, and ?1-3. Oocyte of Xenopus laevis is one of the most frequently used heterologous expression systems, which are used to design and analyze specific combinations of GABA A receptor subunits. In oocytes, a certain GABA A receptor function is studied only by comparing the amplitude of the response to GABA and other drugs by physiological and pharmacological methods. According to the studies on Xenopus laevis oocytes, the ?1?2?2S receptor combination is mostly used. The ?1-containing receptors mediate sedative and anticonvulsant acts. The results of studies on oocytes show that PKA, NKCC1, P2X3 receptors, and GABA A receptor-associated protein, etc., are existing systems that show different reactivity to the GABA A receptors. The GABA A receptor subunits contain distinct binding sites for BZDs, neurosteroids, general anesthetics, etc., which are responsible for the numerous functions of the GABA A receptor. A variety of other drugs, such as topiramate, TG41, (+)- and (-)-borneol, apigenin, and 6-methylflavone could also have modulatory effects on the GABA A receptors. Some of the different models and hypotheses on GABA A receptor structure and function have been achieved by using the two-electrode voltage clamp method in oocytes. PMID:23373649

Abdullah, Jafri Malin; Zhang, Jingli



Critical examination of a correlation between brain gamma-aminobutyric acid (GABA) concentrations and a personality trait of extroversion in healthy volunteers as measured by a 3 Tesla proton magnetic resonance spectroscopy study.  


We hypothesized that brain gamma-aminobutyric acid (GABA) levels are associated with neuroticism, a trait associated with depression and anxiety disorders. We examined the correlation between brain GABA concentrations and the five factors included in the NEO Five-Factor Inventory (NEO-FFI) in healthy volunteers using magnetic resonance spectroscopy (MRS) at 3 T. Forty-one healthy subjects (21 males, 20 females; age: 35+/-7 years) were enrolled in this study. Each subject underwent a 3T 1H-MRS study with a MEGA-PRESS sequence. Spectroscopy voxels (3 cm x 3 cm x 3 cm) were placed in the frontal lobe and the parieto-occipital lobe. A negative correlation was found between the GABA/creatine ratios in the frontal lobe and scores of extroversion on the NEO-FFI. These results suggest that GABAergic neurons are related to personality traits of healthy subjects. PMID:20227251

Goto, Naoki; Yoshimura, Reiji; Moriya, Junji; Kakeda, Shingo; Hayashi, Kenji; Ueda, Nobuhisa; Ikenouchi-Sugita, Atsuko; Umene-Nakano, Wakako; Oonari, Norihiro; Korogi, Yukunori; Nakamura, Jun



Amino acid biogeochemistry and organic matter degradation state across the Pakistan margin oxygen minimum zone  

NASA Astrophysics Data System (ADS)

To assess whether the oxygen minimum zone (OMZ) across the Pakistan Margin causes differences in the lability of sedimentary organic matter, sediments were collected in the core of the OMZ, in the upper and lower transition zones and below the OMZ. Sediment samples were analysed for total nitrogen (TN) and organic carbon (OC) contents, mineral surface area (SA), and total hydrolysable amino acids (THAA) and enzymatically hydrolysable amino acids (EHAA). OC contents and organic carbon per unit of mineral surface area (OC/SA) values were clearly elevated in the core and lower OMZ transition zone. These sediments also contained more labile sedimentary organic matter, as discerned by higher concentrations of THAA and the contribution of N in THAA to TN. A protein amino acid-based degradation index revealed that all sedimentary organic matter has undergone significant degradation, but sediments in the upper OMZ transition zone and below the OMZ are more degraded than inside the OMZ. Changes in amino acid composition during diagenesis are attributed to a combination of factors: (1) selective preservation in which amino acids in cell walls are better preserved than amino acids in cell plasma, (2) formation and accumulation of bacterially derived organic matter; there were relatively more living bacteria in the core of the OMZ and an accumulation of peptidoglycan-derived amino acids in degraded sediments in the upper OMZ transition zone and below the OMZ, and (3) bacterial transformation, as the molar percentages of bacterial transformation products ?-alanine (Bala), ?-amino butyric acid (Gaba), and ornithine (Orn), increased with increasing degradation.

Vandewiele, Sandra; Cowie, Greg; Soetaert, Karline; Middelburg, Jack J.



Elimination of the rho1 subunit abolishes GABA(C) receptor expression and alters visual processing in the mouse retina.  


Inhibition is crucial for normal function in the nervous system. In the CNS, inhibition is mediated primarily by the amino acid GABA via activation of two ionotropic GABA receptors, GABA(A) and GABA(C). GABA(A) receptor composition and function have been well characterized, whereas much less is known about native GABA(C) receptors. Differences in molecular composition, anatomical distributions, and physiological properties strongly suggest that GABA(A) receptors and GABA(C) receptors have distinct functional roles in the CNS. To determine the functional role of GABA(C) receptors, we eliminated their expression in mice using a knock-out strategy. Although native rodent GABA(C) receptors are composed of rho1 and rho2 subunits, we show that after rho1 subunit expression was selectively eliminated there was no GABA(C) receptor expression. We assessed GABA(C) receptor function in the retina because GABA(C) receptors are highly expressed on the axon terminals of rod bipolar cells and because this site modulates the visual signal to amacrine and ganglion cells. In GABA(C)rho1 null mice, GABA-evoked responses, normally mediated by GABA(C) receptors, were eliminated, and signaling from rod bipolar cells to third order cells was altered. These data demonstrate that elimination of the GABA(C)rho1 subunit, via gene targeting, results in the absence of GABA(C) receptors in the retina and selective alterations in normal visual processing. PMID:12019334

McCall, Maureen A; Lukasiewicz, Peter D; Gregg, Ronald G; Peachey, Neal S



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

PubMed Central

?-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.

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



GABA A Receptor Downregulation in Brains of Subjects with Autism  

Microsoft Academic Search

Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary\\u000a reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA\\/glutamate\\u000a system dysregulation. We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3

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



GABA and picrotoxinin receptors in clonal nerve cells  

Microsoft Academic Search

gammaAminobutyric acid (GABA) is a neurotransmitter which seems to mediate inhibitory synaptic transmission in many regions of the central nervous system (CNS) of vertebrates and invertebrates1. GABA has been shown to act by increasing membrane chloride permeability in invertebrate muscle2,3, and a similar mechanism has been suggested for the vertebrate CNS4. The response to GABA is inhibited noncompetitively by the

C. Napias; R. W. Olsen; D. Schubert



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

SciTech Connect

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.

Chu, D.Chin-Mei.



Effects of vigabatrin, an irreversible GABA transaminase inhibitor, on ethanol reinforcement and ethanol discriminative stimuli in mice.  


We tested the hypothesis that the irreversible ?-amino butyric acid transaminase inhibitor, ?-vinyl ?-amino butyric acid [vigabatrin (VGB)], would reduce ethanol reinforcement and enhance the discriminative-stimulus effect of ethanol, effectively reducing ethanol intake. The present studies used adult C57BL/6J (B6) mice in well-established operant, two-bottle choice consumption, locomotor activity, and ethanol discrimination procedures to comprehensively examine the effects of VGB on ethanol-supported behaviors. VGB dose-dependently reduced operant responding for ethanol and ethanol consumption for long periods of time. Importantly, a low dose (200 mg/kg) of VGB was selective for reducing ethanol responding without altering the intake of food or water reinforcement. Higher VGB doses (>200mg/kg) reduced ethanol intake, but also significantly increased water consumption and, more modestly, increased food consumption. Although not affecting locomotor activity on its own, VGB interacted with ethanol to reduce the stimulatory effects of ethanol on locomotion. Finally, VGB (200 mg/kg) significantly enhanced the discriminative-stimulus effects of ethanol as evidenced by significant leftward and upward shifts in ethanol generalization curves. Interestingly, VGB treatment was associated with slight increases in blood ethanol concentrations. The reduction in ethanol intake by VGB appears to be related to the ability of VGB to potentiate the pharmacological effects of ethanol. PMID:22336593

Griffin, William C; Nguyen, Shaun A; Deleon, Christopher P; Middaugh, Lawrence D



Hippocampal hyperexcitability induced by GABA withdrawal is due to down-regulation of GABA A receptors  

Microsoft Academic Search

The sudden interruption of an intracortical instillation of exogenous ?-aminobutyric acid (GABA) generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal (GW) last for weeks. A similar withdrawal-induced hyperexcitability is also produced by several GABAA receptor agonists. This work reports a quantitative analysis of GW-induced hyperexcitability produced in the hippocampus in vitro. GW produced a left-ward displacement of

C Casasola; J Bargas; J.-A Arias-Montaño; E Calixto; T Montiel; E Galarraga; S Brailowsky



Excitatory actions of gaba during development: the nature of the nurture  

Microsoft Academic Search

In the immature brain, GABA (?-aminobutyric acid) is excitatory, and GABA-releasing synapses are formed before glutamatergic contacts in a wide range of species and structures. GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions. I propose that this mechanism provides a solution to the problem of

Yehezkel Ben-Ari



The presence of GABA in gastropod mucus and its role in inducing larval settlement  

Microsoft Academic Search

Chemical substances that induce larval settlement have been the focus of many gastropod studies due to the importance of wild stock recruitment and production within aquaculture facilities. Gamma-aminobutyric acid (GABA), GABA analogs, and GABA-mimetics associated with certain crustose coralline algae (CCA), are known to induce larval settlement in commercial abalone (Haliotis) species, and other gastropods. Furthermore, mucus secreted from these

Praphaporn Laimek; Shona Clark; Michael Stewart; Fred Pfeffer; Chaitip Wanichanon; Peter Hanna; Prasert Sobhon



Actions of picrotoxinin analogues on an expressed, homo-oligorneric GABA receptor receptor of Drosophila melanogaster  

Microsoft Academic Search

The actions of picrotoxinin and four of its analogues were tested on a Drosophila melanogaster homo-oligomeric GABA (?-aminobutyric acid) receptor formed when RDL (resistance to dieldrin) subunits were expressed in Xenopus oocytes. In agreement with previously reported studies on native insect GABA receptors and native and expressed vertebrate GABA receptors, acetylation of the bridgehead hydroxyl group (picrotoxinin acetate) greatly reduced

Y. Shirai; A. M. Hosie; S. D. Buckingham; C. W. Holyoke; H. A. Baylis; D. B. Sattelle



Modulation by GABA of neuroplasticity in the central and peripheral nervous system  

Microsoft Academic Search

Apart from being a prominent (inhibitory) neurotransmitter that is widely distributed in the central and peripheral nervous system, ?-aminobutyric acid (GABA) has turned out to exert trophic actions. In this manner GABA may modulate the neuroplastic capacity of neurons and neuron-like cells under various conditions in situ and in vitro. In the superior cervical ganglion (SCG) of adult rat, GABA

J. R. Wolff; F. Joó; P. Kfisa



The effect of GABA receptor ligands in experimental spina bifida occulta  

Microsoft Academic Search

BACKGROUND: The pathophysiology behind spina bifida and other neural tube defects (NTDs) is unclear. Folic acid is one variable, but other factors remain. Studies suggest that substances active at the GABA receptor may produce NTDs. To test this hypothesis pregnant rats were exposed to either the GABA a agonist muscimol (1, 2 or 4 mg\\/kg), the GABA a antagonist bicuculline

Wayne Briner



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

SciTech Connect

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.

Guastella, J.; Stretton, A.O. (University of Wisconsin, Madison (USA))



Effects of GABA-transaminase inhibition on brain metabolism and amino-acid compartmentation: an in vivo study by 2D 1H-NMR spectroscopy coupled with microdialysis  

Microsoft Academic Search

The aim of this work was to study the neurochemical effects in the brain of GABA-transaminase inhibition by systemic administration\\u000a of gabaculine (100 mg\\/kg, i.a.) in the rat. In order to investigate neurotransmitter and related amino-acid compartmentation\\u000a and metabolism, we have developed an original tool: the coupling, in vivo, on the same animal, of 2D COSY 1H-NMR spectroscopy with intracerebral

C. Piérard; M. Pérès; P. Satabin; C. Y. Guezennec; D. Lagarde



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


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 antioxidant nutraceutical vectors. PMID:22919677

Pessione, Enrica



Regulation of GABA content by glucose in the chick retina.  


Some visual information is processed in the retina by ?-aminobutyric acid (GABA) signaling. Once retinal degeneration and visual impairment caused by diabetic retinopathy (DR) are affecting an increasing number of people worldwide, and the disease is characterized by hyper- and hypoglycemic events, the authors aimed to investigate how retinal GABA cell content is affected by variations in glucose availability. Using the ex vivo chick retinas exposed to different glucose concentrations, we observed that amacrine cells from both inner nuclear layer (INL) and ganglion cell layer (GCL) as well as their processes in the inner plexiform layer (IPL) released GABA through GABA transporter-1 (GAT-1) after 30 min of glucose deprivation. Extending this insult to 60 min triggered a permanent loss of GABA-positive amacrine cells, caused swelling of IPL and cell death. High glucose (35 mM) for 30 min induced an increment in GABA immunolabeling in both outer and inner retina. Further, glucose deprivation effects could not be reverted by basal glucose levels and high glucose did not prevent GABA loss upon a glucose deprivation insult. Therefore, GABA cell content is differently affected by short-term variations in glucose availability. While high glucose modulates outer and inner GABAergic circuits, glucose deprivation affects mainly the inner retina. Also, consecutive alteration in glucose supply was not able to rescue basal GABA content. Therefore, glucose oscillations interfering with GABAergic retinal functioning during early stages of retinopathies should be further investigated. PMID:23920155

Miya-Coreixas, Vivian Sayuri; Maggesissi Santos, Raquel; Carpi Santos, Raul; Gardino, Patrícia Franca; Calaza, Karin



GABA(C) receptors in neuroendocrine gut cells: a new GABA-binding site in the gut.  


Although GABA(C) receptors play a crucial role in the mammalian central nervous system, their functional expression in peripheral tissues has not yet been studied. Using the gut neuroendocrine tumor cell line STC-1 as a model, we provide first evidence for the functional expression of GABA(C) receptors in the gut: mRNAs of the GABA(C) receptor subunits rho1 and rho2 were detected in STC-1 cells by reverse transcription polymerase chain reaction (RT-PCR). Applying anti-rho-antibodies, specific immunostaining for GABA(C) receptors was observed. For functional characterization, the effects of GABA(C) receptor activation on [Ca2+]i and hormone secretion were studied. The selective GABA(C) receptor agonist cis-4-aminocrotonic acid (CACA) induced dose-dependent increases both of [Ca2+]i and of hormone (cholecystokinin) secretion. The stimulatory effects of CACA were antagonized by the GABA(C) receptor blockers (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and 3-aminopropyl(methyl)phosphinic acid (3-APMPA). These results demonstrate that GABA(C) receptors play an important role in neuroendocrine gastrointestinal secretion. PMID:11211116

Jansen, A; Hoepfner, M; Herzig, K H; Riecken, E O; Scherübl, H



The heptahelical domain of GABA(B2) is activated directly by CGP7930, a positive allosteric modulator of the GABA(B) receptor.  


The gamma-aminobutyric acid, type B (GABA(B)) receptor is well recognized as being composed of two subunits, GABA(B1) and GABA(B2). Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA(B1) binds GABA, GABA(B2) is required for GABA(B1) to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA(B2) plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA(B2) can transmit a signal in the absence of GABA(B1). Today only ligands interacting with GABA(B1) ECD have been identified. Thus, the compounds acting exclusively on the GABA(B2) subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA(B) receptor. We showed that it activates the wild type GABA(B) receptor but with a low efficacy. The GABA(B2) HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA(B1). Of interest, CGP7930 could activate GABA(B2) expressed alone and is the first described agonist of GABA(B2). Finally, we show that CGP7930 retains its agonist activity on a GABA(B2) subunit deleted of its ECD. This demonstrates that the HD of GABA(B2) behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA(B) receptor and examine any possible role of homomeric GABA(B2) receptors. PMID:15126507

Binet, Virginie; Brajon, Carole; Le Corre, Laurent; Acher, Francine; Pin, Jean-Philippe; Prézeau, Laurent



Blockade of GABA(B) receptors facilitates evoked neurotransmitter release at spinal dorsal horn synapse.  


Metabotropic GABA type B (GABA(B)) receptors are abundantly expressed in the rat spinal dorsal horn. Activation of GABA(B) receptors by exogenous agonists inhibits synaptic transmission, which is believed to underlie the GABA(B) receptor-mediated analgesia. However, little effort has been made to test whether endogenous GABA might also mediate inhibition by acting on GABA(B) receptors. In this study, whole-cell recording techniques were employed to study the effect of endogenous GABA on GABA(B) receptors in substantia gelatinosa (SG) neurons in adult rat spinal cord slices. In current-clamp mode, blockade of GABA(B) receptors by their selective antagonist 3-[[[(3,4-dichlorophenyl)methyl]amino]propyl] (diethoxy-methyl) phosphinic acid (CGP 52432) facilitated presynaptic stimulation-induced action potential discharge and increased amplitude of postsynaptic potentials (PSPs), meaning a GABA(B) receptor-mediated inhibition of SG neuron excitability. In voltage-clamp mode, blockade of GABA(B) receptors increased the amplitude of evoked excitatory postsynaptic currents (eEPSCs) and decreased paired-pulse ratio, indicating a presynaptic CGP 52432 action. Primary afferent A? or C fiber-evoked EPSCs were also facilitated by CGP 52432 application. Amplitudes of evoked GABAergic and glycinergic inhibitory postsynaptic currents (eIPSCs) were enhanced by GABA(B) receptor blockade. The facilitation of amplitude persisted in the presence of a specific GABA transporter 1 (GAT-1) blocker, tiagabine, or GAT-2/3 blocker SNAP5114. However, blockade of GABA(B) receptors had no effect on action potential-independent miniature EPSCs (mEPSCs), miniature IPSCs (mIPSCs), or membrane conductance. Taken together, these results suggest that endogenous GABA modulates evoked synaptic transmission in SG neurons by acting on GABA(B) receptors. This GABA(B) receptor-mediated homeostatic regulation of neuronal excitability and neurotransmitter release might contribute to modulation of nociception in spinal dorsal horn. PMID:21807068

Yang, K; Ma, H



Drug interactions at GABA A receptors  

Microsoft Academic Search

Neurotransmitter receptor systems have been the focus of intensive pharmacological research for more than 20 years for basic and applied scientific reasons, but only recently has there been a better understanding of their key features. One of these systems includes the type A receptor for the ?-aminobutyric acid (GABA), which forms an integral anion channel from a pentameric subunit assembly

Esa R Korpi; Gerhard Gründer; Hartmut Lüddens



A mitochondrial GABA permease connects the GABA shunt and the TCA cycle, and is essential for normal carbon metabolism.  


In plants, ?-aminobutyric acid (GABA) accumulates in the cytosol in response to a variety of stresses. GABA is transported into mitochondria, where it is catabolized into TCA cycle or other intermediates. Although there is circumstantial evidence for mitochondrial GABA transporters in eukaryotes, none have yet been identified. Described here is an Arabidopsis protein similar in sequence and topology to unicellular GABA transporters. The expression of this protein complements a GABA-transport-deficient yeast mutant. Thus the protein was termed AtGABP to indicate GABA-permease activity. In vivo localization of GABP fused to GFP and immunobloting of subcellular fractions demonstrate its mitochondrial localization. Direct [(3) H]GABA uptake measurements into isolated mitochondria revealed impaired uptake into mitochondria of a gabp mutant compared with wild-type (WT) mitochondria, implicating AtGABP as a major mitochondrial GABA carrier. Measurements of CO(2) release, derived from radiolabeled substrates in whole seedlings and in isolated mitochondria, demonstrate impaired GABA-derived input into the TCA cycle, and a compensatory increase in TCA cycle activity in gabp mutants. Finally, growth abnormalities of gabp mutants under limited carbon availability on artificial media, and in soil under low light intensity, combined with their metabolite profiles, suggest an important role for AtGABP in primary carbon metabolism and plant growth. Thus, AtGABP-mediated transport of GABA from the cytosol into mitochondria is important to ensure proper GABA-mediated respiration and carbon metabolism. This function is particularly essential for plant growth under conditions of limited carbon. PMID:21501262

Michaeli, Simon; Fait, Aaron; Lagor, Kelly; Nunes-Nesi, Adriano; Grillich, Nicole; Yellin, Ayelet; Bar, Dana; Khan, Munziba; Fernie, Alisdair R; Turano, Frank J; Fromm, Hillel



Expression of functional GABA A receptors in neuroendocrine gastropancreatic cells  

Microsoft Academic Search

Gastropancreatic neuroendocrine cells synthesize large amounts of ?-aminobutyric acid (GABA). This amino acid neurotransmitter appears to be stored in and released from, vesicles similar to small synaptic vesicles. So far, the function of GABA in gastropancreatic, neuroendocrine cells has not been clarified. Previous work suggested that only pancreatic, glucagon-producing a2 cells contain functional GABAA receptors. Using subunit-specific antibodies in sections

G. Blankenfeld; M. O. K. Enkvist; H. Kettenmann; J. Turner; G. Ahnert-Hilger; M. John; B. Wiedenmann; F. Stephenson



Redox modulation of homomeric rho1 GABA receptors.  


The activity of many receptors and ion channels in the nervous system can be regulated by redox-dependent mechanisms. Native and recombinant GABA(A) receptors are modulated by endogenous and pharmacological redox agents. However, the sensitivity of GABA(C) receptors to redox modulation has not been demonstrated. We studied the actions of different reducing and oxidizing agents on human homomeric GABArho(1) receptors expressed in Xenopus laevis oocytes. The reducing agents dithiothreitol (2 mM) and N-acetyl-L-cysteine (1 mM) potentiated GABA-evoked Cl(-) currents recorded by two-electrode voltage-clamp, while the oxidants 5-5'-dithiobis-2-nitrobenzoic acid (500 microM) and oxidized dithiothreitol (2 mM) caused inhibition. The endogenous antioxidant glutathione (5 mM) also enhanced GABArho(1) receptor-mediated currents while its oxidized form GSSG (3 mM) had inhibitory effects. All the effects were rapid and easily reversible. Redox modulation of GABArho(1) receptors was strongly dependent on the GABA concentration; dose-response curves for GABA were shifted to the left in the presence of reducing agents, whereas oxidizing agents produced the opposite effect, without changes in the maximal response to GABA and in the Hill coefficient. Our results demonstrate that, similarly to GABA(A) receptors and other members of the cys-loop receptor superfamily, GABA(C) receptors are subjected to redox modulation. PMID:18315569

Calero, Cecilia I; Calvo, Daniel J



Relative efficacies of 1,4-diazepines on GABA-stimulated chloride influx in rat brain vesicles  

SciTech Connect

The effects of 1,4-diazepines with two annelated heterocycles (brotizolam (WE 941), ciclotizolam (WE 973) and WE 1008) on gamma-aminobutyric acid (GABA)-stimulated chloride influx into rat brain membrane vesicles were examined. Brotizolam enhanced GABA-stimulated /sup 36/Cl/sup /minus// influx, while ciclotizolam and WE 1008 showed only a small enhancement of GABA-stimulated /sup 36/Cl/sup /minus// uptake. Brotizolam resulted in a left shift of the GABA dose response curve at lower concentrations of GABA, while at higher concentrations of GABA, brotizolam caused a reduction of the maximal response. The enhancement of GABA-stimulated /sup 36/Cl/sup /minus// uptake by brotizolam was antagonized by Ro 15-1788. At higher concentration of GABA (300 /mu/M), brotizolam inhibited GABA-stimulated /sup 36/Cl/sup /minus// uptake in a dose dependent manner and Ro 15-1788 failed to antagonize this effect.

Ikeda, Masaaki; Weber, K.H.; Bechtel, W.D.; Malatynska, E.; Yamamura, H.I.



Influence of oxygenated fuel additives and their metabolites on the binding of a convulsant ligand of the gamma-aminobutyric acid(A) (GABA(A)) receptor in rat brain membrane preparations.  


As a foundation for evaluating potential mechanisms of the neurological effects (e.g. headache, nausea, dizziness) of some octane boosters, we studied the gamma-aminobutyric acid(A) (GABA(A)) receptor in a series of binding assays in membranes from rat brain. The GABA(A) receptor was probed using the radioligand [3H]t-butylbicycloorthobenzoate ([3H]TBOB) which binds to the convulsant recognition site of the receptor. The results demonstrated that the short-chain t-ethers and their t-alcohol metabolites inhibit binding at the convulsant site of the GABA(A) receptor. The potency of the inhibition tended to correlate with carbon chain length. For agents having an equal number of carbon atoms, potency of inhibition of [3H]TBOB binding was greater in magnitude for the alcohols than for the ethers. The descending rank order of potency for the ethers and alcohols were as follows, t-amyl alcohol (TAA); t-amyl-methyl ether (TAME); ethyl-t-butyl ether (ETBE)>t-butyl alcohol (TBA)>methyl-t-butyl ether (MTBE)>ethanol. In additional saturation binding assays, MTBE reduced apparent density of convulsant binding (B(max)). PMID:11888705

Martin, Joseph V; Bilgin, Nesli M; Iba, M Michael



Endogenous synthesis of taurine and GABA in rat ocular tissues.  


The endogenous production of taurine and gamma-aminobutyric acid (GABA) in rat ocular tissues was investigated. The activities of taurine-producing enzyme, cysteine sulfinic acid decarboxylase (CSAD), and GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD), were observed in the retina, lens, iris-ciliary body and cornea. The highest specific activity of CSAD was in the cornea and that of GAD in the retina. The discrepancy between CSAD activity and taurine content within the ocular tissues indicates that intra- or extraocular transport processes may regulate the concentration of taurine in the rat eye. The GAD activity and the content of GABA were distributed in parallel within the rat ocular tissues. The quantitative results suggest that the GAD/GABA system has functional significance only in the retina of the rat eye. PMID:3364118

Heinämäki, A A



Vibrational circular dichroism (VCD) chiral assignment of atropisomers: application to ?-aminobutyric acid (GABA) modulators designed as potential anxiolytic drugs.  


Atropisomers exist when axial chirality is present as a result of conformationally restricted rotation around a single bond. The interconversion rate of the individual atropisomers is critical to the assessment of chiral stability of a drug throughout scale-up, development, production, and storage as well as in vivo pharmacokinetics. We describe the application of vibrational circular dichroism spectroscopy coupled with quantum mechanics simulations to assign the absolute axial chirality and measure the racemization half-life of a series of potential anxiolytic drugs that act as ?-aminobutyric acid modulators. PMID:23601535

Pivonka, Don E; Wesolowski, Steven S



GABA Acts as a Ligand Chaperone in the Early Secretory Pathway to Promote Cell Surface Expression of GABAA Receptors  

PubMed Central

GABA (?-aminobutyric acid) is the primary inhibitory neurotransmitter in brain. The fast inhibitory effect of GABA is mediated through the GABAA receptor, a postsynaptic ligand-gated chloride channel. We propose that GABA can act as a ligand chaperone in the early secretory pathway to facilitate GABAA receptor cell surface expression. Forty-two hrs of GABA treatment increased the surface expression of recombinant receptors expressed in HEK 293 cells, an effect accompanied by an increase in GABA-gated chloride currents. In time-course experiments, a 1 hr GABA exposure, followed by a 5 hr incubation in GABA-free medium, was sufficient to increase receptor surface expression. A shorter GABA exposure could be used in HEK 293 cells stably transfected with the GABA transporter GAT-1. In rGAT-1HEK 293 cells, the GABA effect was blocked by the GAT-1 inhibitor NO-711, indicating that GABA was acting intracellularly. The effect of GABA was prevented by brefeldin A (BFA), an inhibitor of early secretory pathway trafficking. Coexpression of GABAA receptors with the GABA synthetic enzyme glutamic acid decarboxylase 67 (GAD67) also resulted in an increase in receptor surface levels. GABA treatment failed to promote the surface expression of GABA binding site mutant receptors, which themselves were poorly expressed at the surface. Consistent with an intracellular action of GABA, we show that GABA does not act by stabilizing surface receptors. Furthermore, GABA treatment rescued the surface expression of a receptor construct that was retained within the secretory pathway. Lastly, the lipophilic competitive antagonist (+)bicuculline promoted receptor surface expression, including the rescue of an secretory pathway-retained receptor. Our results indicate that a neurotransmitter can act as a ligand chaperone in the early secretory pathway to regulate the surface expression of its receptor. This effect appears to rely on binding site occupancy, rather than agonist-induced structural changes, since chaperoning is observed with both an agonist and a competitive antagonist.

Eshaq, Randa S.; Stahl, Letha D.; Stone, Randolph; Smith, Sheryl S.; Robinson, Lucy C.; Leidenheimer, Nancy J.



Second Messengers, Trafficking-Related Proteins, and Amino Acid Residues that Contribute to the Functional Regulation of the Rat Brain GABA Transporter GAT1  

Microsoft Academic Search

Recent evidence indicates that several members of the Na1- coupled transporter family are regulated, and this regulation in part occurs by redistribution of transporters between intracel- lular locations and the plasma membrane. We elucidate com- ponents of this process for both wild-type and mutant GABA transporters (GAT1) expressed in Xenopus oocytes using a combination of uptake assays, immunoblots, and electrophys-

Michael W. Quick; Janis L. Corey; Norman Davidson; Henry A. Lester


Characterization of a GABA A receptor ? subunit in the abalone Haliotis asinina that is upregulated during larval development  

Microsoft Academic Search

In the tropical abalone Haliotis asinina, the neurotransmitter ?-aminobutyric acid (GABA) is a potent inducer of larval settlement, a process beginning with the onset of a behavioral search for a suitable substratum and ending with metamorphosis. In the natural environment, larvae can encounter GABA or GABA-like molecules through association with conspecific foot mucus and crustose coralline algae. To understand the

Praphaporn Stewart; Elizabeth A. Williams; Michael J. Stewart; Nantawan Soonklang; Sandie M. Degnan; Scott F. Cummins; Peter J. Hanna; Prasert Sobhon


Phosphatidylserine increases in vivo the synaptosomal uptake of exogenous GABA in rats.  


A sonicated liposome suspension of gamma-aminobutyric acid (GABA) and phosphatidylserine (liposome-entrapped GABA), intraperitoneally administered in rats, inhibited EEG epileptic activity induced by penicillin, whereas GABA did not. A significant increase (20.4%) in brain radioactivity accumulation occurred at 5 min after i.p. administration of [14C]GABA associated with phosphatidylserine in comparison with the administration of [14C]GABA; such an increase persisted after 20 min. However, the accumulation of radioactivity into brain synaptosomes demonstrated a 24.1% increase at 5 min and subsequently showed a 43.3% increase at 20 min after injection of liposome-entrapped GABA. The above findings suggest that phosphatidylserine stimulates exogenous GABA uptake into brain GABAergic nerve terminals. PMID:3338534

Loeb, C; Marinari, U M; Benassi, E; Besio, G; Cottalasso, D; Cupello, A; Maffini, M; Mainardi, P; Pronzato, M A; Scotto, P A



3H-GABA uptake selectively labels identifiable neurons in the leech central nervous system  

SciTech Connect

Segmental ganglia of the leech ventral nerve cord synthesize the neurotransmitter gamma-aminobutyric acid (GABA) when incubated in the presence of the precursor glutamate, suggesting that there may be GABA-ergic neurons in the leech nerve cord. GABA-accumulating neurons of the two taxonomically distant leech species, Haementeria ghilianii and Hirudo medicinalis, have been labeled by taking advantage of their high-affinity uptake system for the neurotransmitter. Autoradiography of sectioned segmental ganglia previously exposed to 3H-GABA reveals a reproducible pattern of about thirty 3H-GABA-labeled neuronal cell bodies per ganglion. The majority of 3H-GABA-labeled neuronal cell bodies are bilaterally paired, although some apparently unpaired cell bodies also accumulate label. Neuronal processes were reproducibly labeled by GABA uptake and could be traced in the neuropil through commissures and fiber tracts into the segmental nerve roots and interganglionic connectives, respectively.

Cline, H.T.



Seizure suppression in kindling epilepsy by intracerebral implants of GABA but not by noradrenaline-releasing polymer matrices  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA)-releasing polymer matrices were implanted bilaterally, immediately dorsal to the substantia nigra, in rats previously kindled in the amygdala. Two days after implantation, rats with GABA-releasing matrices exhibited only focal limbic seizures in response to electrical stimulation, whereas animals with control matrices devoid of GABA had generalized convulsions. GABA release from the polymer matrices was high during the

Merab Kokaia; Patrick Aebischer; Eskil Elmér; Johan Bengzon; Peter Kalén; Zaal Kokaia; Olle Lindvall



Seizure suppression in kindling epilepsy by intracerebral implants of GABA-but not by noradrenalinereleasing polymer matrices  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA)-releasing polymer matrices were implanted bilaterally, immediately dorsal to the substantia\\u000a nigra, in rats previously kindled in the amygdala. Two days after implantation, rats with GABA-releasing matrices exhibited\\u000a only focal limbic seizures in response to electrical stimulation, whereas animals with control matrices devoid of GABA had\\u000a generalized convulsions. GABA release from the polymer matrices was high during the

Merab Kokaia; Patrick Aebischer; Eskil Elmér; Johan Bengzon; Peter Kalén; Zaal Kokaia; Olle Lindvall



A Gut Feeling about GABA: Focus on GABAB Receptors  

PubMed Central

?-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract.

Hyland, Niall P.; Cryan, John F.



Involvement of GABA A and GABA B receptors in afterdischarge generation in rat hippocampal slices  

Microsoft Academic Search

It has been hypothesized that a disruption of ?-aminobutyric acid (GABA) receptor-mediated processes may be involved in the pathophysiology of focal epilepsy. This disinhibition hypothesis has been postulated from the results of in vitro experiments of the interictal activity of focal epilepsy. Less is known, however, about how disinhibition may be involved in the production of the ictal activity. We

Masato Higashima; Koji Ohno; Hiroya Kinoshita; Yoshifumi Koshino



GABA transporters mediate glycine release from cerebellum nerve endings: roles of Ca(2+)channels, mitochondrial Na(+)/Ca(2+) exchangers, vesicular GABA/glycine transporters and anion channels.  


GABA transporters accumulate GABA to inactivate or reutilize it. Transporter-mediated GABA release can also occur. Recent findings indicate that GABA transporters can perform additional functions. We investigated how activation of GABA transporters can mediate release of glycine. Nerve endings purified from mouse cerebellum were prelabeled with [(3)H]glycine in presence of the glycine GlyT1 transporter inhibitor NFPS to label selectively GlyT2-bearing terminals. GABA was added under superfusion conditions and the mechanisms of the GABA-evoked [(3)H]glycine release were characterized. GABA stimulated [(3)H]glycine release in a concentration-dependent manner (EC(50) = 8.26 ?M). The GABA-evoked release was insensitive to GABA(A) and GABA(B) receptor antagonists, but it was abolished by GABA transporter inhibitors. About 25% of the evoked release was dependent on external Ca(2+) entering the nerve terminals through VSCCs sensitive to ?-conotoxins. The external Ca(2+)-independent release involved mitochondrial Ca(2+), as it was prevented by the Na(+)/Ca(2+) exchanger inhibitor CGP37157. The GABA uptake-mediated increases in cytosolic Ca(2+) did not trigger exocytotic release because the [(3)H]glycine efflux was insensitive to clostridial toxins. Bafilomycin inhibited the evoked release likely because it reduced vesicular storage of [(3)H]glycine so that less [(3)H]glycine can become cytosolic when GABA taken up exchanges with [(3)H]glycine at the vesicular inhibitory amino acid transporters shared by the two amino acids. The GABA-evoked [(3)H]glycine efflux could be prevented by niflumic acid or NPPB indicating that the evoked release occurred essentially by permeation through anion channels. In conclusion, GABA uptake into GlyT2-bearing cerebellar nerve endings triggered glycine release which occurred essentially by permeation through Ca(2+)-dependent anion channels. Glial GABA release mediated by anion channels was proposed to underlie tonic inhibition in the cerebellum; the present results suggest that glycine release by neuronal anion channels also might contribute to tonic inhibition. PMID:22579572

Romei, Cristina; Raiteri, Maurizio; Raiteri, Luca



Synthesis of Chick Brain GABA Receptors by Frog Oocytes  

Microsoft Academic Search

Poly(A)-mRNA, extracted from the optic lobe of chick embryos, directs the synthesis of gamma -aminobutyric acid (GABA) receptors in Xenopus laevis oocytes. The receptors are inserted into the oocyte membrane, where they form receptor--channel complexes. When activated by GABA, and related agonists, the chick brain receptors open membrane channels that are permeable to chloride ions. Thus, Xenopus oocytes provide a

R. Miledi; I. Parker; K. Sumikawa



Regulation of Excitation by GABA A Receptor Internalization  

Microsoft Academic Search

Neuronal inhibition is of paramount importance in maintaining the delicate and dynamic balance between\\u000a excitatory and inhibitory influences in the central nervous system. GABA (?-aminobutyric acid), the\\u000a primary inhibitory neurotransmitter in brain, exerts its fast inhibitory effects through ubiquitously expressed\\u000a GABAA receptors. Activation of these heteropentameric receptors by GABA results\\u000a in the gating of an integral chloride channel leading to

Nancy J. Leidenheimer


Alterations of Cortical GABA Neurons and Network Oscillations in Schizophrenia  

Microsoft Academic Search

The hypothesis that alterations of cortical inhibitory ?-aminobutyric acid (GABA) neurons are a central element in the pathology\\u000a of schizophrenia has emerged from a series of postmortem studies. How such abnormalities may contribute to the clinical features\\u000a of schizophrenia has been substantially informed by a convergence with basic neuroscience studies revealing complex details\\u000a of GABA neuron function in the healthy

Guillermo Gonzalez-Burgos; Takanori Hashimoto; David A. Lewis



Phosphorylation of the recombinant rho1 GABA receptor.  


Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. While a growing body of literature indicates that postsynaptic GABA receptors are regulated by phosphorylation, there is discrepancy as to the specific effects of phosphorylation on GABA receptor function. Here, we have identified phosphorylation sites on the human rho1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP-dependent protein kinase (PKA); calmodulin-dependent kinase (CaMKII); casein kinase (CKII); mitogen-activated protein kinase (MAPK); and cGMP-dependent protein kinase (PKG). We demonstrate that in nearly all cases, the consensus sites and actual phosphorylation sites do not agree supporting the risk of relying on a sequence analysis to identify potential phosphorylation sites. In addition, of the six kinases examined, only CKII phosphorylated the human rho2 subunit. Site-directed mutagenesis of the phosphorylation sites, or activation/inhibition of select kinase pathways, did not alter the receptor sensitivity or maximal GABA-activated current of the rho1 GABA receptor expressed in Xenopus laevis oocytes suggesting phosphorylation of rho1 does not directly alter receptor properties. This study is a first and necessary step towards elucidating the regulation of rho1 GABA receptors by phosphorylation. PMID:12175859

Sedelnikova, Anna; Weiss, David S


GABA A autoreceptors enhance GABA release from human neocortex: towards a mechanism for high-frequency stimulation (HFS) in brain?  

Microsoft Academic Search

High-frequency stimulation (HFS) in human neocortical slices induces ?-aminobutyric acid (GABA) release via GABAA receptor (GABAAR) activation. The mechanism of this effect and the localization of these GABAARs were now studied. Fresh human neocortical slices were subjected to HFS (130 Hz) in the presence of veratridine (3 µM).\\u000a As measured by high-performance liquid chromatography, only GABA but not glutamate outflow was affected

Michela Mantovani; Andreas Moser; Carola A. Haas; Josef Zentner; Thomas J. Feuerstein



[Changes in the brain GABA system after repeated injections of pyridoxal-5'-phosphate and its Schiff base with GABA].  


A state of the gamma-aminobutyric acid (GABA) system (glutamate, glutamate decarboxylase, GABA, GABA-alpha-ketoglutarate aminotransferase) and the coupled reactions (alpha-ketoglutarate dehydrogenase complex, aspartate- and alanine aminotransferases) was studied in three brain structures (cerebellum, brain cortex and truncus cerebri) after multiple administration of pyridoxal-5'-phosphate (PALP) and its Shiff base with GABA (5 injections at doses 10.0 and 15.0 mg/kg of body mass, respectively). Non-coenzymatic effects of PALP were found to prevail within 1 hr after its last administration: inhibition of PALP-dependent aminotransferases and activation of the alpha-keto-glutarate oxidative decarboxylation were observed. The opposite effects were detected after addition of PALP to brain homogenates in vitro. Administration of the PALP-GABA complex exhibited qualitatively similar to those of PALP effects on the reactions studied in brain. The data obtained suggest that parenteral administration of the coenzyme preparation caused a number of metabolic effects, which are sometimes far from unambigously predicted theoretical considerations. The similarity of PALP and PALP-GABA effects appears to demonstrate ready biotransformation of the Shiff base with liberation of PALP and GABA. PMID:2741411

Rozanov, V A; Kopelevich, V M; Savitski?, I V


Could Reduced Cerebrospinal Fluid (CSF) Galanin Contribute to Restricted Eating in Anorexia Nervosa?  

Microsoft Academic Search

Galanin (GAL) and gamma amino butyric acid (GABA) are orexigenic neuropeptides that could contribute to the pathogenesis of anorexia nervosa (AN). To avoid the confounding effects of the ill state, we studied women who were recovered (> 1 year, normal weight, and regular menstrual cycles, no bingeing or purging) from AN (REC AN) and matched healthy control women (NC). CSF

Guido K Frank; Walter H Kaye; Abhiram Sahu; John Fernstrom; Claire McConaha



Pregnenolone sulfate and dehydroepiandrosterone sulfate inhibit GABA-gated chloride currents in Xenopus oocytes expressing picrotoxin-insensitive GABA A receptors  

Microsoft Academic Search

We examined the effects of picrotoxinin, pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS) on ?-aminobutyric acid (GABA) responses in Xenopus oocytes injected with wild type ?1, ?2 and ?2 GABAA receptor subunits and in oocytes injected with wild type ?1 and ?2 subunits and a mutated ?2 subunit that eliminates picrotoxin sensitivity. All three agents inhibited GABA currents in oocytes

Weixing Shen; Steven Mennerick; Erik C Zorumski; Douglas F Covey; Charles F Zorumski



Reproducibility of GABA measurements using 2D J-resolved magnetic resonance spectroscopy  

Microsoft Academic Search

We determined the reproducibility of GABA (gamma-aminobutyric acid) measurements using 2D J-resolved magnetic resonance spectroscopy (MRS) on a clinical 1.5-T MR imaging scanner. Two-dimensional J-resolved spectra were acquired in vitro across five GABA concentrations using a volume head coil and a 5-in. surface coil. Additional spectra using a sixth GABA phantom with a very low concentration and from a healthy

Katherine Lymer; Kristin Haga; Ian Marshall; Napapon Sailasuta; Joanna Wardlaw



Alterations of Cortical GABA Neurons and Network Oscillations in Schizophrenia  

PubMed Central

The hypothesis that alterations of cortical inhibitory ?-aminobutyric acid (GABA) neurons are a central element in the pathology of schizophrenia has emerged from a series of postmortem studies. How such abnormalities may contribute to the clinical features of schizophrenia has been substantially informed by a convergence with basic neuroscience studies revealing complex details of GABA neuron function in the healthy brain. Importantly, activity of the parvalbumin-containing class of GABA neurons has been linked to the production of cortical network oscillations. Furthermore, growing knowledge supports the concept that ? band oscillations (30–80 Hz) are an essential mechanism for cortical information transmission and processing. Herein we review recent studies further indicating that inhibition from parvalbumin-positive GABA neurons is necessary to produce ? oscillations in cortical circuits; provide an update on postmortem studies documenting that deficits in the expression of glutamic acid decarboxylase67, which accounts for most GABA synthesis in the cortex, are widely observed in schizophrenia; and describe studies using novel, noninvasive approaches directly assessing potential relations between alterations in GABA, oscillations, and cognitive function in schizophrenia.

Gonzalez-Burgos, Guillermo; Hashimoto, Takanori; Lewis, David A.



GABA and glycine as neurotransmitters: a brief history  

PubMed Central

?-Aminobutyric acid (GABA) emerged as a potentially important brain chemical just over 50 years ago, but its significance as a neurotransmitter was not fully realized until over 16 years later. We now know that at least 40% of inhibitory synaptic processing in the mammalian brain uses GABA. Establishing its role as a transmitter was a lengthy process and it seems hard to believe with our current knowledge that there was ever any dispute about its role in the mammalian brain. The detailed information that we now have about the receptors for GABA together with the wealth of agents which facilitate or reduce GABA receptor mechanisms make the prospects for further research very exciting. The emergence of glycine as a transmitter seems relatively painless by comparison to GABA. Perhaps this is appropriate for the simplest of transmitter structures! Its discovery within the spinal cord and brainstem approximately 40 years ago was followed only 2 years later by the proposal that it be conferred with ‘neurotransmitter' status. It was another 16 years before the receptor was biochemically isolated. Now it is readily accepted as a vital spinal and supraspinal inhibitory transmitter and we know many details regarding its molecular structure and trafficking around neurones. The pharmacology of these receptors has lagged behind that of GABA. There is not the rich variety of allosteric modulators that we have come to readily associate with GABA receptors and which has provided us with a virtual treasure trove of important drugs used in anxiety, insomnia, epilepsy, anaesthesia, and spasticity, all stemming from the actions of the simple neutral amino acid GABA. Nevertheless, the realization that glycine receptors are involved in motor reflexes and nociceptive pathways together with the more recent advent of drugs that exhibit some subtype selectivity make the goal of designing selective therapeutic ligands for the glycine receptor that much closer.

Bowery, N G; Smart, T G



Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits.  


GABA(B) receptors are the G-protein-coupled receptors for gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. They are expressed in almost all neurons of the brain, where they regulate synaptic transmission and signal propagation by controlling the activity of voltage-gated calcium (Ca(v)) and inward-rectifier potassium (K(ir)) channels. Molecular cloning revealed that functional GABA(B) receptors are formed by the heteromeric assembly of GABA(B1) with GABA(B2) subunits. However, cloned GABA(B(1,2)) receptors failed to reproduce the functional diversity observed with native GABA(B) receptors. Here we show by functional proteomics that GABA(B) receptors in the brain are high-molecular-mass complexes of GABA(B1), GABA(B2) and members of a subfamily of the KCTD (potassium channel tetramerization domain-containing) proteins. KCTD proteins 8, 12, 12b and 16 show distinct expression profiles in the brain and associate tightly with the carboxy terminus of GABA(B2) as tetramers. This co-assembly changes the properties of the GABA(B(1,2)) core receptor: the KCTD proteins increase agonist potency and markedly alter the G-protein signalling of the receptors by accelerating onset and promoting desensitization in a KCTD-subtype-specific manner. Taken together, our results establish the KCTD proteins as auxiliary subunits of GABA(B) receptors that determine the pharmacology and kinetics of the receptor response. PMID:20400944

Schwenk, Jochen; Metz, Michaela; Zolles, Gerd; Turecek, Rostislav; Fritzius, Thorsten; Bildl, Wolfgang; Tarusawa, Etsuko; Kulik, Akos; Unger, Andreas; Ivankova, Klara; Seddik, Riad; Tiao, Jim Y; Rajalu, Mathieu; Trojanova, Johana; Rohde, Volker; Gassmann, Martin; Schulte, Uwe; Fakler, Bernd; Bettler, Bernhard



Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse.  


One feature of neuropathic pain is a reduced spinal gamma-aminobutyric acid (GABA)-ergic inhibitory function. However, the mechanisms behind this attenuation remain to be elucidated. This study investigated the involvement of reactive oxygen species in the spinal GABA neuron loss and reduced GABA neuron excitability in spinal nerve ligation (SNL) model of neuropathic pain in mice. The importance of spinal GABAergic inhibition in neuropathic pain was tested by examining the effects of intrathecally administered GABA receptor agonists and antagonists in SNL and naïve mice, respectively. The effects of SNL and antioxidant treatment on GABA neuron loss and functional changes were examined in transgenic GAD67-enhanced green fluorescent protein positive (EGFP+) mice. GABA receptor agonists transiently reversed mechanical hypersensitivity of the hind paw in SNL mice. On the other hand, GABA receptor antagonists made naïve mice mechanically hypersensitive. Stereological analysis showed that the numbers of enhanced green fluorescent protein positive (EGFP+) GABA neurons were significantly decreased in the lateral superficial laminae (I-II) on the ipsilateral L5 spinal cord after SNL. Repeated antioxidant treatments significantly reduced the pain behaviors and prevented the reduction in EGFP+ GABA neurons. The response rate of the tonic firing GABA neurons recorded from SNL mice increased with antioxidant treatment, whereas no change was seen in those recorded from naïve mice, which suggested that oxidative stress impaired some spinal GABA neuron activity in the neuropathic pain condition. Together the data suggest that neuropathic pain, at least partially, is attributed to oxidative stress, which induces both a GABA neuron loss and dysfunction of surviving GABA neurons. PMID:23880056

Yowtak, June; Wang, Jigong; Kim, Hee Young; Lu, Ying; Chung, Kyungsoon; Chung, Jin Mo



Ionic Mechanisms of Neuronal Excitation by Inhibitory GABA_A Receptors  

NASA Astrophysics Data System (ADS)

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.

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



In Vivo Measurements of Glutamate, GABA, and NAAG in Schizophrenia.  


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

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



GABA affects novel object recognition memory and working memory in rats.  


?-Aminobutyric acid (GABA) is an amino acid found in unpolished rice, chocolate, tea, and other foods. It is an important inhibitory neurotransmitter. However, the influence of GABA on object recognition and working memory is still unknown. In this study, the effects of GABA on novel object recognition (NOR) memory and working memory were examined. The proper retention interval and delay time were also investigated for the NOR test and T-maze test, respectively. Male 3-wk-old Wistar rats were allowed free access to food and water containing 0.5% GABA or 1% GABA for a month. After that, the rats performed the NOR test at a 48 h retention interval and T-maze test at a 900 s delay time to estimate the effects of GABA on learning behavior. The results showed that the object information in the NOR test was stored as long-term memory and the recognition index (RI) was significantly increased after GABA administration. The accuracy rate also significantly increased after GABA administration. These indicate that GABA may be involved in long-term object recognition memory and working memory. PMID:23727647

Thanapreedawat, Panicha; Kobayashi, Hiroki; Inui, Naoto; Sakamoto, Kazuhiro; Kim, Mujo; Yoto, Ai; Yokogoshi, Hidehiko



Sodium-independent, bicuculline-sensitive (/sup 3/H)GABA binding to isolated rat hepatocytes  

SciTech Connect

To determine whether hepatocytes possess specific receptor sites for gamma-aminobutyric acid (GABA), a potent amino acid neurotransmitter, (/sup 3/H)GABA, was added to sodium-free suspensions of Percoll-purified hepatocytes derived from collagenase-perfused rat livers under various experimental conditions and in the presence or absence of specific GABA receptor agonists (muscimol) and antagonists (bicuculline). The effects of GABA, muscimol, and bicuculline on hepatocyte resting membrane potentials were also determined. Specific binding of (/sup 3/H)GABA to hepatocytes was a consistent finding. GABA-hepatocyte interactions were reversible and temperature dependent. Muscimol and bicuculline inhibited binding in a dose-dependent manner (IC50, 30 nM and 50 microM, respectively), whereas strychnine (1.0-100 microM), a nonspecific central nervous system stimulant, had no appreciable effect. Both GABA and muscimol (100 microM) caused significant hyperpolarization of hepatocyte resting membrane potential (delta PD 5.4 +/- 3.1 and 22.2 +/- 16.2 mV, respectively, means +/- SD, P less than 0.0005). Bicuculline (100 microM) inhibited the effect of muscimol (P less than 0.05). The results of this study suggest that specific GABA receptor sites exist on the surface of isolated rat hepatocytes. The presence of such sites raises the possibility that, in addition to adrenergic and cholinergic innervation, hepatic function may be influenced by GABA-ergic neurotransmitter mechanisms.

Minuk, G.Y.; Bear, C.E.; Sarjeant, E.J.



Convulsions induced by methylmalonic acid are associated with glutamic acid decarboxylase inhibition in rats: a role for GABA in the seizures presented by methylmalonic acidemic patients?  


Methylmalonic acid (MMA) is an endogenous convulsing compound that accumulates in methylmalonic acidemia, an inborn error of the metabolism characterized by severe neurological dysfunction, including seizures. The mechanisms by which MMA causes seizures involves the activation of the N-methyl-D-aspartate (NMDA) receptors, but whether GABAergic mechanisms are involved in the convulsions induced by MMA is not known. Therefore, in the current study we investigated the involvement of GABAergic mechanisms in the convulsions induced by MMA. Adult rats were injected (i.c.v.) with muscimol (46 pmol/1 microl), baclofen (0.03, 0.1 and 0.3 micromol/1 microl), MK-801 (6 nmol/1 microl), pyridoxine (2 micromol/4 microl) or physiological saline (0.15 micromol/1 microl). After 30 min, MMA (0.3, 0.1 and 3 micromol/1 microl) or NaCl (6 micromol/1 microl, i.c.v.) was injected. The animals were immediately transferred to an open field and observed for the appearance of convulsions. After behavioral evaluation, glutamic acid decarboxylase (GAD) activity was determined in cerebral cortex homogenates by measuring the 14CO2 released from l-[14C]-glutamic acid. Convulsions were confirmed by electroencephalographic recording in a subset of animals. MMA caused the appearance of clonic convulsions in a dose-dependent manner and decreased GAD activity in the cerebral cortex ex vivo. GAD activity negatively correlated with duration of MMA-induced convulsions (r=-0.873, P<0.01), in an individual basis. Muscimol, baclofen, MK-801 and pyridoxine prevented MMA-induced convulsions, but only MK-801 and pyridoxine prevented MMA-induced GAD inhibition. These data suggest GABAergic mechanisms are involved in the convulsive action of MMA, and that GAD inhibition by MMA depends on the activation of NMDA receptors. While in this study we present novel data about the role of the GABAergic system in MMA-induced convulsions, the central role of NMDA receptors in the neurochemical actions of MMA is further reinforced since they seem to trigger GABAergic failure. PMID:17467181

Malfatti, C R M; Perry, M L S; Schweigert, I D; Muller, A P; Paquetti, L; Rigo, F K; Fighera, M R; Garrido-Sanabria, E R; Mello, C F



Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia  

Microsoft Academic Search

In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in ?-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic

T Hashimoto; D Arion; T Unger; J G Maldonado-Avilés; H M Morris; D W Volk; K Mirnics; D A Lewis; DA Lewis



Neuronal Glutamate Uptake Contributes to GABA Synthesis and Inhibitory Synaptic Strength  

Microsoft Academic Search

Neurons must maintain a supply of neurotransmitter in their presynaptic terminals to fill synaptic vesicles. GABA is taken up into inhibitory terminals by transporters or is synthesized from glutamate by glutamic acid decarboxylase. Here we report that glutamate transporters supply GABAergic terminals in the hippocampus with glutamate, which is then used to synthesize GABA for filling synaptic vesicles. Glutamate transporter

Gregory C. Mathews; Jeffrey S. Diamond


Identification of GABA receptors in chick cornea  

PubMed Central

Purpose The cornea has an important role in vision, is highly innervated and many neurotransmitter receptors are present, e.g., muscarine, melatonin, and dopamine receptors. ?-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the retina and central nervous system, but it is unknown whether GABA receptors are present in cornea. The aim of this study was to determine if GABA receptors are located in chick cornea. Methods Corneal tissues were collected from 25, 12-day-old chicks. Real time PCR, western blot, and immunohistochemistry were used to determine whether alpha1 GABAA, GABAB, and rho1 GABAC receptors were expressed and located in chick cornea. Results Corneal tissue was positive for alpha1 GABAA and rho1 GABAC receptor mRNA (PCR) and protein (western blot) expression but was negative for GABAB receptor mRNA and protein. Alpha1 GABAA and rho1 GABAC receptor protein labeling was observed in the corneal epithelium using immunohistochemistry. Conclusions These investigations clearly show that chick cornea possesses alpha1 GABAA, and rho1 GABAC receptors, but not GABAB receptors. The purpose of the alpha1 GABAA and rho1 GABAC receptors in cornea is a fascinating unexplored question.

Cheng, Zhen-Ying; Chebib, Mary



Effects of vigabatrin intake on brain GABA activity as monitored by spectrally edited magnetic resonance spectroscopy and positron emission tomography.  


A deficit in gamma-aminobutyric acid (GABA) levels in the brain or the cerebrospinal fluid (CSF) is found in many epilepsy patients. Frequency and severity of seizures may be reduced by treatment with GABA increasing medicaments as e.g. vigabatrin, an irreversible inhibitor of GABA-transaminase. For a better understanding of the associated effects, healthy volunteers were examined with magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) before and after intake of different doses of vigabatrin. For the MRS examinations, a dedicated localized spectral editing method was developed to determine GABA levels. The 11C-flumazenil (FMZ)-PET protocol allowed determination of GABA-A receptor binding. The results show a clear and dose-dependent increase in the brain GABA levels after the medication period as compared to the baseline values. The GABA-A receptor binding, on the other hand, did not change significantly. PMID:10195585

Weber, O M; Verhagen, A; Duc, C O; Meier, D; Leenders, K L; Boesiger, P



Smoking-mediated up-regulation of GAD67 expression in the human airway epithelium  

Microsoft Academic Search

BACKGROUND: The production of gamma-amino butyric acid (GABA) is dependent on glutamate decarboxylases (GAD65 and GAD67), the enzymes that catalyze the decarboxylation of glutamate to GABA. Based on studies suggesting a role of the airway epithelial GABAergic system in asthma-related mucus overproduction, we hypothesized that cigarette smoking, another disorder associated with increased mucus production, may modulate GABAergic system-related gene expression

Guoqing Wang; Rui Wang; Barbara Ferris; Jacqueline Salit; Yael Strulovici-Barel; Neil R Hackett; Ronald G Crystal



Anticonvulsant activity of new GABA prodrugs.  


4-(3,4-Dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)-butyric acid (7) and its ethyl (6), two potential y-aminobutyric acid (GABA) prodrugs, were synthesized and studied to determine their stability in aqueous buffer and their susceptibility to undergo enzymatic hydrolysis in vitro (mouse plasma). Both compounds were fairly stable in aqueous media, (t((1/2)) = 68.2 h and 25.7 h, respectively). The 3,4-dihydro-2,4-dioxo-2 H-I,3-benzoxazine ring underwent enzymatic hydrolysis (t((1/2)) =5.8 h) in compound 7, whereas in compound 6 it seemed not to be opened by mouse plasma esterases within the observation lime (3 h). Both compounds were tested for their central nervous system activity by using both anticonvulsive and behavioral tests. The anticonvulsive study was performed using the convulsive agent pentetrazole (PTX) and bicuculline. The anticonvulsive study indicated that compound both compounds 6 and 7 (10, 20 and 40 mg/kg, i.p.), injected 60 min before PTX (75 mg/kg, i.p.) or bicuculline (10 microg/intracerebroventricular (i.c.v.)/mouse) induced a dose-dependent and significant reduction of the convulsive activity of PTZ and bicuculline whereas it was ineffective if injected immediately before the convulsive agent. Both compounds 6 and 7 (10, 20 and 40 mg/kg, i.p.) did not significantly modify animal behavior or the nociceptive threshold of the animals. However, in PTZ- and bicuculline- treated mice, compound 7 showed significant activity, compared to compound 6, because it was active at relatively low doses. The behavior elements considered were locomotor activity, motor coordination, catalepsy, behavior and antinociception. The results of the behavoral study indicate that these new GABA mimetic drugs did not modify the animal behavior. Our data indicate that these new GABA mimetic drug possesses good anticonvulsive activity without altering the animalbehavior and their ability to block bicuculline-induced convulsions suggests that they could be a GABA(A) mimetic drug. Furthermore, since these compounds are able to act after systemic administration, our data suggest that these new GABA mimetic drug cross the blood-brain barrier. PMID:19689391

Capasso, A; Gallo, C



Inhibition of the rate of GABA synthesis in regions of rat brain following a convulsion.  

PubMed Central

1 The rate of synthesis of gamma-aminobutyric acid (GABA) in the cortex, hippocampus and striatum of rat brain was assessed by measuring the linear rate of accumulation of GABA following injection of amino-oxyacetic acid (AOAA). 2 Five min after a single electrically induced seizure there was a rise in GABA content in these brain regions and an almost total inhibition of the rate of synthesis. 3 Five min after seizure induced by the inhalant convulsant flurothyl there was no rise in GABA content in these brain regions but a similar marked degree of inhibition of GABA synthesis. 4 Two hours after the convulsion the rate of GABA synthesis had returned to control values in all three brain regions. 5 A single convulsion did not alter the glutamic acid decarboxylase activity in these brain regions either in the absence or presence of added co-factor (pyridoxal phosphate). 6 Evidence for an inhibition of GABA release following a convulsion which may be associated with the inhibition of GABA synthesis is presented in the following paper.

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



Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro  

PubMed Central

The excitatory action of gamma-aminobutyric acid (GABA) is considered to be a hallmark of the developing nervous system. However, in immature brain slices, excitatory GABA actions may be secondary to neuronal injury during slice preparation. Here, we explored GABA actions in the rodent intact hippocampal preparations and at different depths of hippocampal slices during the early post-natal period [post-natal days (P) 1–7]. We found that in the intact hippocampus at P1–3: (i) GABA exerts depolarizing action as seen in cell-attached single GABA(A) channel recordings; (ii) GABA(A) receptor (GABA(A)-R) agonist isoguvacine and synaptic activation of the GABA(A)-Rs increase the frequency of multiple unit activity and the frequency of the network-driven giant depolarizing potentials (GDPs); and that (iii) Na+–K+–2Cl- cotransporter (NKCC1) antagonist bumetanide suppresses GDPs and the excitatory actions of isoguvacine. In the hippocampal slices at P2–5, isoguvacine and synaptic activation of GABA(A)-Rs-evoked excitatory responses at all slice depths, including surface and core. Thus, GABA exerts excitatory actions in the intact hippocampus (P1–3) and at all depths of hippocampal slices (P2–5). Therefore, the excitatory actions of GABA in hippocampal slices during the first post-natal days are not due to neuronal injury during slice preparation, and the trauma-related excitatory GABA actions at the slice surface are a fundamentally different phenomenon observed during the second post-natal week.

Valeeva, Guzel; Valiullina, Fliza; Khazipov, Roustem



Reproducibility of GABA measurements using 2D J-resolved magnetic resonance spectroscopy.  


We determined the reproducibility of GABA (gamma-aminobutyric acid) measurements using 2D J-resolved magnetic resonance spectroscopy (MRS) on a clinical 1.5-T MR imaging scanner. Two-dimensional J-resolved spectra were acquired in vitro across five GABA concentrations using a volume head coil and a 5-in. surface coil. Additional spectra using a sixth GABA phantom with a very low concentration and from a healthy volunteer were recorded in the 5-in. surface coil only. In each case, the 3.01-ppm GABA resonance was quantified; for comparison, the peak integrals of choline (3.2 ppm) and creatine (3.03 ppm) were recorded. At a physiological concentration (1.2 mM), in vitro GABA measurement was significantly more reproducible in the surface coil than in the volume coil (P=.005), with coefficients of variation (CVs) being less than 16% with the surface coil and up to 68% with the volume head coil. At the smallest concentration of in vivo GABA reported using other spectroscopy techniques (0.8 mM) and detected only using the surface coil, the CV for GABA was 23% and was less than 10% for choline and creatine, which compare favorably with results from published studies. In vivo, the CV for GABA measurement was 26%, suggesting that 2D J-resolved MRS would be suitable for detecting physiological changes in GABA, similar to those reported using other methods. PMID:17540274

Lymer, Katherine; Haga, Kristin; Marshall, Ian; Sailasuta, Napapon; Wardlaw, Joanna



Proline antagonizes GABA-induced quenching of quorum-sensing in Agrobacterium tumefaciens.  


Plants accumulate free L-proline (Pro) in response to abiotic stresses (drought and salinity) and presence of bacterial pathogens, including the tumor-inducing bacterium Agrobacterium tumefaciens. However, the function of Pro accumulation in host-pathogen interaction is still unclear. Here, we demonstrated that Pro antagonizes plant GABA-defense in the A. tumefaciens C58-induced tumor by interfering with the import of GABA and consequently the GABA-induced degradation of the bacterial quorum-sensing signal, 3-oxo-octanoylhomoserine lactone. We identified a bacterial receptor Atu2422, which is implicated in the uptake of GABA and Pro, suggesting that Pro acts as a natural antagonist of GABA-signaling. The Atu2422 amino acid sequence contains a Venus flytrap domain that is required for trapping GABA in human GABA(B) receptors. A constructed atu2422 mutant was more virulent than the wild type bacterium; moreover, transgenic plants with a low level of Pro exhibited less severe tumor symptoms than did their wild-type parents, revealing a crucial role for Venus flytrap GABA-receptor and relative abundance of GABA and Pro in host-pathogen interaction. PMID:19706545

Haudecoeur, E; Planamente, S; Cirou, A; Tannières, M; Shelp, B J; Moréra, S; Faure, D



Presynaptic GABA-A receptors prevent depression of nicotinic transmission in rabbit coeliac ganglion neurones.  


We investigated the involvement of GABA-A receptors in the modulation of the nicotinic transmission of central origin in isolated rabbit coeliac ganglia. Our study was performed in vitro and the electrical activity of the ganglionic neurones was recorded using intracellular recording techniques. During iterative stimulation of the splanchnic nerves, the synaptic action potential probability decreased gradually, indicating a depression of the nicotinic activation. Pharmacological agents acting at GABA-A receptors modulated the action potential probability during the train of pulses. Muscimol (a GABA-A receptor agonist), diazepam (a benzodiazepine site agonist) and 1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (a GABA uptake blocker) increased this probability. Conversely, gabazine or bicuculline (two GABA-A receptor antagonists), picrotoxin (a picrotoxin site agonist) and flumazenil (a benzodiazepine site antagonist) reduced it. These results demonstrate that endogenous GABA, released during the train of pulses, facilitates the central nicotinic activation of the ganglionic neurones by acting on GABA-A receptors. Muscimol also reduced the amplitude ratio of excitatory postsynaptic potentials triggered during the paired-pulse protocol without any change in postsynaptic properties. This result is consistent with a presynaptic action of GABA-A receptors. Our study shows that presynaptic GABA-A receptors facilitate the central nicotinic activation of prevertebral ganglionic neurones and thus play a novel role in the integrative properties of the sympathetic prevertebral ganglia. PMID:17425557

Ercoli, Jennifer; Miolan, Jean Pierre; Niel, Jean Pierre; Quinson, Nathalie



Pretreatment of rat brain synaptosomes with GABA increases subsequent GABA uptake via GABA(B) receptor activation.  


Pretreatment with 100 microM GABA of synaptosomes purified from rat brain results in an increased uptake of the labelled neurotransmitter in subsequent incubations. The effect is blocked by a GABA(B) receptor antagonist, 2-hydroxy-saclofen. The effect is mimicked by baclofen and the baclofen effect is blocked by saclofen too. Lower GABA concentrations (up to 50 microM) do not result in an increase of subsequent GABA uptake. Treatment of synaptosomes with 8-Br-cAMP results in a decreased GABA uptake. Since the uptake incubations were run with saturating concentrations of labelled GABA, the data indicates that GABA(B) receptor activation in brain synaptosomes up-regulates their GABA uptake capacity by an increase in Vmax. This mechanism appears of physiological relevance under conditions of sustained GABA release and substantial increase of its extracellular concentration. PMID:11358276

Cupello, A; Scarrone, S



Focal uncaging of GABA reveals a temporally defined role for GABAergic inhibition during appetitive associative olfactory conditioning in honeybees.  


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 different approaches to activate GABA receptors during appetitive olfactory conditioning in the honeybee. Injection of GABA-A receptor agonist muscimol 20 min before but not 20 min after associative conditioning affects memory performance. These memory deficits were attenuated by additional training sessions. Muscimol has no effect on sensory perception, odor generalization, and nonassociative learning, indicating a specific role of GABA during associative conditioning. We used photolytic uncaging of GABA to identify the GABA-sensitive time window during the short pairing of the conditioned stimulus (CS) and the unconditioned stimulus (US) that lasts only seconds. Either uncaging of GABA in the antennal lobes or the mushroom bodies during the CS presentation of the CS-US pairing impairs memory formation, while uncaging GABA during the US phase has no effect on memory. Uncaging GABA during the CS presentation in memory retrieval also has no effect. Thus, in honeybee appetitive olfactory learning GABA specifically interferes with the integration of CS and US during associative conditioning and exerts a modulatory role in memory formation depending on the training strength. PMID:23860600

Raccuglia, Davide; Mueller, Uli



Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia.  


In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in gamma-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD(67)) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA(A) receptor subunits (alpha1, alpha4, beta3, gamma2 and delta). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD(67), SST and alpha1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABA(A) receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits. PMID:17471287

Hashimoto, T; Arion, D; Unger, T; Maldonado-Avilés, J G; Morris, H M; Volk, D W; Mirnics, K; Lewis, D A



Potentiation of the ionotropic GABA receptor response by whiskey fragrance.  


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

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



The Arabidopsis pop2-1 mutant reveals the involvement of GABA transaminase in salt stress tolerance  

Microsoft Academic Search

BACKGROUND: GABA (?-aminobutyric acid) is a non protein amino acid that has been reported to accumulate in a number of plant species when subjected to high salinity and many other environmental constraints. However, no experimental data are to date available on the molecular function of GABA and the involvement of its metabolism in salt stress tolerance in higher plants. Here,

Hugues Renault; Valérie Roussel; Abdelhak El Amrani; Matthieu Arzel; David Renault; Alain Bouchereau; Carole Deleu



Inward current caused by sodium-dependent uptake of GABA in the crayfish stretch receptor neurone.  

PubMed Central

A two-microelectrode current-voltage clamp and Cl(-)-selective microelectrodes were used to examine the effects of gamma-aminobutyric acid (GABA) on membrane potential, current and intracellular Cl- activity (aiCl) in the crayfish stretch receptor neurone. All experimental solutions were CO2-HCO3- free. 2. GABA (500 microM) produced a mono- or biphasic depolarization (amplitude < or = 10 mV), often with a prominent initial depolarizing component followed by a transient shift to a more negative level. In some neurones, an additional depolarizing phase was seen upon washout of GABA. Receptor desensitization, being absent, played no role in the multiphasic actions of GABA. 3. The pronounced increase in membrane conductance evoked by GABA (500 microM) was associated with an increase in aiCl which indicates that the depolarizing action was not due to a current carried by Cl- ions. 4. The currents activated by GABA under voltage clamp conditions were inwardly directed when recorded at the level of the resting membrane potential, and they often revealed a biphasic character. The reversal potential of peak currents activated by pulses of 500 microM-GABA (EGABA) was 9-12 mV more positive than the reversal potential of the simultaneously measured net Cl- flux (ECl). ECl was 2-7 mV more negative than the resting membrane potential. 5. EGABA (measured using pulses of 500 microM-GABA) was about 10 mV more positive than the reversal potential of the current activated by 500 microM-muscimol, a GABA agonist that is a poor substrate of the Na(+)-dependent GABA uptake system. 6. In the absence of Na+, the depolarization and inward current caused by 500 microM-GABA were converted to a hyperpolarization and to an outward current. Muscimol produced an immediate outward current both in the presence and absence of Na+. 7. Following block of the inhibitory channels by picrotoxin (100-200 microM), the depolarizing effect of 500 microM-GABA was enhanced and the transient hyperpolarizing shifts were abolished. 8. In the presence of picrotoxin, GABA (> or = 2 microM) produced a concentration-dependent monophasic inward current which had a reversal potential of +30 to +60 mV. This current was inhibited in the absence of Na+ and by the GABA uptake blocker, nipecotic acid. Unlike the channel-mediated current, the picrotoxin-insensitive current was activated without delay also at low (2-10 microM) concentrations of GABA.(ABSTRACT TRUNCATED AT 400 WORDS)

Kaila, K; Rydqvist, B; Pasternack, M; Voipio, J



GABA and chloride permeate via the same channels across single plasma membranes microdissected from rabbit Deiters' vestibular neurones.  


The permeation of labelled gamma-aminobutyric acid (GABA) across single microdissected Deiters' membranes has been studied in a microchamber system. The GABA permeation is via pores which are blocked by 4,4'-diisothiocyanato stilbene-2-2'disulphonic acid (DIDS). As this substance blocks as well chloride permeation across these membranes we tested whether GABA and chloride permeate across the same pores. Membrane pre-treatment with different doses of corticotropin releasing factor (CRF), a membrane permeant cyclic AMP analogue and phalloidin parallelly block the permeation of the two substances. Thus, it is most probable that GABA and chloride pass across the same pores. These pores may be swelling activated ones, opened by the mechanical stress on the membranes in the microchamber system. The passage of GABA across these pores may be of physiological importance in the termination of GABA inhibitory action on the vestibular Deiters' neurones. PMID:11683681

Rapallino, M V; Cupello, A



GABA as an Inhibitory Neurotransmitter in Human Cerebral Cortex  

Microsoft Academic Search

1. The possible role of y-aminobutyric acid (GABA) as an in- hibitory neurotransmitter in the human cerebral cortex was in- vestigated with the use of intracellular recordings from neocorti- cal slices maintained in vitro. 2. Electrical stimulation of afferents to presumed pyramidal cells resulted in an initial excitatory postsynaptic potential (EPSP) followed by fast and slow inhibitory postsynaptic potentials (IPSPs).




Development of GABA innervation in the cerebral and cerebellar cortices  

Microsoft Academic Search

In many areas of the vertebrate brain, such as the cerebral and cerebellar cortices, neural circuits rely on inhibition mediated by GABA (?-aminobutyric acid) to shape the spatiotemporal patterns of electrical signalling. The richness and subtlety of inhibition are achieved by diverse classes of interneurons that are endowed with distinct physiological properties. In addition, the axons of interneurons display highly

G. Di Cristo; F. Ango; Z. J. Huang



Analysis of gaba and glutamate in the mouse dorsal striatum  

Microsoft Academic Search

\\u000aANALYSIS OF GABA AND GLUTAMATE IN MICE BRAIN\\u000aby\\u000aSTELLA WISIDAGAMA\\u000aMay 2011\\u000aAdvisor: Dr. Tiffany Mathews\\u000aMajor: Chemistry (Analytical)\\u000aDegree: Master of Science\\u000aGABA and glutamate are the predominant inhibitory and excitatory amino acid neurotransmitters in the central nervous system (CNS), respectively. However, their altered levels cause several neurological diseases including Parkinson's and Huntington's disease, schizophrenia, and epilepsy. It

Stella Wisidagamage



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


GABA (?-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

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



GABA Accumulation Causes Cell Elongation Defects and a Decrease in Expression of Genes Encoding Secreted and Cell Wall-Related Proteins in Arabidopsis thaliana  

PubMed Central

GABA (?-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.

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



Actions of insecticides on the insect GABA receptor complex  

SciTech Connect

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.

Bermudez, I.; Hawkins, C.A.; Taylor, A.M.; Beadle, D.J. (School of Biological and Molecular Sciences, Oxford Polytechnic, Headington, Oxford (England))



Dopamine and Serotonin Modulate Human GABA?1 Receptors Expressed in Xenopus laevis Oocytes  

PubMed Central

GABA?1 receptors are highly expressed in bipolar neurons of the retina and to a lesser extent in several areas of the central nervous system (CNS), and dopamine and serotonin are also involved in the modulation of retinal neural transmission. Whether these biogenic amines have a direct effect on ionotropic GABA receptors was not known. Here, we report that GABA?1 receptors, expressed in X. laevis oocytes, were negatively modulated by dopamine and serotonin and less so by octopamine and tyramine. Interestingly, these molecules did not have effects on GABAA receptors. 5-Carboxamido-tryptamine and apomorphine did not exert evident effects on any of the receptors. Schild plot analyses of the inhibitory actions of dopamine and serotonin on currents elicited by GABA showed slopes of 2.7 ± 0.3 and 6.1 ± 1.8, respectively, indicating a noncompetitive mechanism of inhibition. The inhibition of GABA?1 currents was independent of the membrane potential and was insensitive to picrotoxin, a GABA receptor channel blocker and to the GABA?-specific antagonist (1,2,5,6-tetrahydropyridine-4-yl)methyl phosphinic acid (TPMPA). Dopamine and serotonin changed the sensitivity of GABA?1 receptors to the inhibitory actions of Zn2+. In contrast, La3+ potentiated the amplitude of the GABA currents generated during negative modulation by dopamine (EC50 146 ?M) and serotonin (EC50 196 ?M). The functional role of the direct modulation of GABA? receptors by dopamine and serotonin remains to be elucidated; however, it may represent an important modulatory pathway in the retina, where GABA? receptors are highly expressed and where these biogenic amines are abundant.



Decreased GABA and glutamate concentration in rat brain after treatment with 6-aminonicotinamide  

Microsoft Academic Search

The effect of 6-aminonicotinamide (6-AN) on putative amino acid neurotransmitters, namely glutamate, GABA and aspartate was studied on brains of rats treated with this antimetabolite (35 mg\\/kg i.p.).

L. Bielicki; J. Krieglstein



Components of basal and GABA activated 36Cl- influx in rat cerebral cortex microsacs.  


The basal and GABA activated accumulation of labelled chloride in rat cerebral cortex microsacs has been studied as a function of incubation time. Basal accumulation has biphasic kinetics within 2 minutes of incubation with two components clearly visible. GABA activated stimulation has two phases as well, starting from (GABA) = 10(-5) M, one appearing within seconds of incubation range and the other one within tens of seconds. Both GABA-activated components are blocked by bicuculline methiodide (BMI). Practically no effect by 10(-3) M nipecotic acid was found on either the comparatively rapid or the slower phase. The two GABA activated components may correspond to two different populations of sealed vesicles with different receptor concentration per internal volume. PMID:1342012

Cupello, A; Rapallino, M V; Mainardi, P



Presynaptic but not postsynaptic GABA signaling at unitary mossy fiber synapses.  


Dentate gyrus granule cells have been suggested to corelease GABA and glutamate both in juvenile animals and under pathological conditions in adults. Although mossy fiber terminals (MFTs) are known to express glutamic acid decarboxylase (GAD) in early postnatal development, the functional role of GABA synthesis in MFTs remains controversial, and direct evidence for synaptic GABA release from MFTs is missing. Here, using GAD67-GFP transgenic mice, we show that GAD67 is expressed only in a population of immature granule cells in juvenile animals. We demonstrate that GABA can be released from these cells and modulate mossy fiber excitability through activation of GABAB autoreceptors. However, unitary postsynaptic currents generated by individual, GAD67-expressing granule cells are purely glutamatergic in all postsynaptic cell types tested. Thus GAD67 expression does not endow dentate gyrus granule cells with a full GABAergic phenotype and GABA primarily instructs the pre- rather than the postsynaptic element. PMID:22915124

Cabezas, Carolina; Irinopoulou, Theano; Gauvain, Grégory; Poncer, Jean Christophe



Neuronal glutamate uptake Contributes to GABA synthesis and inhibitory synaptic strength.  


Neurons must maintain a supply of neurotransmitter in their presynaptic terminals to fill synaptic vesicles. GABA is taken up into inhibitory terminals by transporters or is synthesized from glutamate by glutamic acid decarboxylase. Here we report that glutamate transporters supply GABAergic terminals in the hippocampus with glutamate, which is then used to synthesize GABA for filling synaptic vesicles. Glutamate transporter antagonists reduced IPSC and miniature IPSC (mIPSC) amplitudes, consistent with a reduction in the amount of GABA packaged into each synaptic vesicle. This reduction occurred rapidly and independently of synaptic activity, suggesting that modulation of vesicular GABA content does not require vesicle release and refilling. Raising extracellular glutamate levels increased mIPSC amplitudes by enhancing glutamate uptake and, consequently, GABA synthesis. These results indicate that neuronal glutamate transporters strengthen inhibitory synapses in response to extracellular glutamate. This modulation appears to occur under normal conditions and may constitute a negative feedback mechanism to combat hyperexcitability. PMID:12657662

Mathews, Gregory C; Diamond, Jeffrey S



The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus  

PubMed Central

The extracellular space of the brain contains ?-aminobutyric acid (GABA) that activates extrasynaptic GABAA receptors mediating tonic inhibition. The source of this GABA is uncertain: it could be overspill of vesicular release, non-vesicular leakage, reverse transport, dying cells or glia. Using a novel approach, we simultaneously measured phasic and tonic inhibitory currents and assessed their correlation. Enhancing or diminishing vesicular GABA release in hippocampal neurons caused highly correlated changes in the two inhibitions. During high-frequency phasic inhibitory bursts, tonic current was also enhanced as shown by simulating the summation of IPSCs and by recordings in knockout mice devoid of tonic inhibitory current. When vesicular release was reduced by blocking action potentials or the vesicular GABA transporter, phasic and tonic currents decreased in a correlated fashion. Our results are consistent with most of hippocampal tonic inhibitory current being mediated by GABA released from the very vesicles responsible for activating phasic inhibition.

Glykys, Joseph; Mody, Istvan



Excitatory Synaptic Responses Mediated by GABA_A Receptors in the Hippocampus  

NASA Astrophysics Data System (ADS)

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cortex. Activation of postsynaptic GABA_A receptors hyperpolarizes cells and inhibits neuronal activity. Synaptic responses mediated by GABA_A receptors also strongly excited hippocampal neurons. This excitatory response was recorded in morphologically identified interneurons in the presence of 4-aminopyridine or after elevation of extracellular potassium concentrations. The synaptic excitation sustained by GABA_A receptors synchronized the activity of inhibitory interneurons. This synchronized discharge of interneurons in turn elicited large-amplitude inhibitory postsynaptic potentials in pyramidal and granule cells. Excitatory synaptic responses mediated by GABA_A receptors may thus provide a mechanism for the recruitment of GABAergic interneurons through their recurrent connections.

Michelson, Hillary B.; Wong, Robert K. S.



Glycine, GABA and synaptic inhibition of reticulospinal neurones of lamprey.  

PubMed Central

1. Intracellular recordings were made from the cell bodies and axons of giant reticulospinal neurones (Müller cells) of the lamprey and the effects of a variety of putative neurotransmitters tested. Bath-applied acetylcholine, carbamylcholine, norepinephrine, dopamine, histamine and serotonin were without effect. Glycine and gamma-aminobutyric acid (GABA) hyperpolarized and reduced the input resistance of cell bodies but had no effect on the membrane conductance of axons. 2. The threshold dose of bath-applied GABA or glycine for a conductance change in somata was about 0.5 mM and the maximum effect was reached at about 10 mM. The maximum conductance change produced by glycine was always greater than that produced by GABA. 3. Replacement of the sodium in the bathing saline with lithium or choline prolonged the conductance change produced by ionophoretically applied glycine or GABA, suggesting the presence of sodium-dependent uptake systems for glycine and GABA. 4. The reversal potentials for responses to ionophoretically applied glycine and GABA average about --83 mV, the same as that for the inhibitory post-synaptic potential (i.p.s.p.) produced in Müller cells by stimulation of the ipsilateral vestibular nerve. 5. The i.p.s.p. and drug responses appeared to involve an increase in chloride conductance, since their reversal potentials were shifted appropriately by changes in either internal or external chloride. 6. Changes in extracellular potassium concentration also changed i.p.s.p. and drug reversal potentials. However, these effects could be attributed to secondary changes in internal chloride. 7. The receptors for GABA and glycine appeared to be different because of the absence of cross-desensitization and because, at doses below 20 microM, picrotoxin and bicuculline selectively blocked GABA responses while strychnine selectively blocked glycine responses. 8. At concentrations of 20 microM, strychnine eliminated the i.p.s.p. while picrotoxin and bicuculline had no effect. Further, the i.p.s.p. and glycine response of Müller cells located in the isthmic region of the midbrain had the same threshold sensitivity to strychnine. However, the glycine response of other Müller cells was more sensitive to strychnine than was the i.p.s.p. 9. We conclude that glycine is a better candidate for the inhibitory transmitter onto Müller cells than is GABA.

Matthews, G; Wickelgren, W O



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

PubMed Central

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.

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



GABA receptor ameliorates ventilator-induced lung injury in rats by improving alveolar fluid clearance  

PubMed Central

Introduction Mechanical ventilators are increasingly used in critical care units. However, they can cause lung injury, including pulmonary edema. Our previous studies indicated that ?-aminobutyric acid (GABA) receptors are involved in alveolar-fluid homeostasis. The present study investigated the role of GABA receptors in ventilator-induced lung injury. Methods Adult female Sprague-Dawley rats were subjected to high-tidal-volume ventilation of 40 ml/kg body weight for 1 hour, and lung injuries were assessed. Results High-tidal-volume ventilation resulted in lung injury, as indicated by an increase in total protein in bronchoalveolar fluid, wet-to-dry ratio (indication of pulmonary edema), and Evans Blue dye extravasation (indication of vascular damage). Intratracheal administration of GABA before ventilation significantly reduced the wet-to-dry ratio. Further, histopathologic analysis indicated that GABA reduced ventilator-induced lung injury and apoptosis. GABA-mediated reduction was effectively blocked by the GABAA-receptor antagonist, bicuculline. The GABA-mediated effect was not due to the vascular damage, because no differences in Evans Blue dye extravasation were noted. However, the decrease in alveolar fluid clearance by high-tidal-volume ventilation was partly prevented by GABA, which was blocked by bicuculline. Conclusions These results suggest that GABA reduces pulmonary edema induced by high-tidal-volume ventilation via its effects on alveolar fluid clearance and apoptosis.



Proline antagonizes GABA-induced quenching of quorum-sensing in Agrobacterium tumefaciens  

PubMed Central

Plants accumulate free L-proline (Pro) in response to abiotic stresses (drought and salinity) and presence of bacterial pathogens, including the tumor-inducing bacterium Agrobacterium tumefaciens. However, the function of Pro accumulation in host-pathogen interaction is still unclear. Here, we demonstrated that Pro antagonizes plant GABA-defense in the A. tumefaciens C58-induced tumor by interfering with the import of GABA and consequently the GABA-induced degradation of the bacterial quorum-sensing signal, 3-oxo-octanoylhomoserine lactone. We identified a bacterial receptor Atu2422, which is implicated in the uptake of GABA and Pro, suggesting that Pro acts as a natural antagonist of GABA-signaling. The Atu2422 amino acid sequence contains a Venus flytrap domain that is required for trapping GABA in human GABAB receptors. A constructed atu2422 mutant was more virulent than the wild type bacterium; moreover, transgenic plants with a low level of Pro exhibited less severe tumor symptoms than did their wild-type parents, revealing a crucial role for Venus flytrap GABA-receptor and relative abundance of GABA and Pro in host-pathogen interaction.

Haudecoeur, E.; Planamente, S.; Cirou, A.; Tannieres, M.; Shelp, B. J.; Morera, S.; Faure, D.



Brain GABA editing by localized in vivo (1)H magnetic resonance spectroscopy.  


Editing of GABA by (1)H MRS in a specific brain area is a unique tool for in vivo non-invasive investigation of neurotransmission disorders. Selective GABA detection is achieved using sequences based on double quantum coherence (DQC). Our pulse sequence makes accurate measurements without artefacts due to spatial localization. The sequence was tested on a phantom solution. The effect of vigabatrin, a specific inhibitor of GABA transaminase, was measured in rat brain and GABA detection was performed in vivo in monkey brain using this procedure. Rats were split into two groups. In the control group, the rats had access to water and, in the other group (vigabatrin, VGB, rats), animals were allowed free access to drinking water containing vigabatrin. After 3 weeks of treatment, rats were anesthetized for in vivo NMR spectroscopy investigation. At the end of the experiment, brains were quickly removed, freeze-clamped and extracted with 4% perchloric acid. One part of the acid extract was used for GABA concentrations assessment by ion exchange chromatography with ninhydrin detection. The second was used for high-resolution NMR analysis. By chromatography measurements, the GABA concentration was 1.23+/-0.06 micromol/g for controls, while for vigabatrin-treated rats the GABA concentration was 4.89+/-1.60 micromol/g. The NMR in vivo results were closely correlated with the NMR ex vivo (r=0.99, p<0.01) and chromatography results (r=0.98, p<0.01). The correlation between ex vivo results and chromatography results was also high (r=0.99, p<0.001). This pulse sequence performed GABA editing from a 376 microl voxel located on the right basal ganglia area in a non-human primate brain. This in vivo GABA editing scheme can thus be proposed for accurate measurement of brain GABA concentrations. PMID:15052553

Bielicki, G; Chassain, C; Renou, J P; Farges, M C; Vasson, M P; Eschalier, A; Durif, F



Oncosecretomics coupled to bioenergetics identifies ?-amino adipic acid, isoleucine and GABA as potential biomarkers of cancer: Differential expression of c-Myc, Oct1 and KLF4 coordinates metabolic changes.  


Bioenergetic profiling of tumors is a new challenge of cancer research and medicine as therapies are currently being developed. Meanwhile, methodological means must be proposed to gather information on tumor metabolism in order to adapt these potential therapies to the bioenergetic specificities of tumors. Studies performed on tumors and cancer cell lines have shown that cancer cells bioenergetics is highly variable. This profile changes with microenvironmental conditions (eg. substrate availability), the oncogenes activated (and the tumor suppressors inactivated) and the interaction with the stroma (i.e. reverse Warburg effect). Here, we assessed the power of metabolic footprinting (MFP) to unravel the bioenergetics and associated anabolic changes induced by three oncogenes, c-Myc, KLF4 and Oct1. The MFP approach provides a quantitative analysis of the metabolites secreted and consumed by cancer cells. We used ultra performance liquid chromatography for quantifying the amino acid uptake and secretion. To investigate the potential oncogene-mediated alterations in mitochondrial metabolism, we measured oxygen consumption rate and ATP production as well as the glucose uptake and lactate release. Our findings show that c-Myc deficiency initiates the Warburg effect along with a reduction of mitochondrial respiration. KLF4 deficiency also stimulated glycolysis, albeit without cellular respiration impairment. In contrast, Oct1 deficiency reduced glycolysis and enhanced oxidative phosphorylation efficiency. MFP revealed that c-Myc, KLF4 and Oct1 altered amino acid metabolism with specific patterns. We identified isoleucine, ?-aminoadipic acid and GABA (?-aminoisobutyric acid) as biomarkers related. Our findings establish the impact of Oct1, KLF4 and c-Myc on cancer bioenergetics and evidence a link between oncosecretomics and cellular bioenergetics profile. PMID:22842522

Bellance, Nadège; Pabst, Lisa; Allen, Genevara; Rossignol, Rodrigue; Nagrath, Deepak



Heterogenous GABA(B) receptor-mediated pathways are involved in the local GABAergic system of the rat trigeminal ganglion: possible involvement of KCTD proteins.  


It is well known that Gamma-aminobutyric acid (GABA) plays an important role in signal transduction in the central nervous system. However, the function of GABA in the peripheral nervous system, including sensory ganglions, is still unclear. In this study we have characterized the expression, cellular distribution, and function of GABA(B) receptor subunits, and the recently discovered GABA(B) auxiliary subunits, K(+) channel tetramerization domain-containing (KCTD) proteins, in rat trigeminal ganglion (TG) neuronal cells, which are devoid of synapses. We found heterogeneous expression of both GABA(B1) and GABA(B2) subunits, and a near-plasma membrane localization of KCTD12. In addition, we found that GABA(B2) subunits correlated with KCTD16. Whole-cell current-clamp recordings showed that responses to the GABA(B) receptor agonist, baclofen, were variable and both increases and decreases in excitability were observed. This correlated with observed differences in voltage-dependent K(+) current responses to baclofen in voltage-clamped TG neuronal cells. The functional diversity of the GABA(B)ergic regulation on the excitability of the TG neuronal cell bodies could be due to the heterogenous expression of KCTD proteins, and subsequent regulation of plasma membrane K(+) channels. Taken together with our previous demonstration of a local GABA(A) receptor-mediated system in rat TG, we provide an updated GABAergic model in the rat TG that incorporates both GABA(A)- and GABA(B)-receptor systems. PMID:22626642

Hayasaki, H; Sohma, Y; Kanbara, K; Otsuki, Y



Discriminative stimulus effects of gamma-hydroxybutyrate in pigeons: role of diazepam-sensitive and -insensitive GABA(A) and GABA(B) receptors.  


gamma-Hydroxybutyrate (GHB) is an emerging drug of abuse with multiple mechanisms of action. This study is part of an effort to examine the role of GHB, GABA(A), and GABA(B) receptors in the discriminative stimulus (DS) effects of GHB. In pigeons trained to discriminate 100 mg/kg GHB from saline, GHB and its precursors gamma-butyrolactone and 1,4-butanediol produced 80 to 100% GHB-appropriate responding, whereas other compounds such as morphine, naltrexone, cocaine, and haloperidol produced no more than 34%. Compounds interacting with GABA receptors produced different maximal levels of GHB-appropriate responding. For example, the GABA(A) agonist muscimol produced 3%; the GABA(A)-positive modulators diazepam, pentobarbital, and ethanol, and the GABA(B) agonist baclofen produced levels ranging from 54 to 73%; and the benzodiazepine antagonist flumazenil and inverse agonist Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-alpha]-[1,4]-benzodiazepine-3-carboxylate) both produced 96%. The putative GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) produced 70% GHB-appropriate responding. The GABA(B) antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) completely blocked the GHB-like DS effects of NCS-382 and baclofen at a dose of 56 mg/kg. CGP 35348 also blocked the DS effects of GHB, but incompletely and only at a dose of 560 mg/kg. Together, these results are consistent with a role for diazepam-sensitive and -insensitive GABA(A) and GABA(B) receptors in the DS effects of GHB. Together with previous findings, the present results suggest that diazepam-insensitive GABA(A) receptors are more prominently involved in the DS effects of GHB in pigeons than in rats, whereas GABA(B) receptors are less prominently involved. Exploring the role of GHB receptors with NCS-382 is hampered by its GABA(B) receptor-mediated, GHB-like agonist activity. PMID:14718595

Koek, Wouter; Flores, Lauren R; Carter, Lawrence P; Lamb, R J; Chen, Weibin; Wu, Huifang; Coop, Andrew; France, Charles P



GABA-B receptors in the PNS have a role in Schwann cells differentiation?  

PubMed Central

?-aminobutyric acid type B (GABA-B) receptor mediates the inhibitory transmission of ?-aminobutyric acid in the mammalian nervous system, being present in neurons and also in glial cells. Recently the presence of GABA-B has been demonstrated in Schwann cells (SC) suggesting its contribution in regulating the cell fate, maturation, and plasticity. Here, we further support the functional presence of GABA-B receptor in SC plasma membrane. By confocal microscopy immunofluorescence we provide evidences that GABA-B localization on the cell elongated processes correlates with the morphological changes occurring in the differentiated SC. In vivo most of the GABA-B receptors seem to be present in non-myelinating SC, which are committed to ensheath the nociceptive fibers. Therefore, we argue that GABA-B receptors do not control exclusively the in vivo differentiation yielding the myelinating SC, but are also fundamental in regulating the SC plasticity versus the non-myelinating state. Data from the literature and our recent findings corroborate the role of the GABAergic system and GABA-B receptors in the peripheral nervous system, opening new perspectives on the mechanisms controlling the differentiation of SC.

Procacci, Patrizia; Ballabio, Marinella; Castelnovo, Luca F.; Mantovani, Cristina; Magnaghi, Valerio



Measuring T2 In Vivo With J-Difference Editing: Application to GABA at 3 Tesla  

PubMed Central

Purpose To develop an experimental approach for determining in vivo transverse relaxation rates (T2) of metabolites that are detected by spectral editing without using simulations, and to demonstrate this approach to measure the T2 of ?-aminobutyric acid (GABA). Materials and Methods The proposed method first determines the TE-dependence of the edited signals using measurements in a pure phantom solution (10 mM ?-aminobutyric acid; GABA); the phantom T2 is also determined. Once the editing echo time (TE) -modulation pattern is known, it can then be used to determine T2 in vivo. The method was applied to measure GABA T2 in the occipital lobe of five healthy adult subjects at 3T, using a J-difference editing method. Unwanted macromolecular contributions to the GABA signal were also measured. Results The in vivo T2 of edited GABA signal was 88 ± 12 ms; this preliminary result is somewhat shorter than other metabolite T2 values in the literature at this field strength. Conclusion Spectral editing methods are now widely used to detect low concentration metabolites, such as GABA, but to date no edited acquisition methods have been proposed for the measurement of transverse relaxation times (T2). The method described has been successfully applied to measuring the T2 of GABA.

Edden, Richard A.E.; Intrapiromkul, Jarunee; Zhu, He; Cheng, Ying; Barker, Peter B.



Non-neuronal, slow GABA signalling in the ventrobasal thalamus targets ?-subunit-containing GABA(A) receptors.  


The rodent ventrobasal (VB) thalamus contains a relatively uniform population of thalamocortical (TC) neurons that receive glutamatergic input from the vibrissae and the somatosensory cortex, and inhibitory input from the nucleus reticularis thalami (nRT). In this study we describe ?-aminobutyric acid (GABA)(A) receptor-dependent slow outward currents (SOCs) in TC neurons that are distinct from fast inhibitory postsynaptic currents (IPSCs) and tonic currents. SOCs occurred spontaneously or could be evoked by hypo-osmotic stimulus, and were not blocked by tetrodotoxin, removal of extracellular Ca(2+) or bafilomycin A1, indicating a non-synaptic, non-vesicular GABA origin. SOCs were more common in TC neurons of the VB compared with the dorsal lateral geniculate nucleus, and were rarely observed in nRT neurons, whilst SOC frequency in the VB increased with age. Application of THIP, a selective agonist at ?-subunit-containing GABA(A) receptors, occluded SOCs, whereas the benzodiazepine site inverse agonist ?-CCB had no effect, but did inhibit spontaneous and evoked IPSCs. In addition, the occurrence of SOCs was reduced in mice lacking the ?-subunit, and their kinetics were also altered. The anti-epileptic drug vigabatrin increased SOC frequency in a time-dependent manner, but this effect was not due to reversal of GABA transporters. Together, these data indicate that SOCs in TC neurons arise from astrocytic GABA release, and are mediated by ?-subunit-containing GABA(A) receptors. Furthermore, these findings suggest that the therapeutic action of vigabatrin may occur through the augmentation of this astrocyte-neuron interaction, and highlight the importance of glial cells in CNS (patho) physiology. PMID:21395866

Jiménez-González, Cristina; Pirttimaki, Tiina; Cope, David W; Parri, H R



In vivo GABA detection with improved selectivity and sensitivity by localized double quantum filter technique at 4.1T  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter for the normal function of mammal and human brain. It is difficult to detect GABA signal with the conventional single quantum technique due to its relatively low concentration and overlapping with other signals from creatine (Cr), glutathione (GSH), as well as macromolecules. Using a high-selective read pulse, DANTE, and at the facility

Fei Du; Wen-Jang Chu; Baolian Yang; Jan A. Den Hollander; Thian C. Ng



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

ERIC Educational Resources Information Center

|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…

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



Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits  

Microsoft Academic Search

Background. The amino acid neurotransmitter GABA is abundant in the central nervous system (CNS) of both invertebrates and vertebrates. Receptors of this neurotransmitter play a key role in important processes such as learning and memory. Yet, little is known about the mode and tempo of evolution of the receptors of this neurotransmitter. Here, we investigate the phylogenetic relationships of GABA

Christopher J. Martyniuk; Stéphane Aris-Brosou; Guy Drouin; Joel Cahn; Vance L. Trudeau



Chloride permeation across the Deiters' neuron plasma membrane: activation by GABA on the membrane cytoplasmic side.  


Single plasma membranes were microdissected from Deiters' neurons freshly obtained from the lateral vestibular nucleus of the rabbit and their chloride permeability was studied in a microchamber system. The basal in-->out 36Cl- permeation initially found was brought to zero by Zn2+, 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid and iodide. GABA on the membrane cytoplasmic side resulted in a measurable in-->out 36Cl- passage, which was blocked by the GABA(A) antagonists bicuculline and picrotoxin. This effect peaked at 1 microM GABA on the inner side of the membrane. At higher GABA concentrations, a strong desensitization of the effect was found. Stimulation of Cl- permeability by GABA on the extracellular side of the membrane peaked at much higher GABA concentrations, 10-100 microM. This excludes an effect due to passage of the neurotransmitter from the inner to the outer compartment in our microchamber device. Moreover, this possibility is also dismissed by the fact that 1 microM GABA on the membrane outside did not evoke any 36Cl- in-->out permeation. In addition, pentobarbitone by itself could also stimulate 36Cl- in-->out permeation when added on the cytoplasmic side of Deiters' membrane. On these bases and in agreement with our previous reports, we propose that structures behaving pharmacologically as GABA(A) receptors respond to low levels of GABA on the cytoplasmic side of these neurons' membranes. We suggest that these structures are devices that, at the expense of ATP consumed in their phosphorylation, extrude Cl- after postsynaptic GABA uptake into the Deiters' neuron. PMID:10362323

Hydén, H; Cupello, A; Rapallino, M V



GABA release from mouse axonal growth cones  

PubMed Central

Using developing hypothalamic neurons from transgenic mice that express high levels of green fluorescent protein in growing axons, and an outside-out patch from mature neuronal membranes that contain neurotransmitter receptors as a sensitive detector, we found that GABA is released by a vesicular mechanism from the growth cones of developing axons prior to synapse formation. A low level of GABA release occurs spontaneously from the growth cone, and this is substantially increased by evoked action potentials. Neurotransmitters such as acetylcholine can enhance protein kinase C (PKC) activity even prior to synapse formation; PKC activation caused a substantial increase in spontaneous GABA release from the growth cone, probably acting at the axon terminal. These data indicate that GABA is secreted from axons during a stage of neuronal development when GABA is excitatory, and that neuromodulators could alter GABA release from the growing axon, potentially enabling other developing neurons of different transmitter phenotype to modulate the early actions of GABA.

Gao, Xiao-Bing; van den Pol, Anthony N



Gat1 (Gaba:Na+:Cl?) Cotransport Function  

PubMed Central

Neurotransmitter transporters are reported to mediate transmembrane ion movements that are poorly coupled to neurotransmitter transport and to exhibit complex “channel-like” behaviors that challenge the classical “alternating access” transport model. To test alternative models, and to develop an improved model for the Na+- and Cl?-dependent ?-aminobutyric acid (GABA) transporter, GAT1, we expressed GAT1 in Xenopus oocytes and analyzed its function in detail in giant membrane patches. We detected no Na+- or Cl?- dependent currents in the absence of GABA, nor did we detect activating effects of substrates added to the trans side. Outward GAT1 current (“reverse” transport mode) requires the presence of all three substrates on the cytoplasmic side. Inward GAT1 current (“forward” transport mode) can be partially activated by GABA and Na+ on the extracellular (pipette) side in the nominal absence of Cl?. With all three substrates on both membrane sides, reversal potentials defined with specific GAT1 inhibitors are consistent with the proposed stoichiometry of 1GABA:2Na+:1Cl?. As predicted for the “alternating access” model, addition of a substrate to the trans side (120 mM extracellular Na+) decreases the half-maximal concentration for activation of current by a substrate on the cis side (cytoplasmic GABA). In the presence of extracellular Na+, the half-maximal cytoplasmic GABA concentration is increased by decreasing cytoplasmic Cl?. In the absence of extracellular Na+, half-maximal cytoplasmic substrate concentrations (8 mM Cl?, 2 mM GABA, 60 mM Na+) do not change when cosubstrate concentrations are reduced, with the exception that reducing cytoplasmic Cl? increases the half-maximal cytoplasmic Na+ concentration. The forward GAT1 current (i.e., inward current with all extracellular substrates present) is inhibited monotonically by cytoplasmic Cl? (Ki, 8 mM); cytoplasmic Na+ and cytoplasmic GABA are without effect in the absence of cytoplasmic Cl?. In the absence of extracellular Na+, current–voltage relations for reverse transport current (i.e., outward current with all cytoplasmic substrates present) can be approximated by shallow exponential functions whose slopes are consistent with rate-limiting steps moving 0.15–0.3 equivalent charges. The slopes of current–voltage relations change only little when current is reduced four- to eightfold by lowering each cosubstrate concentration; they increase twofold upon addition of 100 mM Na+ to the extracellular (pipette) side.

Lu, Chin-Chih; Hilgemann, Donald W.



The alterations of rat brain GABA and glutamine induced by the organophosphorus compound cyolane.  


Levels of the amino acids GABA and glutamine were determined in the whole brain of the white albino rat Rattus norvegicus after daily injection of 1/2, 1/4, 1/8, 1/16, 1/32 and 1/100 LD50 of cyolane. With 1/2 LD50 an increase in the level of both GABA and glutamine in the brain was recorded. Dose levels of 1/4 and 1/8 LD50 caused an increase in the level of GABA and a decrease in glutamine concentration followed by an increase from the 7th and 11th days for 1/4 and 1/8 LD50, respectively. The induced increase in GABA level started from the 2nd week for 1/16 and 1/32 LD50 and from the 3rd week for 1/100 LD50. Dose levels of 1/16, 1/32 and 1/100 LD50 caused a fluctuating increase in glutamine concentration starting from the 2nd, 3rd and 6th weeks, respectively, which was followed by a fluctuating decrease at the 9th week for 1/32 and 1/100 LD50. These findings support previous findings that the enhanced transformation of glutamic acid to GABA and glutamine is a result of a disturbance in the metabolism of the glutamic acid-GABA and the glutamic acid-glutamine systems in the rat brain. PMID:2873949

Hussein, M F; Ahmed, N A; Rawi, S M



Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia  

PubMed Central

In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in ?-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD67) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABAA receptor subunits (?1, ?4, ?3, ?2 and ?). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD67, SST and ?1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABAA receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.

Hashimoto, T; Arion, D; Unger, T; Maldonado-Aviles, JG; Morris, HM; Volk, DW; Mirnics, K; Lewis, DA



Characterization of GABA release from intrastriatal striatal transplants: dependence on host-derived afferents.  


Extracellular levels of GABA, derived from cell suspension transplants of embryonic day 14-15 rat striatal primordia implanted into the previously excitotoxically lesioned striatum, were measured using intracerebral microdialysis in halothane-anaesthetized rats. GABA overflow was monitored using loop type dialysis probes implanted into grafted, age-matched ibotenic acid-lesioned and intact striata, under baseline conditions and after different pharmacological manipulations. Basal and evoked GABA release, which was reduced by 58 and 96%, respectively, in the excitotoxin-lesioned striatum, was restored by the striatal grafts to levels close to or above those observed in normal striata. The graft-derived release of GABA was most likely of neuronal origin, since the K(+)-evoked (100 mM) GABA overflow was reduced by almost 80% when Ca++ was replaced by 20 mM Mg++ in the perfusion medium, and blockade of GABA uptake by nipecotic acid (0.5 mM), induced a greater than six-fold increase in GABA overflow. However, perfusion of the graft with 1 microM tetrodotoxin in combination with K+ (100 mM) resulted in little if any reduction in the K(+)-evoked overflow. Histological analysis demonstrated a dense tyrosine hydroxylase-positive fibre network in the grafts, which was removed after a 6-hydroxydopamine lesion of the ipsilateral nigrostriatal pathway. The dopamine denervating lesion resulted in an increased K(+)-evoked GABA overflow both in the intact (+76%) and the grafted striata (+181%), suggesting that the tonic dopaminergic inhibitory control of GABA release, seen in the intact striatum, is also present in the grafted striata. The glutamate analogue, kainic acid (1 mM added to the perfusion fluid), evoked a 60-74% increase in GABA overflow both in intact striata (with or without dopaminergic denervation) and in the striatal grafts. This effect seemed to be dependent on an intact corticostriatal projection, since knife-cut transections of the frontal cortex at the level of the forceps minor, abolished the response in both the intact and grafted striata. These results demonstrate that grafts of fetal striatal tissue implanted into the excitotoxically lesioned striatum restore striatal GABA overflow in a neuron-dependent manner, close to or above that seen in the normal intact striatum. Furthermore, the graft-derived GABA release appears to be under normal regulatory control from the host dopaminergic and glutamatergic systems. Since the GABAergic striatal output system is critical for the expression of striatum-related behaviours, it is proposed that the graft-induced behavioural recovery in the striatal lesion model, at least in part, may depend on the restoration of striatal GABAergic neurotransmission. PMID:8098510

Campbell, K; Kalén, P; Wictorin, K; Lundberg, C; Mandel, R J; Björklund, A



Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABA(C) receptors.  


The effects of the enantiomers of a number of flexible and cis-constrained GABA analogues were tested on GABA(C) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (1S,2R)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((+)-CAMP), a potent and full agonist at the rho1 (EC(50) approximately 40 microM, I(max) approximately 100%) and rho 2 (EC(50) approximately 17 microM, I(max) approximately 100%) receptor subtypes, was found to be a potent partial agonist at rho3 (EC(50) approximately 28 microM, I(max) approximately 70%). (1R,2S)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((-)-CAMP), a weak antagonist at human rho1 (IC(50) approximately 890 microM) and rho2 (IC(50) approximately 400 microM) receptor subtypes, was also found to be a moderately potent antagonist at rat rho3 (IC(50) approximately 180 microM). Similarly, (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid ((+)-ACPECA) was a full agonist at rho1 (EC(50) approximately 135 microM, I(max) approximately 100%) and rho2 (EC(50) approximately 60 microM, I(max) approximately 100%), but only a partial agonist at rho3 (EC(50) approximately 112 microM, I(max) approximately 37%), while (1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid ((-)-ACPECA) was a weak antagonist at all three receptor subtypes (IC(50)>300 microM). 4-Amino-(S)-2-methylbutanoic acid ((S)-2MeGABA) and 4-amino-(R)-2-methylbutanoic acid ((R)-2MeGABA) followed the same trend, with (S)-2MeGABA acting as a full agonist at the rho1 (EC(50) approximately 65 microM, I(max) approximately 100%), and rho2 (EC(50) approximately 20 microM, I(max) approximately 100%) receptor subtypes, and a partial agonist at rho3 (EC(50) approximately 25 microM, I(max) approximately 90%). (R)-2MeGABA, however, was a moderately potent antagonist at all three receptor subtypes (IC(50) approximately 16 microM at rho1, 125 microM at rho2 and 35 microM at rho3). On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect. PMID:16183289

Crittenden, Deborah L; Park, Anna; Qiu, Jian; Silverman, Richard B; Duke, Rujee K; Johnston, Graham A R; Jordan, Meredith J T; Chebib, Mary



Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia  

Microsoft Academic Search

In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in c-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic

T Hashimoto; D Arion; T Unger; JG Maldonado-Aviles; HM Morris; DW Volk; K Mirnics; DA Lewis



GABA Has Excitatory Actions on GnRH-Secreting Immortalized Hypothalamic (GT1-7) Neurons  

Microsoft Academic Search

The effects of ?-aminobutyric acid (GABA) on clonal gonadotropin-releasing hormone (GnRH)-secreting hypothalamic (GT1-7) neurons were investigated using patch-clamp and fura-2 imaging techniques. Local application of GABA (100 ?M) to GT1-7 cells voltage-clamped in the whole-cell configuration immediately increased membrane conductance and noise consistent with activation of the GABAA receptor-Cl– channel complex. Depolarization activated transient Na+ currents which were abolished by

Tim G. Hales; Michael J. Sanderson; Andrew C. Charles



Assessment of GABA concentration in human brain using two-dimensional proton magnetic resonance spectroscopy  

Microsoft Academic Search

A quantitative method to assess in vivo brain gamma-aminobutyric acid (GABA) levels is proposed using a J-resolved, two-dimensional (2D) magnetic resonance spectroscopy (MRS) technique. Localized, J-resolved 2D MR spectra were obtained from a 12-cm3 voxel in the occipital lobe of 36 healthy volunteers (18 male and 18 female, age: 25.1±4.8 years). Based on phantom measurements, a GABA resonance peak located

Yong Ke; Bruce M Cohen; Jeannette Y Bang; Manqiu Yang; Perry F Renshaw



Steroid Hormone Metabolites are Barbiturate-Like Modulators of the GABA Receptor  

Microsoft Academic Search

Two metabolites of the steroid hormones progesterone and deoxycorticosterone, 3alpha -hydroxy-5alpha -dihydroprogesterone and 3alpha ,5alpha -tetrahydrodeoxycorticosterone, are potent barbiturate-like ligands of the gamma -aminobutyric acid (GABA) receptor--chloride ion channel complex. At concentrations between 10-7 and 10-5 M both steroids inhibited binding of the convulsant t-butylbicyclophosphorothionate to the GABA-receptor complex and increased the binding of the benzodiazepine flunitrazepam; they also stimulated

Maria Dorota Majewska; Neil L. Harrison; Rochelle D. Schwartz; Jeffery L. Barker; Steven M. Paul



An association study between polymorphisms in five genes in glutamate and GABA pathway and paranoid schizophrenia  

Microsoft Academic Search

Dysfunctions of glutamatergic and GABAergic neurotransmission are two important hypotheses for the pathogenesis of schizophrenia. Thus, genes in the pathway are candidates for schizophrenia susceptibility. Phosphate-activated glutaminase (GLS), glutamine synthetase (GLUL), glutamic acid decarboxylase (GAD), GABA transaminase (ABAT) and succinic semialdehyde dehydrogenase (ALDH5A1) are five primary enzymes in glutamate and GABA synthetic and degradative pathway. In order to investigate the

Boyu Zhang; Yanbo Yuan; Yanbin Jia; Xin Yu; Qi Xu; Yucun Shen; Yan Shen



Knockout of GAD65 has major impact on synaptic GABA synthesized from astrocyte-derived glutamine  

Microsoft Academic Search

?-Aminobutyric acid (GABA) synthesis from glutamate is catalyzed by glutamate decarboxylase (GAD) of which two isoforms, GAD65 and GAD67, have been identified. The GAD65 has repeatedly been shown to be important during intensified synaptic activity. To specifically elucidate the significance of GAD65 for maintenance of the highly compartmentalized intracellular and intercellular GABA homeostasis, GAD65 knockout and corresponding wild-type mice were

Anne B Walls; Elvar M Eyjolfsson; Olav B Smeland; Linn Hege Nilsen; Inger Schousboe; Arne Schousboe; Ursula Sonnewald; Helle S Waagepetersen



Modification of orientation sensitivity of cat visual cortex neurons by removal of GABA-mediated inhibition  

Microsoft Academic Search

Summary  The effects of an inhibitor of GABA synthesis, 3-mercaptopropionic acid (MP), and of the GABA antagonist bicuculline (BIC), on the direction and orientation sensitivity of visual cortical neurons were investigated using a computer-controlled stimulus presentation system. Intravenous administration of MP, which was usually more effective than if administered microelectrophoretically, induced a slight, but significant reduction in these properties of about

T. Tsumoto; W. Eckart; O. D. Creutzfeldt



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


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

Kulinski?, V I; Klimova, A D


Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA.  


Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir(3)) channels, however, are poorly understood. Here, we show that 1 day after methamphetamine (METH) or cocaine exposure both synaptically evoked and baclofen-activated GABA(B)R-GIRK currents were significantly depressed in VTA GABA neurons and remained depressed for 7 days. Presynaptic inhibition mediated by GABA(B)Rs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABA(B1) and GIRK2, which occurred coincident with dephosphorylation of serine 783 (S783) in GABA(B2), a site implicated in regulating GABA(B)R surface expression. Inhibition of protein phosphatases recovered GABA(B)R-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABA(B)R signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system. PMID:22405207

Padgett, Claire L; Lalive, Arnaud L; Tan, Kelly R; Terunuma, Miho; Munoz, Michaelanne B; Pangalos, Menelas N; Martínez-Hernández, José; Watanabe, Masahiko; Moss, Stephen J; Luján, Rafael; Lüscher, Christian; Slesinger, Paul A



In Vivo Detection of GABA and Glutamate With MEGA-PRESS: Reproducibility and Gender Effects  

PubMed Central

Purpose To evaluate the reproducibility of ?-aminobutyric acid (GABA) and glutamate concentrations derived using three different spectral fitting methods, and to investigate gender-related differences in neurotransmitter levels. Materials and Methods Single voxel MEGA-edited PRESS MR spectra were acquired from a 30-mL voxel in the dorsolateral prefrontal cortex in 14 adult volunteers (7 female) at 3 Tesla (3T). For each participant, four consecutive resting spectra were acquired within the same scanning session. Metabolite concentrations were derived using LCModel, jMRUI, and locally written peak fitting software. The within-session reproducibility for each analysis method was calculated as the average coefficient of variation (CV) of the GABA and Glx (glutamate+glutamine) concentrations. Gender differences in GABA and Glx were evaluated using a two-tailed unpaired t-test. Results LCModel provided the best reproducibility for both GABA (CV 7%) and Glx (CV 6%). GABA, Glx, and glutamate concentrations were significantly higher in the male participants, (P = 0.02, P = 0.001, and P < 0.001, respectively). Conclusion GABA and glutamate can be quantified in vivo with high reproducibility (CV 6–7%) using frequency-domain spectral fitting methods like LCModel. However, the GABA and glutamate concentrations vary significantly between men and women, emphasizing the importance of gender-matching for studies investigating differences in neurotransmitter concentrations between mixed-cohort groups.

O'Gorman, Ruth L.; Michels, Lars; Edden, Richard A.; Murdoch, James B.; Martin, Ernst



Noradrenergic control of neuronal firing in cerebellar nuclei: modulation of GABA responses.  


The effects of noradrenaline (NA) on inhibitory responses to gamma aminobutyric acid (GABA) in neurones of the deep cerebellar nuclei were studied in vivo in rats, using extracellular single-unit recordings and microiontophoretic drug application. NA application altered GABA-evoked responses in 95 % of the neurones tested, but the effects differed between nuclei. Application of NA depressed GABA responses in the medial (MN) and posterior interpositus (PIN) nuclei, but enhanced GABA responses in the anterior interpositus nucleus (AIN). Comparable proportions of enhancing (57 %) and depressive (43 %) effects were found in the lateral nucleus (LN). The alpha2 noradrenergic receptor agonist clonidine mimicked the depressive effect of NA on GABA responses in MN and PIN and its enhancing effects in AIN and LN, while the alpha2 antagonist yohimbine partially blocked these effects. The beta-adrenergic agonist isoproterenol and antagonist timolol respectively induced and partially blocked enhancements of GABA responses in all nuclei except for LN, where isoproterenol had a weak depressive effect. It is concluded that NA modulates GABA responses by acting on both alpha2 and beta receptors. Activation of these receptors appears to be synergistic in the AIN and opposite in the remaining deep nuclei. These results support the hypothesis that the noradrenergic system participates in all the regulatory functions involving the cerebellum in a specific and differential manner, and suggest that any change in NA content, as commonly observed in ageing or stress, could influence cerebellar activity. PMID:23096094

Di Mauro, Michela; Li Volsi, Guido; Licata, Flora



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

SciTech Connect

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.

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



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


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. PMID:23618076

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



An Update on GABA? Receptors  

PubMed Central

The present review discusses the functional and molecular diversity of GABA? receptors. These receptors were originally described in the mammalian retina, and their functional role in the visual pathway has been recently elucidated; however new studies on their distribution in the brain and spinal cord have revealed that they are more spread than originally thought, and thus it will be important to determine their physiological contribution to the GABAergic transmission in other areas of the central nervous system. In addition, molecular modeling has revealed peculiar traits of these receptors that have impacted on the interpretations of the latest pharmacolgical and biophysical findings. Finally, sequencing of several vertebrate genomes has permitted a comparative analysis of the organization of the GABA? genes.

Martinez-Delgado, Gustavo; Estrada-Mondragon, Argel; Miledi, Ricardo; Martinez-Torres, Ataulfo



Micromethods for the study of GABA biochemistry and function at single GABA acceptive membranes.  


Three different micromethods for studying GABA biochemistry and function at single microdissected GABA-acceptive neuronal membranes are discussed. The basis for such studies is the possibility of obtaining by microdissection single Deiters' neurons from the lateral vestibular nucleus of the rat and the rabbit. From these isolated cells the plasma membrane may be prepared and studied. The first micromethod allows the study of the Na+ independent diffusion of GABA through such a plasma membrane which is postsynaptic to GABA-ergic boutons. A modification of such method allows also the study of the effects of GABA-ergic drugs on Cl- permeability. The second method allows the study by microelectrophoresis in capillaries of GABA catabolism by GABA-T associated with microdissected single Deiters' membranes. The third one was developed in order to study the characteristics of Na+ dependent GABA carrier activity present on such membranes. PMID:3679687

Hydén, H; Rapallino, M V; Cupello, A



GABA-elevating effects of the antidepressant\\/antipanic drug phenelzine in brain: effects of pretreatment with tranylcypromine, (?)-deprenyl and clorgyline  

Microsoft Academic Search

The antidepressant\\/antipanic drug phenelzine (PLZ) is both an inhibitor of, and a substrate for, monoamine oxidase (MAO). PLZ also causes an elevation of brain levels of the amino acid neurotransmitter ?-aminobutyric acid (GABA); this action can be reversed by pretreatment with the MAO inhibitor tranylcypromine (TCP), suggesting that the GABA-elevating effect is largely the result of a metabolite of PLZ

Kathryn G. Todd; Glen B. Baker



Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: Protean additions to the autoimmune central neuropathies  

Microsoft Academic Search

Stiff Person Syndrome (SPS) is a rare autoimmune neurological disease attributable to autoantibodies to glutamic acid decarboxylase (anti-GAD) more usually associated with the islet beta cell destruction of autoimmune type 1 diabetes (T1D). SPS is characterized by interference in neurons with the synthesis\\/activity of the inhibitory neurotransmitter gamma amino butyric acid (GABA) resulting in the prototypic progressive spasmodic muscular rigidity

Fatima Ali; Merrill Rowley; Bindu Jayakrishnan; Suzanne Teuber; M. Eric Gershwin; Ian R. Mackay



Effect of riluzole and gabapentin on cocaine- and methamphetamine-induced behavioral sensitization in mice  

Microsoft Academic Search

Rationale: Recent studies have suggested the involvement of excitatory amino acid (EAA) and inhibitory gamma amino butyric acid (GABA)\\u000a transmission in the effects of psychostimulants such as cocaine and amphetamines. Objectives: The present study was undertaken to investigate whether drugs that are considered to inhibit glutamate release (e.g., riluzole)\\u000a or increase GABAergic transmission (e.g., gabapentin) attenuate the induction and expression

Yossef Itzhak; Julio L. Martin



Anion transport and GABA signaling  

PubMed Central

Whereas activation of GABAA receptors by GABA usually results in a hyperpolarizing influx of chloride into the neuron, the reversed chloride driving force in the immature nervous system results in a depolarizing efflux of chloride. This GABAergic depolarization is deemed to be important for the maturation of the neuronal network. The concept of a developmental GABA switch has mainly been derived from in vitro experiments and reliable in vivo evidence is still missing. As GABAA receptors are permeable for both chloride and bicarbonate, the net effect of GABA also critically depends on the distribution of bicarbonate. Whereas chloride can either mediate depolarizing or hyperpolarizing currents, bicarbonate invariably mediates a depolarizing current under physiological conditions. Intracellular bicarbonate is quickly replenished by cytosolic carbonic anhydrases. Intracellular bicarbonate levels also depend on different bicarbonate transporters expressed by neurons. The expression of these proteins is not only developmentally regulated but also differs between cell types and even subcellular regions. In this review we will summarize current knowledge about the role of some of these transporters for brain development and brain function.

Hubner, Christian A.; Holthoff, Knut



GABA Coordinates with Insulin in Regulating Secretory Function in Pancreatic INS-1 ?-Cells  

PubMed Central

Pancreatic islet ?-cells produce large amounts of ?-aminobutyric acid (GABA), which is co-released with insulin. GABA inhibits glucagon secretion by hyperpolarizing ?-cells via type-A GABA receptors (GABAARs). We and others recently reported that islet ?-cells also express GABAARs and that activation of GABAARs increases insulin release. Here we investigate the effects of insulin on the GABA-GABAAR system in the pancreatic INS-1 cells using perforated-patch recording. The results showed that GABA produces a rapid inward current and depolarizes INS-1 cells. However, pre-treatment of the cell with regular insulin (1 µM) suppressed the GABA-induced current (IGABA) by 43%. Zinc-free insulin also suppressed IGABA to the same extent of inhibition by regular insulin. The inhibition of IGABA occurs within 30 seconds after application of insulin. The insulin-induced inhibition of IGABA persisted in the presence of PI3-kinase inhibitor, but was abolished upon inhibition of ERK, indicating that insulin suppresses GABAARs through a mechanism that involves ERK activation. Radioimmunoassay revealed that the secretion of C-peptide was enhanced by GABA, which was blocked by pre-incubating the cells with picrotoxin (50 µM, p<0.01) and insulin (1 µM, p<0.01), respectively. Together, these data suggest that autocrine GABA, via activation of GABAARs, depolarizes the pancreatic ?-cells and enhances insulin secretion. On the other hand, insulin down-regulates GABA-GABAAR signaling presenting a feedback mechanism for fine-tuning ?-cell secretion.

Bansal, Paul; Wang, Shuanglian; Liu, Shenghao; Xiang, Yun-Yan; Lu, Wei-Yang; Wang, Qinghua



GABA-A channel subunit expression in human glioma correlates with tumor histology and clinical outcome.  


GABA (?-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS and is present in high concentrations in presynaptic terminals of neuronal cells. More recently, GABA has been ascribed a more widespread role in the control of cell proliferation during development where low concentrations of extrasynaptic GABA induce a tonic activation of GABA receptors. The GABA-A receptor consists of a ligand-gated chloride channel, formed by five subunits that are selected from 19 different subunit isoforms. The functional and pharmacological properties of the GABA-A channels are dictated by their subunit composition. Here we used qRT-PCR to compare mRNA levels of all 19 GABA-A channel subunits in samples of human glioma (n = 29) and peri-tumoral tissue (n = 5). All subunits except the ?1 and ?3 subunit were consistently detected. Lowest mRNA levels were found in glioblastoma compared to gliomas of lower malignancy, except for the ? subunit. The expression and cellular distribution of the ?1, ?1, ?2 and ? subunit proteins was investigated by immunohistochemistry on tissue microarrays containing 87 gliomas grade II. We found a strong co-expression of ?2 and ? subunits in both astrocytomas (r = 0.86, p<0.0001) and oligodendroglial tumors (r = 0.66, p<0.0001). Kaplan-Meier analysis and Cox proportional hazards modeling to estimate the impact of GABA-A channel subunit expression on survival identified the ?2 subunit (p = 0.043) but not the ? subunit (p = 0.64) as an independent predictor of improved survival in astrocytomas, together with established prognostic factors. Our data give support for the presence of distinct GABA-A channel subtypes in gliomas and provide the first link between specific composition of the A-channel and patient survival. PMID:22615883

Smits, Anja; Jin, Zhe; Elsir, Tamador; Pedder, Hugo; Nistér, Monica; Alafuzoff, Irina; Dimberg, Anna; Edqvist, Per-Henrik; Pontén, Fredrik; Aronica, Eleonora; Birnir, Bryndis



GABA-A Channel Subunit Expression in Human Glioma Correlates with Tumor Histology and Clinical Outcome  

PubMed Central

GABA (?-aminobutyric acid) is the main inhibitory neurotransmitter in the CNS and is present in high concentrations in presynaptic terminals of neuronal cells. More recently, GABA has been ascribed a more widespread role in the control of cell proliferation during development where low concentrations of extrasynaptic GABA induce a tonic activation of GABA receptors. The GABA-A receptor consists of a ligand-gated chloride channel, formed by five subunits that are selected from 19 different subunit isoforms. The functional and pharmacological properties of the GABA-A channels are dictated by their subunit composition. Here we used qRT-PCR to compare mRNA levels of all 19 GABA-A channel subunits in samples of human glioma (n?=?29) and peri-tumoral tissue (n?=?5). All subunits except the ?1 and ?3 subunit were consistently detected. Lowest mRNA levels were found in glioblastoma compared to gliomas of lower malignancy, except for the ? subunit. The expression and cellular distribution of the ?1, ?1, ?2 and ? subunit proteins was investigated by immunohistochemistry on tissue microarrays containing 87 gliomas grade II. We found a strong co-expression of ?2 and ? subunits in both astrocytomas (r?=?0.86, p<0.0001) and oligodendroglial tumors (r?=?0.66, p<0.0001). Kaplan-Meier analysis and Cox proportional hazards modeling to estimate the impact of GABA-A channel subunit expression on survival identified the ?2 subunit (p?=?0.043) but not the ? subunit (p?=?0.64) as an independent predictor of improved survival in astrocytomas, together with established prognostic factors. Our data give support for the presence of distinct GABA-A channel subtypes in gliomas and provide the first link between specific composition of the A-channel and patient survival.

Smits, Anja; Jin, Zhe; Elsir, Tamador; Pedder, Hugo; Nister, Monica; Alafuzoff, Irina; Dimberg, Anna; Edqvist, Per-Henrik; Ponten, Fredrik; Aronica, Eleonora; Birnir, Bryndis



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


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

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



The Arabidopsis pop2-1 mutant reveals the involvement of GABA transaminase in salt stress tolerance  

PubMed Central

Background GABA (?-aminobutyric acid) is a non protein amino acid that has been reported to accumulate in a number of plant species when subjected to high salinity and many other environmental constraints. However, no experimental data are to date available on the molecular function of GABA and the involvement of its metabolism in salt stress tolerance in higher plants. Here, we investigated the regulation of GABA metabolism in Arabidopsis thaliana at the metabolite, enzymatic activity and gene transcription levels upon NaCl stress. Results We identified the GABA transaminase (GABA-T), the first step of GABA catabolism, as the most responsive to NaCl. We further performed a functional analysis of the corresponding gene POP2 and demonstrated that the previously isolated loss-of-function pop2-1 mutant was oversensitive to ionic stress but not to osmotic stress suggesting a specific role in salt tolerance. NaCl oversensitivity was not associated with overaccumulation of Na+ and Cl- but mutant showed a slight decrease in K+. To bring insights into POP2 function, a promoter-reporter gene strategy was used and showed that POP2 was mainly expressed in roots under control conditions and was induced in primary root apex and aerial parts of plants in response to NaCl. Additionally, GC-MS- and UPLC-based metabolite profiling revealed major changes in roots of pop2-1 mutant upon NaCl stress including accumulation of amino acids and decrease in carbohydrates content. Conclusions GABA metabolism was overall up-regulated in response to NaCl in Arabidopsis. Particularly, GABA-T was found to play a pivotal function and impairment of this step was responsible for a decrease in salt tolerance indicating that GABA catabolism was a determinant of Arabidopsis salt tolerance. GABA-T would act in salt responses in linking N and C metabolisms in roots.



Interrelations between dopaminergic and GABA-ergic transmitter mechanisms in apomorphine stereotypy.  


The effects of dopamine (DA)-ergic and GABA-ergic pharmacological agents on apomorphine stereotypy upon intraperitoneal administration in male albino rats has been studied. It has been found that: the DA-ergic agonist L-DOPA increases the intensity of apomorphine stereotypy, without influencing its total duration. The DA-ergic antagonist haloperidol inhibits significantly apomorphine stereotypy, with marked dose-effect dependence, shortening its duration. The GABA-ergic antagonist picrotoxin potentiates nearly twice apomorphine stereotypy and increases its duration. The GABA-ergic agonists depakine and aminooxyacetic acid (AOAA) inhibit substantially apomorphine stereotypy and shorten its duration. Participation of DA-ergic and GABA-ergic transmitter mechanisms in apomorphine stereotypy as well as interactions of these two transmitter systems in the nigrostriatum, are assumed. PMID:6820612

Markovska, V; Georgiev, V



Presynaptic mGlu7 receptors control GABA release in mouse hippocampus.  


The functional role of presynaptic release-regulating metabotropic glutamate type 7 (mGlu7) receptors in hippocampal GABAergic terminals was investigated. Mouse hippocampal synaptosomes were preloaded with [(3)H]D-?-aminobutyric acid ([(3)H]GABA) and then exposed in superfusion to 12 mM KCl. The K(+)-evoked [(3)H]GABA release was inhibited by the mGlu7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082, 0.001-10 ?M), as well as by the group III mGlu receptor agonist l-(+)-2-amino-4-phosphonobutyric acid [(l)-AP4, 0.01-1 mM]. The mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG, 10-100 nM] was ineffective. AMN082 and (l)-AP4-induced effects were recovered by the mGlu7 negative allosteric modulator (NAM) 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). AMN082 also inhibited in a MMPIP-sensitive manner the K(+)-evoked release of endogenous GABA. AMN082 and the adenylyl cyclase (AC) inhibitor MDL-12,330A reduced [(3)H]GABA exocytosis in a 8-Br-cAMP-sensitive. AMN082-inhibitory effect was additive to that caused by (-)baclofen, but insensitive to the GABA(B) antagonist 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid (CGP52432). Conversely, (-)baclofen-induced inhibition of GABA exocytosis was insensitive to MMPIP. Finally, the forskolin-evoked [(3)H]GABA release was reduced by AMN082 or (-)baclofen but abolished when the two agonists were added concomitantly. Mouse hippocampal synaptosomal plasmamembranes posses mGlu7 receptor proteins; confocal microscopy analysis unveiled that mGlu7 proteins colocalize with syntaxin-1A (Stx-1A), with vesicular GABA transporter (VGAT)-proteins and with GABA(B) receptor subunit proteins. We propose that presynaptic inhibitory mGlu7 heteroreceptors, negatively coupled to AC-dependent intraterminal pathway, exist in mouse hippocampal GABA-containing terminals, where they colocalize, but do not functionally cross-talk, with GABA(B) autoreceptors. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID:22564442

Summa, Maria; Di Prisco, Silvia; Grilli, Massimo; Usai, Cesare; Marchi, Mario; Pittaluga, Anna



Idensei Undo Shiccho Mausu to Ganmasen Hibaku Mausu No No Ni Okeru GABA Nyuron No Bunpu (Distribution of GABA Immunoreactive Neurons in the Brain of Rolling Mouse Nagoya and gamma-Irradiated Mouse).  

National Technical Information Service (NTIS)

A rolling mouse Nagoya has been used as a model of human spinocerebellar degeneration presenting hereditary ataxia. In this study, distribution of neurons containing Gamma-Aminobutyric Acid (GABA) in the brain of a rolling mouse Nagoya was determined immu...

T. Imai Y. Takagishi S. Hayasaka M. Inouye H. Yamamura



Effects of the MAO inhibitor phenelzine on glutamine and GABA concentrations in rat brain.  


Phenelzine (PLZ), a frequently prescribed monoamine oxidase (MAO) inhibitor, is used as an antidepressant/antipanic drug and has been shown to cause marked increases in rat brain levels of the amino acids gamma-aminobutyric acid (GABA) and alanine. In an extension of previous studies related to GABA metabolism, we investigated the effects of PLZ on rat brain levels of glutamine (GLN). At 1, 3 or 6 h after injection of PLZ (15 mg kg-1 i.p.), rats were killed and the brains removed. Analyses (using HPLC with fluorescence detection of OPT derivatives) of whole brain or hypothalamus revealed a decrease in brain levels of GLN and an increase in GABA levels at 3 and 6 h after PLZ injection. The effects of PLZ on GLN and GABA were blocked by prior treatment of the rats with tranylcypromine, a MAO inhibitor that had been shown previously to have no direct effect itself on GABA levels in rat brain. Since PLZ is known to be a substrate (as well as an inhibitor) of MAO, the studies with tranylcypromine pretreatment suggest that the effects on GLN and GABA are caused, at least in part, by a metabolite of PLZ. PMID:8584653

Paslawski, T M; Sloley, B D; Baker, G B



Pharmacological analysis of the activation and receptor properties of the tonic GABA(C)R current in retinal bipolar cell terminals.  


GABAergic inhibition in the central nervous system (CNS) can occur via rapid, transient postsynaptic currents and via a tonic increase in membrane conductance, mediated by synaptic and extrasynaptic GABA(A) receptors (GABA(A)Rs) respectively. Retinal bipolar cells (BCs) exhibit a tonic current mediated by GABA(C)Rs in their axon terminal, in addition to synaptic GABA(A)R and GABA(C)R currents, which strongly regulate BC output. The tonic GABA(C)R current in BC terminals (BCTs) is not dependent on vesicular GABA release, but properties such as the alternative source of GABA and the identity of the GABA(C)Rs remain unknown. Following a recent report that tonic GABA release from cerebellar glial cells is mediated by Bestrophin 1 anion channels, we have investigated their role in non-vesicular GABA release in the retina. Using patch-clamp recordings from BCTs in goldfish retinal slices, we find that the tonic GABA(C)R current is not reduced by the anion channel inhibitors NPPB or flufenamic acid but is reduced by DIDS, which decreases the tonic current without directly affecting GABA(C)Rs. All three drugs also exhibit non-specific effects including inhibition of GABA transporters. GABA(C)R ? subunits can form homomeric and heteromeric receptors that differ in their properties, but BC GABA(C)Rs are thought to be ?1-?2 heteromers. To investigate whether GABA(C)Rs mediating tonic and synaptic currents may differ in their subunit composition, as is the case for GABA(A)Rs, we have examined the effects of two antagonists that show partial ? subunit selectivity: picrotoxin and cyclothiazide. Tonic and synaptic GABA(C)R currents were differentially affected by both drugs, suggesting that a population of homomeric ?1 receptors contributes to the tonic current. These results extend our understanding of the multiple forms of GABAergic inhibition that exist in the CNS and contribute to visual signal processing in the retina. PMID:21949779

Jones, Stefanie M; Palmer, Mary J



Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition.  


Benzodiazepines potentiate ?-aminobutyric acid type A receptor (GABA(A)R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an ? and ? subunit of GABA(A)Rs, preferentially enhancing synaptic receptors largely composed of ?(1-3, 5), ?3, and ?2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA(A)R surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of ?2 subunit-containing GABA(A)Rs occurred within 24 h of flurazepam treatment, whereas GABA(A)Rs incorporating ?1 subunits showed little alteration. The GABA(A)R surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA(A)R surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA(A)R endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA(A)Rs. Together, these data suggest that flurazepam exposure enhances degradation of ?2 subunit-containing GABA(A)Rs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA(A)R trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment. PMID:23091016

Jacob, Tija C; Michels, Guido; Silayeva, Liliya; Haydon, Julia; Succol, Francesca; Moss, Stephen J



The Effects of Anticonvulsant Drugs on NMDA-EPSP, AMPA-EPSP, and GABA-IPSP in the Rat Hippocampus  

Microsoft Academic Search

The effects of phenobarbital, phenytoin, and valproic acid on pharmacologically isolated NMDA-EPSP, AMPA-EPSP, and GABA-IPSPs were examined in rat hippocampal slices. Phenobarbital (0.05 mg\\/ml) had no effect on the NMDA-EPSP, but decreased the slope of the AMPA-EPSP by 13.4% and facilitated the GABA-IPSP slope by 77.12%. Phenytoin (0.02 mg\\/ml) had no effects on the NMDA-EPSP, AMPA-EPSP, or GABA-IPSP. Valproic acid

Gladys Yi-Ping Lee Ko; Laurie M Brown-Croyts; Timothy J Teyler



High pH accelerates GABA deactivation on perch-rho1B receptors.  


The ionotropic GABA(C) receptor, formed by GABA rho subunits, is known to be modulated by a variety of endogenous compounds, as well as by changes in pH. In this study, we explore the proton sensitivity of the GABA rho subunits cloned from the perch retina, and report a novel action of high pH on the homomeric receptor formed by one of the GABA rho subunits, the perch-rho(1B) subunit. Raising extracellular pH to 9.5 significantly accelerated GABA deactivation responses elicited from oocytes expressing the perch-rho(1B) subunit, and reduced its sensitivity to GABA. The change in the kinetics of the GABA-offset response occurred without altering the maximum response amplitude, and the reduced GABA sensitivity was independent of membrane potential. Although acidification of the extracellular solution also accelerated GABA deactivation for all other GABA rho receptors examined in this study, the effects of high pH were unique to the homomeric receptor formed by the perch-rho(1B) subunit. In addition, we found that, unlike the effects on the response to the naturally occurring full agonist GABA, the responses elicited by partial agonists (imidazole-4-acetic acid (I4AA) and beta-alanine) in the presence of the high pH solution showed a significant reduction in the maximum response amplitude. When considered in terms of a model describing the activation of GABA(C) receptors, in which pH can potentially affect either the binding affinity or the rate of channel closure, the results were consistent with the view that external alkalization reduces the gating efficiency of the receptor. To identify the proton sensitive domain(s) of the perch-rho(1B) receptor, chimeras were constructed by domain swapping with other perch-rho subunits. Analysis of the pH sensitivities of the various chimeric receptors revealed that the alkaline-sensitive residues are located in the N-terminal region of the perch-rho(1B) subunit. PMID:16920274

Qian, H; Pan, Y; Choi, B; Ripps, H



Inhibition of GABA uptake potentiates the conductance increase produced by GABA-mimetic compounds on single neurones in isolated olfactory cortex slices of the guinea-pig.  

PubMed Central

Membrane potential and input conductance were recorded in single neurones in slices of guinea-pig olfactory cortex in vitro. gamma-Aminobutyric acid (GABA) and GABA-mimetic compounds were applied by bath-perfusion. Potency was measured as the concentration required to double the input conductance. The potency of GABA was increased (i.e. the equi-effective concentrations were reduced) by 15.5 +/- 2.3 times (mean +/- s.e. mean) on reducing external [Na+] from 144 to 20 mmol l-1, by replacement with Mg2+. Corresponding potency changes for other agonists were + 10.8 +/- 2.5 for 3-aminopropanesulphonic acid (3-APS); 3.25 +/- 1.06 for isoguvacine and 2.43 +/- 0.69 for muscimol. Nipecotic acid (0.5 mM) produced the following increases in potency: GABA 2.68 +/- 0.02; 3-aminopropanesulphonic acid, 3.11 +/- 0.07; isoguvacine, 1.92 +/- 0.34; muscimol, 2.24 +/- 0.17. The concentration of GABA in the bathing fluid necessary to double input conductance increased with increasing depth of the recording site from the cut surface. The apparent potency fell 10 times for each 60 micron depth increment up to 150 micron. The recording depth also affected the apparent potency of muscimol and 3-APS but to a lesser extent. Reduction of external [Na+] reduced the depth-dependence of both GABA and 3-APS potency. No clear change in the duration of the recurrent inhibitory postsynaptic conductance could be detected in the presence of 0.5 mmol l-1 nipecotic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Brown, D. A.; Scholfield, C. N.



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

|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…

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



In vivo GABA detection with improved selectivity and sensitivity by localized double quantum filter technique at 4.1T.  


Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter for the normal function of mammal and human brain. It is difficult to detect GABA signal with the conventional single quantum technique due to its relatively low concentration and overlapping with other signals from creatine (Cr), glutathione (GSH), as well as macromolecules. Using a high-selective read pulse, DANTE, and at the facility of increased sensitivity and chemical shift resolution at high-field 4.1T, GABA editing by double quantum filter (DQF) with robust suppression of Cr and GSH was achieved. Our editing efficiency of 40-50% was achievable on a GABA phantom (50 mM GABA and 61 mM choline). Furthermore, GABA editing spectra were acquired with echo time TE = 77 ms, and any possible macromolecular contamination to GABA editing spectra was found to be negligible. This high-field DQF setup was applied to 11 healthy volunteers, and the mean GABA level was measured to be 1.12 +/- 0.15 mM in the occipital lobe in reference to 7.1 mM Cr concentration. PMID:14972399

Du, Fei; Chu, Wen-Jang; Yang, Baolian; Den Hollander, Jan A; Ng, Thian C



Cyclooxygenase2 inhibitor inhibits the hippocampal synaptic reorganization by inhibiting MAPK\\/ERK activity and modulating GABAergic transmission in pilocarpine-induced status epilepticus rats  

Microsoft Academic Search

Recurring and spontaneous seizures in epilepsy result from cell signaling aberrations thought to include synaptic reorganization\\u000a and various neurotransmitter abnormalities, especially gamma-amino butyric acid (GABA) and glutamate. Cyclooxygenase-2 (COX-2)\\u000a activity produces oxidative stress and results in the production of prostaglandins that have many injurious effects. COX-2\\u000a transcription is induced by synaptic activity; therefore COX-2 may play a significant role in

Zhang Haiju; Sun Ruopeng; Lei Gefei; Yang Lu; Liu Chunxi



Ontogeny of the calcium binding protein parvalbumin in the rat nervous system  

Microsoft Academic Search

In the adult rat brain, the calcium-binding protein parvalbumin is preferentially associated with spontaneously fast-firing, metabolically active neurons and coexists with gamma-amino-butyric acid (GABA) in cortical inhibitory interneurons. Whether this is so in developing neurons has not been explored. To this end, we have used parvalbumin immunohistochemistry to study expression of this protein in the rat nervous system during pre-

Sven Solbach; Marco R. Celio



Selective antagonists of benzodiazepines  

Microsoft Academic Search

Benzodiazepines produce most, if not all, of their numerous effects on the central nervous system (CNS) primarily by increasing the function of those chemical synapses that use gamma-amino butyric acid (GABA) as transmitter1,2. This specific enhancing effect on GABAergic synaptic inhibition is initiated by the interaction of benzodiazepines with membrane proteins of certain central neurones, to which drugs of this

W. Hunkeler; H. Möhler; L. Pieri; P. Polc; E. P. Bonetti; R. Cumin; R. Schaffner; W. Haefely



Neurochemical characterization of nervous elements innervating the body wall of earthworms ( Lumbricus , Eisenia ): immunohistochemical and pharmacological studies  

Microsoft Academic Search

The distribution and chemical neuroanatomy of nervous elements and certain pharmacological–physiological characteristics of the innervation of the body wall in earthworms are described. Solitary sensory bipolar cells can be found among the epithelial cells. These bipolar cells contain serotonin, tyrosine hydroxylase, histamine, gamma-amino-butyric acid (GABA), Eisenia tetradecapeptide, proctolin or rhodopsin in various combinations. In the body wall, the plexus submuscularis

Mária Csoknya; Boglárka Takács; Anna Koza; Viktória Dénes; Márta Wilhelm; László Hiripi; Jan Kaslin; Károly Elekes



Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates.  


By bioisosteric transformations and successive optimization of known GABA uptake inhibitors, several series of novel GABA uptake inhibitors have been prepared by different synthetic approaches. These compounds are derivatives of nipecotic acid and guvacine, substituted at the nitrogen of these amino acids by various lipophilic moieties such as diarylaminoalkoxyalkyl or diarylalkoxyalkyl. The in vitro values for inhibition of [(3)H]GABA uptake in rat synaptosomes was determined for each compound, and it was found that the most potent compound from this series, (R)-1-(2-(3,3-diphenyl-1-propyloxy)ethyl)-3-piperidinecarboxyli c acid hydrochloride (29), is so far the most potent parent compound inhibiting GABA uptake into synaptosomes. Structure-activity results confirm our earlier observations, that an electronegative center in the chain connecting the amino acid and diaryl moiety is very critical in order to obtain high in vitro potency. Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). Some of the compounds tested show a high in vivo potency comparable with that of the recently launched anticonvulsant product 6 ((R)-1-(4, 4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid). PMID:10543872

Andersen, K E; Sørensen, J L; Huusfeldt, P O; Knutsen, L J; Lau, J; Lundt, B F; Petersen, H; Suzdak, P D; Swedberg, M D



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

NASA Astrophysics Data System (ADS)

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 (?-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.

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



Altered GABA and somatostatin modulation of proprioceptive feedback after spinal cord injury in lamprey.  


While various changes occur after spinal cord lesions, their influence on functional recovery is generally unclear. We have shown changes in proprioceptor and locomotor network properties below lesion sites in the lamprey spinal cord. The proprioceptive system offers a particularly tractable model for analyzing these changes. Here, we have sought evidence for changes in neuromodulatory effects below lesion sites by comparing the effects of gamma-aminobutyric acid (GABA) and somatostatin, both of which are located around the edge cells, on proprioceptive responses in lesioned and unlesioned spinal cords. Exogenously applied GABA significantly reduced or abolished bending-evoked responses in unlesioned animals. In lesioned animals bending-evoked responses were stronger and certain of the effects of exogenously applied GABA were reduced. However, blocking endogenous GABA with bicuculline significantly potentiated responses in lesioned but not unlesioned animals. This suggested that the potentiated responses in lesioned animals were nevertheless associated with stronger tonic GABAergic inhibition. There were significant differences in these effects when lesioned animals were separated on the basis of their degree of recovery: notably, bicuculline only potentiated responses in animals that recovered good locomotor function, suggesting a need for raised endogenous GABA levels. Somatostatin alone did not affect edge cell responses in lesioned or unlesioned animals, but in lesioned animals it reduced and thus further weakened the inhibitory effects of GABA. There are thus multiple changes in sensory modulation in the lesioned spinal cord, and differences in these effects may influence the degree of recovery. PMID:23333673

Svensson, E; Kim, O; Parker, D



Temperature elevation increases GABA(A) -mediated cortical inhibition in a mouse model of genetic epilepsy.  


A missense mutation (R43Q) in the ?2 subunit of the ?-aminobutyric acid (GABA)(A) receptor is associated with generalized (genetic) epilepsy with febrile seizures plus (GEFS+). Heterozygous GABA(A) ?2(R43Q) mice displayed a lower temperature threshold for thermal seizures as compared to wild-type littermates. Temperature-dependent internalization of GABA(A) ?2(R43Q)-containing receptors has been proposed as a mechanism underlying febrile seizure genesis in patients with this mutation. We tested this idea using the GABA(A) ?2(R43Q) knockin mouse model and analyzed GABAergic miniature postsynaptic inhibitory currents (mIPSCs) in acute brain slices after exposure to varying temperatures. Incubation of slices at an elevated temperature increased mIPSC amplitude in neurons from heterozygous mice, with no change seen in wild-type controls. [³H]Flumazenil binding measured in whole-brain homogenates from mutant and control mice following elevation of body temperature showed no temperature-dependent differences in ?2-containing receptor density. Therefore, in vivo mouse data do not support earlier in vitro observations that proposed temperature-dependent internalization of ?2 R43Q containing GABA(A) receptors as the cellular mechanism underlying febrile seizure genesis in patients with the GABA(A) ?2(R43Q) mutation. PMID:21219304

Hill, Elisa L; Hosie, Suzanne; Mulligan, Rachel S; Richards, Kay L; Davies, Philip J; Dubé, Celine M; Baram, Tallie Z; Reid, Christopher A; Jones, Mathew V; Petrou, Steven



GABA Depolarizes Neuronal Progenitors of the Postnatal Subventricular Zone Via GABAA Receptor Activation  

PubMed Central

Previous studies have reported the presence of migrating and dividing neuronal progenitors in the subventricular zone (SVZ) and rostral migratory stream (RMS) of the postnatal mammalian brain. Although the behaviour of these progenitors is thought to be influenced by local signals, the nature and mode of action of the local signals are largely unknown. One of the signalling molecules known to affect the behaviour of embryonic neurons is the neurotransmitter GABA. In order to determine whether GABA affects neuronal progenitors via the activation of specific receptors, we performed cell-attached, whole-cell and gramicidin perforated patch-clamp recordings of progenitors in postnatal mouse brain slices containing either the SVZ or the RMS. Recorded cells displayed a morphology typical of migrating neuronal progenitors had depolarized zero-current resting potentials, and lacked action potentials. A subset of progenitors contained GABA and stained positive for glutamic acid decarboxylase 67 (GAD-67) as shown by immunohistochemistry. In addition, every neuronal progenitor responded to GABA via picrotoxin-sensitive GABAA receptor (GABAAR) activation. GABAARs displayed an ATP-dependent rundown and a low sensitivity to Zn2+. GABA responses were sensitive to benzodiazepine agonists, an inverse agonist, as well as a barbiturate agonist. While GABA was hyperpolarizing at the zero-current resting potentials, it was depolarizing at the cell resting potentials estimated from the reversal potential of K+ currents through a cell-attached patch. Thus, our study demonstrates that neuronal progenitors of the SVZ/RMS contain GABA and are depolarized by GABA, which may constitute the basis for a paracrine signal among neuronal progenitors to dynamically regulate their proliferation and/or migration.

Wang, D D; Krueger, D D; Bordey, A



State-Related Inhibition by GABA and Glycine of Transmission in Clarke's Column  

Microsoft Academic Search

During the state of active sleep (AS), Clarke's column dorsal spinocerebellar tract (DSCT) neurons undergo a marked reduc- tion in their spontaneous and excitatory amino acid (EAA)- evoked responses. The present study was performed to exam- ine the magnitude, consistency of AS-specific suppression, and potential role of classical inhibitory amino acids GABA and glycine (GLY) in mediating this phenomenon. AS-specific

Niwat Taepavarapruk; Shelly A. McErlane; Peter J. Soja



Electroacupuncture modulates vlPAG release of GABA through presynaptic cannabinoid CB1 receptors  

PubMed Central

Previous studies have demonstrated that electroacupuncture (EA) attenuates sympathoexcitatory reflex responses by activating a long-loop pathway involving the hypothalamic arcuate nucleus (ARC), midbrain ventrolateral periaqueductal gray (vlPAG), and rostral ventrolateral medulla (rVLM). Neurons in the ARC provide excitatory input to the vlPAG, whereas the vlPAG inhibits neuronal activity in the rVLM. ?-Aminobutyric acid (GABA) and glutamate (Glu) have been identified in the vlPAG. Endocannabinoids (ECs), acting as atypical neurotransmitters, inhibit the release of both neurotransmitters in the hypothalamus and midbrain through a presynaptic cannabinoid type 1 (CB1) receptor mechanism. The EC system has been observed in the dorsal but not in the vlPAG. Since it is uncertain whether ECs influence GABA and Glu in the vlPAG, the present study tested the hypothesis that EA modulates the release of these neurotransmitters in the vlPAG through a presynaptic CB1 receptor mechanism. We measured the release of GABA and Glu simultaneously by using HPLC to assess samples collected with microdialysis probes inserted unilaterally into the vlPAG of intact anesthetized rats. Twenty-eight min of EA (2 Hz, 2–4 mA, 0.5 ms) at the P5–6 acupoints reduced the release of GABA by 39% during EA and by 44% 15 min after EA. Thirty-five minutes after EA, GABA concentrations returned to pre-EA levels. In contrast, sham EA did not change the vlPAG GABA concentration. Blockade of CB1 receptors with AM251, a selective CB1 receptor antagonist, reversed the EA-modulated changes in GABA concentration, whereas microinjection of vehicle into the vlPAG did not alter EA-modulated GABA changes. In addition, we observed no changes in the vlPAG Glu concentrations during EA, although the baseline concentration of Glu was much higher than that of GABA (3,541 ± 373 vs. 33.8 ± 8.7 nM, Glu vs. GABA). These results suggest that EA modulates the sympathoexcitatory reflex responses by decreasing the release of GABA, but not Glu, in the vlPAG, most likely through a presynaptic CB1 receptor mechanism.

Fu, Liang-Wu; Longhurst, John C.



Growth cones isolated from developing rat forebrain: uptake and release of GABA and noradrenaline.  


A growth cone-enriched fraction isolated from neonatal rat forebrain was shown to accumulate gamma-amino [3H]butyric acid ([3H]-GABA) and [3H]noradrenaline ([3H]NA). Uptake of both neurotransmitters was sodium- and temperature-dependent and exhibited saturation kinetics with Km values of 17.7 microM and 4.5 microM respectively and Vmax values of 114 pmol/min/mg protein and 59 pmol/min/mg protein respectively. Electron microscopic autoradiography showed that about 50% of isolated growth cones can accumulate [3H]GABA. Inhibitor studies showed that beta-alanine was a relatively weak inhibitor of [3H]GABA uptake compared to nipecotic acid and diamino-butyric acid. Growth cone fractions preloaded with [3H]GABA and [3H]NA demonstrated a K+ (25 mM) -induced release of both neurotransmitters. Of the K+-stimulated release of [3H]GABA 50% was Ca2+-dependent, whereas the release of [3H]NA was entirely Ca2+-independent. PMID:4041908

Lockerbie, R O; Gordon-Weeks, P R; Pearce, B R



The pharmacological profile of ELIC, a prokaryotic GABA-gated receptor.  


The Erwinia ligand-gated ion channel (ELIC) is a bacterial homologue of vertebrate Cys-loop ligand-gated ion channels. It is activated by GABA, and this property, combined with its structural similarity to GABA(A) and other Cys-loop receptors, makes it potentially an excellent model to probe their structure and function. Here we characterise the pharmacological profile of ELIC, examining the effects of compounds that could activate or inhibit the receptor. We confirm that a range of amino acids and classic GABA(A) receptor agonists do not elicit responses in ELIC, and we show the receptor can be at least partially activated by 5-aminovaleric acid and ?-hydroxybutyric acid, which are weak agonists. A range of GABA(A) receptor non-competitive antagonists inhibit GABA-elicited ELIC responses including ?-endosulfan (IC?? = 17 ?M), dieldrin (IC?? = 66 ?M), and picrotoxinin (IC?? = 96 ?M) which were the most potent. Docking suggested possible interactions at the 2' and 6' pore-lining residues, and mutagenesis of these residues supports this hypothesis for ?-endosulfan. A selection of compounds that act at Cys-loop and other receptors also showed some efficacy at blocking ELIC responses, but most were of low potency (IC?? > 100 ?M). Overall our data show that a number of compounds can inhibit ELIC, but it has limited pharmacological similarity to GLIC and to Cys-loop receptors. PMID:22677470

Thompson, Andrew J; Alqazzaz, Mona; Ulens, Chris; Lummis, Sarah C R



Newer N-Phthaloyl GABA Derivatives with Antiallodynic and Antihyperalgesic Activities in Both Sciatic Nerve and Spinal Nerve Ligation Models of Neuropathic Pain  

Microsoft Academic Search

Background: There is considerable research evidence supporting a palliative role for ?-aminobutyric acid (GABA)-ergic neurotransmission and voltage-gated sodium channel blockade in neuropathic pain conditions. Hence, the present study was undertaken to assess the peripheral analgesic, antiallodynic and antihyperalgesic activities of the synthesized structural analogues of GABA. Methods: The screening study included acute tissue injury, chronic constriction injury (CCI), and spinal

Perumal Yogeeswari; Jegadeesan Vaigunda Ragavendran; Dharmarajan Sriram; Ramkumar Kavya; Kaliappan Vanitha; Harshini Neelakantan



Responses to GABA(A) receptor activation are altered in NTS neurons isolated from chronic hypoxic rats.  


The inhibitory amino acid GABA is released within the nucleus of the solitary tract (NTS) during hypoxia and modulates the respiratory response to hypoxia. To determine if responses of NTS neurons to activation of GABA(A) receptors are altered following exposure to chronic hypoxia, GABA(A) receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from normoxic and chronic hypoxic rats. Chronic hypoxic rats were exposed to 10% O(2) for 9-12 days. Membrane capacitance was the same in neurons from normoxic (6.9+/-0.5 pF, n=16) and hypoxic (6.3+/-0.5 pF, n=15) rats. The EC(50) for peak GABA-evoked current density was significantly greater in neurons from hypoxic (21.7+/-2.2 microM) compared to normoxic rats (12.2+/-0.9 microM) (p<0.001). Peak and 5-s adapted GABA currents evoked by 1, 3 and 10 microM were greater in neurons from normoxic compared to hypoxic rats (p<0.05) whereas peak and 5-s adapted responses to 30 and 100 microM GABA were not different comparing normoxic to hypoxic rats. Desensitization of GABA(A)-evoked currents was observed at concentrations greater than 3 microM and, measured as the ratio of the current 5 s after the onset of 100 microM GABA application to the peak GABA current, was the same in neurons from normoxic (0.37+/-0.03) and hypoxic rats (0.33+/-0.04). Reduced sensitivity to GABA(A) receptor-evoked inhibition in chronic hypoxia could influence chemoreceptor afferent integration by NTS neurons. PMID:15047029

Tolstykh, Gleb; Belugin, Sergei; Mifflin, Steve



GABA-benzodiazepine receptor function in alcohol dependence: a combined 11 C-flumazenil PET and pharmacodynamic study  

Microsoft Academic Search

Rationale  Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence.\\u000a \\u000a \\u000a \\u000a Objectives  We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship\\u000a between BDZ receptor occupancy by an agonist, midazolam, and its functional effects.\\u000a \\u000a \\u000a \\u000a Methods  Abstinent male alcohol dependent subjects underwent [11C]flumazenil PET to measure occupancy of

A. R. Lingford-Hughes; S. J. Wilson; V. J. Cunningham; A. Feeney; B. Stevenson; D. J. Brooks; D. J. Nutt



Cyclopropane-based conformational restriction of GABA by a stereochemical diversity-oriented strategy: identification of an efficient lead for potent inhibitors of GABA transports.  


A series of cyclopropane-based conformationally restricted ?-aminobutyric acid (GABA) analogs with stereochemical diversity, that is, the trans- and cis-2,3-methano analogs Ia and Ib and their enantiomers ent-Ia and ent-Ib, and also the trans- and cis-3,4-methano analogs IIa and IIb and their enantiomers ent-IIa and ent-Iib, were synthesized from the chiral cyclopropane units Type-a and Type-b that we developed. These analogs were systematically evaluated with four GABA transporter (GAT) subtypes. The trans-3,4-methano analog IIa had inhibitory effects on GAT3 (IC50=23.9?M) and betaine-GABA transporter1 (5.48?M), indicating its potential as an effective lead compound for the development of potent GAT inhibitors due to its hydrophilic and low molecular weight properties and excellent ligand efficiency. PMID:23886812

Nakada, Kazuaki; Yoshikawa, Mamie; Ide, Soichiro; Suemasa, Akihiro; Kawamura, Shuhei; Kobayashi, Takaaki; Masuda, Eiji; Ito, Yoshihiko; Hayakawa, Wataru; Katayama, Takahiro; Yamada, Shizuo; Arisawa, Mitsuhiro; Minami, Masabumi; Shuto, Satoshi



A microelectrophoretic method for the evaluation of GABA transaminase activity.  


The reduction to the micro-scale of a recently described electrophoretic method for the evaluation of GABA catabolism by GABA-T is presented. The micromethod involves the electrophoresis, in 1 mm diam. capillaries, of small samples of mixtures of [14C]GABA and its metabolites. By coupling this procedure to previously devised micromethods, it was possible to evaluate GABA-T attack to 14C labeled GABA diffusing across a single microdissected neuronal membrane. PMID:3412552

Cupello, A; Larsson, S; Palm, A; Rapallino, M V



{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

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.

Zheng Gang; Zhang Wenbin [Department of Occupational and Environmental Health, School of Public Health and Military Preventive Medicine, Fourth Military Medical University, Xi'an 710032 (China); Zhang Yun [465 Hospital, Jilin Medical College, Jilin 132001 (China); Chen Yaoming; Liu Mingchao; Yao Ting; Yang Yanxia; Zhao Fang [Department of Occupational and Environmental Health, School of Public Health and Military Preventive Medicine, Fourth Military Medical University, Xi'an 710032 (China); Li Jingxia; Huang Chuanshu [Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987 (United States); Luo Wenjing [Department of Occupational and Environmental Health, School of Public Health and Military Preventive Medicine, Fourth Military Medical University, Xi'an 710032 (China)], E-mail:; Chen Jingyuan [Department of Occupational and Environmental Health, School of Public Health and Military Preventive Medicine, Fourth Military Medical University, Xi'an 710032 (China)], E-mail:



gamma-Aminobutyric acid uptake by a bacterial system with neurotransmitter binding characteristics.  

PubMed Central

gamma-Aminobutyric acid (GABA), an amino acid, has been found in every class of living organisms. In higher organisms, GABA is a neurotransmitter and binds with high affinity and specificity to GABA receptors on neurons in a sodium-independent reaction that is saturable. The role of GABA in organisms lacking nervous tissue is not known. This report describes, in a strain of Pseudomonas fluorescens, a GABA uptake system with binding characteristics like those of the GABA (type A) brain receptor. The binding was saturable and specific for GABA, was sodium-independent, was of high affinity (Km = 65 nM), and was inhibited competitively by muscimol, a potent GABA analogue. The bacterial GABA system included a homogeneous binding site, and no cooperative interaction was found between sites. To our knowledge, such a system for GABA, or other neurotransmitters, in a bacterium has not been reported.

Guthrie, G D; Nicholson-Guthrie, C S



In vivo regulation of specific GABA A receptor subunit messenger rnas by increased gaba concentrations in rat brain  

Microsoft Academic Search

This study has examined whether changes in endogenous GABA concentrations influence GABAA receptor subunit mRNA expression in vivo. Increased GABA concentrations were achieved by treating female rats with ?-vinyl-GABA (15 mg\\/100 g), an irreversible inhibitor of the GABA transaminase, daily for three days. High performance liquid chromatography analysis of brain punches from specific brain regions showed that ?-vinyl-GABA treatment resulted

V. S. Fénelon; A. E. Herbison



Alternative splicing of a Drosophila GABA receptor subunit gene identifies determinants of agonist potency.  


Alternative splicing of the Drosophila melanogaster Rdl gene yields four ionotropic GABA receptor subunits. The two Rdl splice variants cloned to date, RDL(ac) and RDL(bd) (DRC17-1-2), differ in their apparent agonist affinity. Here, we report the cloning of a third splice variant of Rdl, RDL(ad). Two-electrode voltage clamp electrophysiology was used to investigate agonist pharmacology of this expressed subunit following cRNA injection into Xenopus laevis oocytes. The EC(so) values for GABA and its analogues isoguvacine, muscimol, isonipecotic acid and 3-amino sulphonic acid on the RDL(ad) homomeric receptor differed from those previously described for RDL(ac) and DRC17-1-2 receptors. In addition to providing a possible physiological role for the alternative splicing of Rdl, these data delineate a hitherto functionally unassigned region of the N-terminal domain of GABA receptor subunits, which affects agonist potency and aligns closely with known determinants of potency in nicotinic acetylcholine receptors. Thus, using expression in Xenopus oocytes, we have demonstrated differences in agonist potency for the neurotransmitter GABA (and four analogues) between splice variant products of the Drosophila melanogaster Rdl gene encoding homomer-forming GABA receptor subunits. PMID:11226707

Hosie, A M; Buckingham, S D; Presnail, J K; Sattelle, D B



Coexistence of GABA-and choline acetyltransferase (ChAT)-like immunoreactivity in the hypoglossal nucleus of the rat  

Microsoft Academic Search

Single and sequential double immunocytochemical techniques were applied to localize gamma-aminobutyric acid (GABA)-and choline acetyltransferase (ChAT)-like immunoreactivity (-LI) in the hypoglossal nucleus of the rat. After subsequential double staining a relatively high number of hypoglossal motor neurons showed the coexistence of both ChAT-and GABA-LI. Coexistence of both substances was also revealed in the axons of the hypoglossal nerve situated within

M. S. Davidoff; W. Schulze



GABA A Receptor Chloride Ion Channels  

Microsoft Academic Search

\\u000a GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). Virtually all neurons respond to GABA,\\u000a while about 30% of them make and utilize it as a neurotransmitter. The GABAB receptors are defined as bicuculline-insensitive and baclofen-sensitive. They are members of the G protein-coupled, 7 membrane-spanning\\u000a receptor family, and are associated with activation of K+ channels or inhibition

R. W. Olsen; M. Gordey


Single-shot two-echo technique for simultaneous measurement of GABA and creatine in the human brain in vivo.  


A single-shot, two-echo method for the simultaneous detection of multiple-quantum (MQ)-filtered gamma-aminobutyric acid (GABA) and creatine (Cr) was developed and demonstrated in the human brain in vivo at 3 Tesla. The simultaneously measured Cr singlet served as a navigator for the spectral phase of GABA and any frequency shift during measurements due to drift in the static magnetic field (B(0)) or subject movement, as well as an internal concentration reference. In addition, the use of a double-band frequency-selective MQ filter for C(3) and C(4) methylene protons of GABA provided a very robust measurement of GABA, with excellent suppression of overlapping metabolites such as Cr and glutathione (GSH) in each single scan. Contamination from overlapping macromolecules was also demonstrated to be negligible with this method. The GABA-to-Cr ratio was 0.09 +/- 0.03 (mean +/- SD, N = 17) and the estimated concentration of GABA in the frontoparietal region of the human brain in vivo was 0.66 +/- 0.19 micromol/g (mean +/- SD, N = 17) with the internal reference method, and 0.69 +/- 0.18 micromol/g (mean +/- SD, N = 17) with the external reference method. The observed pattern of GABA doublet was consistent among all subjects, with a frequency separation of approximately 13 Hz. PMID:15170830

Choi, In-Young; Lee, Sang-Pil; Merkle, Hellmut; Shen, Jun



Identification of GABA A receptor modulators in Kadsura longipedunculata and assignment of absolute configurations by quantum-chemical ECD calculations.  


A petroleum ether extract of Kadsura longipedunculata enhanced the GABA-induced chloride current (I(GABA)) by 122.5±0.3% (n=2) when tested at 100 ?g/ml in Xenopuslaevis oocytes expressing GABA A receptors (?(1)?(2)?(2S) subtype) in two-microelectrode voltage clamp measurements. Thirteen compounds were subsequently identified by HPLC-based activity profiling as responsible for GABA A receptor activity and purified in preparative scale. 6-Cinnamoyl-6,7-dihydro-7-myrceneol and 5,6-dihydrocuparenic acid were thereby isolated for the first time. The determination of the absolute stereochemistry of these compounds was achieved by comparison of experimental and calculated ECD spectra. All but one of the 13 isolated compounds from K. longipedunculata potentiated I(GABA) through GABA A receptors composed of ?(1)?(2)?(2S) subunits in a concentration-dependent manner. Potencies ranged from 12.8±3.1 to 135.6±85.7 ?M, and efficiencies ranged from 129.7±36.8% to 885.8±291.2%. The phytochemical profiles of petroleum ether extracts of Kadsura japonica fruits (114.1±2.6% potentiation of I(GABA) at 100 ?g/ml, n=2), and Schisandra chinensis fruits (inactive at 100 ?g/ml) were compared by HPLC-PDA-ESIMS with that of K. longipedunculata. PMID:21889177

Zaugg, Janine; Ebrahimi, Samad Nejad; Smiesko, Martin; Baburin, Igor; Hering, Steffen; Hamburger, Matthias



A conserved mechanism of GABA binding and antagonism is revealed by structure-function analysis of the periplasmic binding protein Atu2422 in Agrobacterium tumefaciens.  


Bacterial periplasmic binding proteins (PBPs) and eukaryotic PBP-like domains (also called as Venus flytrap modules) of G-protein-coupled receptors are involved in extracellular GABA perception. We investigated the structural and functional basis of ligand specificity of the PBP Atu2422, which is implicated in virulence and transport of GABA in the plant pathogen Agrobacterium tumefaciens. Five high-resolution x-ray structures of Atu2422 liganded to GABA, Pro, Ala, and Val and of point mutant Atu2422-F77A liganded to Leu were determined. Structural analysis of the ligand-binding site revealed two essential residues, Phe(77) and Tyr(275), the implication of which in GABA signaling and virulence was confirmed using A. tumefaciens cells expressing corresponding Atu2422 mutants. Phe(77) restricts ligand specificity to ?-amino acids with a short lateral chain, which act as antagonists of GABA signaling in A. tumefaciens. Tyr(275) specifically interacts with the GABA ?-amino group. Conservation of these two key residues in proteins phylogenetically related to Atu2422 brought to light a subfamily of PBPs in which all members could bind GABA and short ?-amino acids. This work led to the identification of a fingerprint sequence and structural features for defining PBPs that bind GABA and its competitors and revealed their occurrence among host-interacting proteobacteria. PMID:20630861

Planamente, Sara; Vigouroux, Armelle; Mondy, Samuel; Nicaise, Magali; Faure, Denis; Moréra, Solange



Effects of Yoga Versus Walking on Mood, Anxiety, and Brain GABA Levels: A Randomized Controlled MRS Study  

PubMed Central

Abstract Objectives Yoga and exercise have beneficial effects on mood and anxiety. ?-Aminobutyric acid (GABA)-ergic activity is reduced in mood and anxiety disorders. The practice of yoga postures is associated with increased brain GABA levels. This study addresses the question of whether changes in mood, anxiety, and GABA levels are specific to yoga or related to physical activity. Methods Healthy subjects with no significant medical/psychiatric disorders were randomized to yoga or a metabolically matched walking intervention for 60 minutes 3 times a week for 12 weeks. Mood and anxiety scales were taken at weeks 0, 4, 8, 12, and before each magnetic resonance spectroscopy scan. Scan 1 was at baseline. Scan 2, obtained after the 12-week intervention, was followed by a 60-minute yoga or walking intervention, which was immediately followed by Scan 3. Results The yoga subjects (n?=?19) reported greater improvement in mood and greater decreases in anxiety than the walking group (n?=?15). There were positive correlations between improved mood and decreased anxiety and thalamic GABA levels. The yoga group had positive correlations between changes in mood scales and changes in GABA levels. Conclusions The 12-week yoga intervention was associated with greater improvements in mood and anxiety than a metabolically matched walking exercise. This is the first study to demonstrate that increased thalamic GABA levels are associated with improved mood and decreased anxiety. It is also the first time that a behavioral intervention (i.e., yoga postures) has been associated with a positive correlation between acute increases in thalamic GABA levels and improvements in mood and anxiety scales. Given that pharmacologic agents that increase the activity of the GABA system are prescribed to improve mood and decrease anxiety, the reported correlations are in the expected direction. The possible role of GABA in mediating the beneficial effects of yoga on mood and anxiety warrants further study.

Whitfield, Theodore H.; Owen, Liz; Rein, Tasha; Karri, Surya K.; Yakhkind, Aleksandra; Perlmutter, Ruth; Prescot, Andrew; Renshaw, Perry F.; Ciraulo, Domenic A.; Jensen, J. Eric



Phenotypic characterization of orofacial movement topography in mutants with disruption of amino acid mechanisms: Glutamate N2A/B/D [GluR?1/2/4] subtypes and the GABA synthesizing enzyme GAD65.  


To investigate the role of glutamate receptor subtypes and GABA in orofacial function, six individual topographies of orofacial movement, both spontaneous and induced by the dopamine D1-like receptor agonist [R/S]-3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 83959), were quantified in mutant mice with deletion of (a) GluN2A, B or D receptors, and (b) the GABA synthesizing enzyme, 65-kD isoform of glutamate decarboxylase (GAD65). In GluN2A mutants, habituation of head movements was disrupted and vibrissae movements were reduced, with an overall increase in locomotion; responsivity to SKF 83959 was unaltered. In GluN2B mutants, vertical and horizontal jaw movements and incisor chattering were increased, with an overall decrease in locomotion; under challenge with SKF 83959, head and vibrissae movements were reduced. In GluN2D mutants, horizontal jaw movements, incisor chattering and vibrissae movements were increased, with reduced tongue protrusions and no overall change in locomotion; under challenge with SKF 83959, horizontal jaw movements were increased. In GAD65 mutants, vertical jaw movements were increased, with disruption to habituation of locomotion; under challenge with SKF 83959, vertical and horizontal jaw movements and incisor chattering were decreased. Effects on orofacial movements differed from their effects on regulation of overall locomotor behavior. These findings (a) indicate novel, differential roles for GluN2A, B and D receptors and for GAD65-mediated GABA in the regulation of individual topographies of orofacial movement and (b) reveal how these roles differ from and/or interact with the established role of D1-like receptors in pattern generators and effectors for such movements. PMID:23892010

Tomiyama, K; Kato, R; Hara, Y; Kobayashi, M; Mishina, M; Yanagawa, Y; Kinsella, A; Koshikawa, N; Waddington, J L



The ? and ? subunit-dependent effects of local anesthetics on recombinant GABA A receptors  

Microsoft Academic Search

Although convulsions due to local anesthetic systemic toxicity are thought to be due to inhibition of GABAA receptor-linked currents in the central nervous system, the mechanism of action remains unclear. We therefore examined the effects of local anesthetics on ?-aminobutyric acid (GABA)-induced currents using recombinant GABAA receptors with specific combinations of subunits. Murine GABAA receptors were expressed by injection of

Masahiro Sugimoto; Ichiro Uchida; Sakae Fukami; Makoto Takenoshita; Takashi Mashimo; Ikuto Yoshiya



Human locus coeruleus neurons express the GABA A receptor ?2 subunit gene and produce benzodiazepine binding  

Microsoft Academic Search

Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for ?-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABAA

Kati S. Hellsten; Saku T. Sinkkonen; Thomas M. Hyde; Joel E. Kleinman; Terttu Särkioja; Anu Maksimow; Mikko Uusi-Oukari; Esa R. Korpi



Comparison of the antiepileptic properties of transmeningeally delivered muscimol, lidocaine, midazolam, pentobarbital and GABA, in rats  

Microsoft Academic Search

This study compared the potencies of epidurally delivered muscimol, lidocaine, midazolam, pentobarbital and ?-aminobutyric acid (GABA) to prevent focal neocortical seizures induced by locally applied acetylcholine (Ach), in rats (n=5). An epidural cup was chronically implanted over the right somatosensory cortex in each animal, with epidural EEG electrodes placed posterior to the edge of the cup. After recovery, either artificial

Shirn L. Baptiste; Hai M. Tang; Ruben I. Kuzniecky; Orrin Devinsky; Jacqueline A. French; Nandor Ludvig



GABA and Epilepsy: Their Complex Relationship and the Evolution of Our Understanding  

Microsoft Academic Search

Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, ?-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that \\

S. Robert Snodgrass



Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABA A receptor point-mutated mice  

Microsoft Academic Search

Ionotropic ?-aminobutyric acid (GABAA) receptors control the relay of nociceptive signals at several levels of the neuraxis. Experiments with systemically applied benzodiazepines, which enhance the action of GABA at these receptors, have suggested both anti- and pronociceptive effects. The interpretation of such experiments has been notoriously difficult because of confounding sedation. Here, we have used genetically engineered mice, which carry

Julia Knabl; Ulrike B. Zeilhofer; Florence Crestani; Uwe Rudolph; Hanns Ulrich Zeilhofer



GABA and the ornithine ? -aminotransferase gene in vigabatrin-associated visual field defects  

Microsoft Academic Search

Vigabatrin use in some epilepsy patients has been associated with persistent visual field constriction and retinal dysfunction. The mechanism is unknown, but could be related to vigabatrin, chronic epilepsy, GABA toxicity, or the effect of a metabolite in combination with a predisposing genotype. The aim of this study was to investigate the latter two hypotheses. Levels of brain gamma-aminobutyric acid

Fuki M Hisama; Richard H Mattson; Helen H Lee; Kristin Felice; Ognen A. C Petroff



Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats  

Microsoft Academic Search

Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and ?-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects

Nurith Amitai; Ronald Kuczenski; M. Margarita Behrens; Athina Markou


A role for GABA A receptors in the modulation of Paramecium swimming behavior  

Microsoft Academic Search

The presence in Paramecium of ?-aminobutyric acid A-type receptors (GABAA) and the capability of the protozoon to synthesize and release the GABA neurotransmitter into the environment have already been demonstrated. This study investigates the involvement of the GABAA complex in the swimming control of the ciliated protozoon. The GABAA receptors were pharmacologically activated by the selective agonist muscimol and the

Giovanna Bucci; Paola Ramoino; Alberto Diaspro; Cesare Usai



Responses to GABA A receptor activation are altered in NTS neurons isolated from chronic hypoxic rats  

Microsoft Academic Search

The inhibitory amino acid GABA is released within the nucleus of the solitary tract (NTS) during hypoxia and modulates the respiratory response to hypoxia. To determine if responses of NTS neurons to activation of GABAA receptors are altered following exposure to chronic hypoxia, GABAA receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from normoxic and chronic hypoxic

Gleb Tolstykh; Sergei Belugin; Steve Mifflin



GABA-synthesizing enzyme, GAD67, from dermal fibroblasts: Evidence for a new skin function  

Microsoft Academic Search

Glutamate decarboxylase (GAD) catalyzes the synthesis of ?-aminobutyric acid (GABA), an inhibitory neurotransmitter, from glutamate. An expression of GAD protein has been reported for brain and pancreas, but not for skin. In this study, we present evidence that GAD67 mRNA and protein are expressed in mouse skin and in human dermal fibroblasts. The expression of GAD67 gene is weaker in

Kenichi Ito; Kiyotaka Tanaka; Yukinobu Nishibe; Junichi Hasegawa; Hiroshi Ueno



Reversal or reduction of glutamate and GABA transport in CNS pathology and therapy  

Microsoft Academic Search

A dysfunction of amino acid neurotransmitter transporters occurs in a number of central nervous system disorders, including stroke, epilepsy, cerebral palsy and amyotrophic lateral sclerosis. This dysfunction can comprise a reversal of transport direction, leading to the release of neurotransmitter into the extracellular space, or an alteration in transporter expression level. This review analyses the role of glutamate and GABA

Nicola J. Allen; Ragnhildur Káradóttir; David Attwell



Proton inhibition of GABA-activated current in rat primary sensory neurons  

Microsoft Academic Search

The modulation of the Cl– current activated by ?-aminobutyric acid (GABA) by changes in extracellular pH in freshly isolated rat dorsal root ganglia\\u000a (DRG) neurons was studied using the whole-cell patch-clamp technique. In the pH range of 5.0–9.0, increased extracellular\\u000a pH enhanced, and decreased extracellular pH suppressed, current activated by 10 ?M GABA in a reversible and concentration-dependent\\u000a manner with an

J. Zhai; Robert W. Peoples; Chaoying Li



GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery?  


The clinical importance of benzodiazepines, barbiturates and general anesthetics, all of which act through the gamma-aminobutyric acid (GABA)-A neurotransmitter receptor, is testament to its significance as a CNS drug target. These drugs were all developed before there was any understanding of the diversity of this receptor gene family. Recent studies using genetically modified mice and GABA-A receptor-subtype-selective compounds have helped to delineate the function of some of these subtypes, and have revealed that it might be possible to develop a new generation of selective drugs with improved profiles or novel applications. PMID:12801796

Whiting, Paul J



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

SciTech Connect

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.

Marley, R.J.



Activation of GABA-A Receptor Ameliorates Homocysteine-Induced MMP-9 Activation by ERK Pathway  

PubMed Central

Hyperhomocysteinemia (HHcy) is a risk factor for neuroinflammatory and neurodegenerative diseases. Homocysteine (Hcy) induces redox stress, in part, by activating matrix metalloproteinase-9 (MMP-9), which degrades the matrix and leads to blood–brain barrier dysfunction. Hcy competitively binds to ?-aminbutyric acid (GABA) receptors, which are excitatory neurotransmitter receptors. However, the role of GABA-A receptor in Hcy-induced cerebrovascular remodeling is not clear. We hypothesized that Hcy causes cerebrovascular remodeling by increasing redox stress and MMP-9 activity via the extracellular signal-regulated kinase (ERK) signaling pathway and by inhibition of GABA-A receptors, thus behaving as an inhibitory neurotransmitter. Hcy-induced reactive oxygen species production was detected using the fluorescent probe, 2?–7?-dichlorodihydrofluorescein diacetate. Hcy increased nicotinamide adenine dinucleotide phosphate-oxidase-4 concomitantly suppressing thioredoxin. Hcy caused activation of MMP-9, measured by gelatin zymography. The GABA-A receptor agonist, muscimol ameliorated the Hcy-mediated MMP-9 activation. In parallel, Hcy caused phosphorylation of ERK and selectively decreased levels of tissue inhibitors of metalloproteinase-4 (TIMP-4). Treatment of the endothelial cell with muscimol restored the levels of TIMP-4 to the levels in control group. Hcy induced expression of iNOS and decreased eNOS expression, which lead to a decreased NO bioavailability. Furthermore muscimol attenuated Hcy-induced MMP-9 via ERK signaling pathway. These results suggest that Hcy competes with GABA-A receptors, inducing the oxidative stress transduction pathway and leading to ERK activation.




Determining the in vivo transverse relaxation time of GABA in the human brain at 7T.  


PURPOSE: To measure in vivo transverse relaxation times (T(2) ) of gamma-aminobutyric acid (GABA) at 7T using the experimental spectral-editing method. MATERIALS AND METHODS: Experiments were performed at 7T in a 10 mM GABA phantom to determine the intrinsic TE-dependence of the edited signal. Then the same method was applied with editing-based suppression of coedited macromolecular signals to five healthy volunteers to determine T(2) of GABA in vivo. RESULTS: From in vivo data acquired at multiple echo times, the in vivo GABA T(2) relaxation time was estimated to be 63 ± 19 msec. CONCLUSION: We present a measurement of the T(2) of edited GABA signal at 7T by first using phantom measurements to determine the echo time-dependence of edited signal. The method is purely experimental and does not rely on prior knowledge of coupling constants or simulation of realistic experiments. J. Magn. Reson. Imaging 2013;. © 2013 Wiley Periodicals, Inc. PMID:23239232

Intrapiromkul, Jarunee; Zhu, He; Cheng, Ying; Barker, Peter B; Edden, Richard A E



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

SciTech Connect

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.

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



Amyloid beta proteins reduce the GABA-induced Cl- current in identified Aplysia neurons.  


The amyloid beta protein (A beta P) is the major component of the amyloid deposition which characterizes Alzheimer's disease. Effects of extracellularly applied A beta P on the gamma-aminobutyric acid (GABA)-induced Cl- current recorded from identified neurons (R9 and R12) of Aplysia kurodai were investigated with conventional voltage-clamp and pressure ejection techniques. Focal application of 100 nM A beta P (1-40) reduced the GABA-induced hyperpolarization at resting membrane potential and the GABA-induced Cl- current in the neurons held at -50 mV. Bath-applied 100 nM A beta P fragments (1-40) and (25-35) but not A beta P (1-16) inhibited the GABA-induced Cl- current as well as muscimol-induced Cl- currents in the neurons without affecting the resting membrane conductance or holding current. These results suggest that A beta P may increase neuronal excitability by inhibiting GABA-induced Cl- current in the neurons of mammalian central nervous system. PMID:8873152

Sawada, M; Ichinose, M



SDF and GABA interact to regulate axophilic migration of GnRH neurons.  


Stromal derived growth factor (SDF-1) and gamma-aminobutyric acid (GABA) are two extracellular cues that regulate the rate of neuronal migration during development and may act synergistically. The molecular mechanisms of this interaction are still unclear. Gonadotropin releasing hormone-1 (GnRH) neurons are essential for vertebrate reproduction. During development, these neurons emerge from the nasal placode and migrate through the cribriform plate into the brain. Both SDF-1 and GABA have been shown to regulate the rate of GnRH neuronal migration by accelerating and slowing migration, respectively. As such, this system was used to explore the mechanism by which these molecules act to produce coordinated cell movement during development. In the present study, GABA and SDF-1 are shown to exert opposite effects on the speed of cell movement by activating depolarizing or hyperpolarizing signaling pathways, GABA via changes in chloride and SDF-1 via changes in potassium. GABA and SDF-1 were also found to act synergistically to promote linear rather than random movement. The simultaneous activation of these signaling pathways, therefore, results in tight control of cellular speed and improved directionality along the migratory pathway of GnRH neurons. PMID:22976302

Casoni, Filippo; Hutchins, B Ian; Donohue, Duncan; Fornaro, Michele; Condie, Brian G; Wray, Susan



GABA Heteroreceptors Modulate Noradrenaline Release in Human Dental Pulp.  


?-aminobutyric-acid-containing neurons and GABAB receptors have been identified in human dental pulp; however, their significance in pulpal physiology is unclear. The purpose of this study was to determine whether pre-synaptic GABAergic heteroreceptors influence the release of noradrenaline (NA). Segments of vital pulp were incubated in [(3)H]NA (0.6 ?M) and superfused with Krebs solution. GABA, a GABAB receptor agonist (baclofen), GABAA and B receptor antagonists [bicuculline and (+)-(S)-5, 5-dimethylmorpholinyl-2-acetic acid (Sch 50911), respectively], and a GABAA receptor-mediated Cl(-) channel inhibitor (picrotoxin) were added to the superfusion medium at least 10 min prior to the second period of stimulation (S2). Sympathetic nerves were stimulated electrically after 70 (S1) and 115 (S2) min. We determined the effects of agonists/antagonists by comparing the overflow of [(3)H]NA at S2 with that at S1 in the presence and absence of the compound. Baclofen (3 µM) inhibited the release of [(3)H]NA (IC50 = 2 µM), an action reversed by Sch 50911 (10 µM). GABA (100 µM) inhibited the release of [(3)H]NA (IC50 = 75 µM), an effect reversed by Sch 50911 (10 µM) but not by bicuculline (10 µM). However, picrotoxin (100 µM) prevented the inhibitory action of GABA. GABAB and GABAA heteroceptors mediate the release of NA from sympathetic nerves in human dental pulp in vitro. PMID:24056226

Parker, D A S; Marino, V



GABA-A receptors play a minor role in cortical epileptic afterdischarges in immature rats.  


The role of inhibitory ?-aminobutyric acid-A (GABA-A) system in the cortical epileptic afterdischarges (ADs) was studied at three different developmental stages of rats. Animals 12, 18 and 25days old with implanted epidural electrodes were pretreated with bicuculline (1 and 2mg/kgi.p.) and 15min later repeatedly stimulated with low frequency trains with stepwise increasing current intensity. Bicuculline only exceptionally decreased threshold current intensities necessary for elicitation of movements directly bound to stimulation, spike-and wave ADs, clonic seizures and transition into a limbic type of ADs. Duration of ADs was not systematically affected by either dose of bicuculline. In contrast, transcallosal evoked potentials exhibited under the influence of bicuculline steeper curve expressing relation between intensity of stimuli and amplitude of responses. In contrast to GABA-B receptors, GABA-A receptors do not play an important role in generation and arrest of cortical epileptic ADs in immature rats. PMID:21824607

Tabashidze, N; Mareš, P



Demonstration of GABA immunoreactive cells in the inferior olive of baboons (Papio papio and Papio anubis).  


The distribution of gamma-aminobutyric acid (GABA)-like immunoreactivity was studied in semithin sections through the inferior olivary complex in two baboon species. About 5% of the olivary neurons were GABA-immunoreactive. The GABA-immunoreactive neurons differed from the large majority of olivary neurons by their smaller size and their lower contents of aspartate, as judged by analysis of alternate sections labelled with an aspartate antiserum. The present observations raise the possibility that in primates the GABAergic modulation of the activity of the climbing fibre system is effected not only by the previously described input from the cerebellar nuclei and other extrinsic sources, but that intrinsic neurons also participate. PMID:2671810

Walberg, F; Ottersen, O P



Interleukin-2 inhibits the GABA-induced Cl- current in identified Aplysia neurons.  


The effects of extracellularly applied recombinant human interleukin-2 (rhIL-2) on the gamma-aminobutyric acid (GABA)-induced Cl- current recorded from identified neurons (R9 and R12) of Aplysia kurodai were investigated with conventional voltage-clamp and pressure ejection techniques. Bath-applied rhIL-2 (10-40 U/ml) reduced the GABA-induced current in the neurons without affecting resting membrane conductance and the holding current. The suppressing effect of rhIL-2 on the current was completely reversible. Heat-inactivated rhIL-2 was without effect. These results suggest that the immunomodulator IL-2 can modulate the GABA-induced response in the nervous system. PMID:1281891

Sawada, M; Hara, N; Ichinose, M



Molecular Mechanisms of the Partial Allosteric Modulatory Effects of Bretazenil at gamma-Aminobutyric Acid Type A Receptor  

Microsoft Academic Search

In central nervous system gamma-aminobutyric acid (GABA) inhibits neuronal activity by acting on GABA type A (GABA_A) receptors. These heterooligomeric integral membrane proteins include a GABA-gated Cl^- channel and various allosteric modulatory sites where endogenous modulators and anxiolytic drugs act to regulate GABA action. In vivo, various anxiolytic drugs exhibit a wide range of variability in their modulatory efficacy and

G. Puia; I. Ducic; S. Vicini; E. Costa



Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats  

PubMed Central

Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and ?-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug-free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction.

Amitai, Nurith; Kuczenski, Ronald; Behrens, M. Margarita; Markou, Athina



Neurochemicals for the investigation of GABA(C) receptors.  


GABA(C) receptors are being investigated for their role in many aspects of nervous system function including memory, myopia, pain and sleep. There is evidence for functional GABA(C) receptors in many tissues such as retina, hippocampus, spinal cord, superior colliculus, pituitary and the gut. This review describes a variety of neurochemicals that have been shown to be useful in distinguishing GABA(C) receptors from other receptors for the major inhibitory neurotransmitter GABA. Some selective agonists (including (+)-CAMP and 5-methyl-IAA), competitive antagonists (such as TPMPA, (±)-cis-3-ACPBPA and aza-THIP), positive (allopregnanolone) and negative modulators (epipregnanolone, loreclezole) are described. Neurochemicals that may assist in distinguishing between homomeric ?1 and ?2 GABA(C) receptors (2-methyl-TACA and cyclothiazide) are also covered. Given their less widespread distribution, lower abundance and relative structural simplicity compared to GABA(A) and GABA(B) receptors, GABA(C) receptors are attractive drug targets. PMID:20963487

Johnston, Graham A R; Chebib, Mary; Hanrahan, Jane R; Mewett, Kenneth N



Concentration-dependent effects of GABA on insensitivity to fipronil in the A2'S mutant RDL GABA receptor from fipronil-resistant Oulema oryzae (Coleoptera: Chrysomelidae).  


The beetle Oulema oryzae Kuwayama (Coleoptera: Chrysomelidae), an important pest of rice, has developed fipronil resistance in Japan. Molecular cloning and sequence analysis of O. oryzae RDL gamma-aminobutyric acid (GABA) receptor subunit (OO-RDL) genes from fipronil-susceptible and -resistant O. oryzae identified the A2'S mutation (index number for the M2 membrane-spanning region). To investigate the effect of the A2'S mutation on fipronil resistance, we stably expressed the wild-type and mutant OO-RDL homomers in Drosophila Mel-2 cells. A membrane potential assay exhibited that the IC50 values of fipronil for inhibition of the response to EC80 GABA of the wild-type and A2'S mutant OO-RDL homomers were 0.09 microM and 0.11 microM, respectively. However, the IC50 values of fipronil for inhibition of the response to EC95 GABA of the wild-type and A2'S mutant OO-RDL homomers were 0.11 microM and approximately equal to 5 microM, respectively. These results suggest that the GABA concentration is an important factor affecting fipronil resistance in O. oryzae carrying the A2'S mutation in OO-RDL. PMID:23156177

Nakao, Toshifumi; Naoi, Atsuko; Hama, Masako; Kawahara, Nobuyuki; Hirase, Kangetsu



GABA-ergic neurons in the leach central nervous system  

SciTech Connect

GABA is a candidate for an inhibitory neurotransmitter in the leech central nervous system because of the well-documented inhibitory action of GABA in other invertebrates. To demonstrate that GABA meets the criteria used to identify a substance as a neurotransmitter, the author examined GABA metabolism and synaptic interactions of inhibitory motor neurons in two leech species, Hirudo medicinalis and Haementeria ghilianii. Segmental ganglia of the leech ventral nerve cord and identified inhibitors have the capacity to synthesize GABA when incubated in the presence of the precursor glutamate. Application of GABA to cell bodies of excitatory motor neurons or muscle fibers innervated by the inhibitors hyperpolarizes the membrane potential of the target cell and activates a chloride ion conductance channel, similar to the inhibitory membrane response following intracellular stimulation of the inhibitor. Bicuculline methiodide (5 x 10/sup -5/M), GABA receptor antagonist, blocks reversibly the response to applied GABA and the inhibitory synaptic inputs onto the postsynaptic neurons or muscle fibers without interfering with their excitatory inputs. Furthermore, the inhibitors are included among approximately 25 neurons per segmental ganglion that take up GABA by a high affinity uptake system, as revealed by /sup 3/H-GABA-autoradiography. The development of the capacities to synthesize and to take up GABA were examined in leech embryos. The embryos are able to synthesize GABA at early stages of the development of the nervous system, before any neurons have extended neutrites.

Cline, H.T.



Localization of GABA receptors in the basal ganglia.  


The majority of neurons in the basal ganglia utilize GABA as their principal neurotransmitter and, as a consequence, most basal ganglia neurons receive extensive GABAergic inputs derived from multiple sources. In order to understand the diverse roles of GABA in the basal ganglia it is necessary to define the precise localization of GABA receptors in relation to known neuron subtypes and known afferents. In this chapter, we summarize data on the ultrastructural localization of ionotropic GABA(A) receptors and metabotropic GABA(B) receptors in the basal ganglia. In each of the regions of the basal ganglia that have been studied, GABA(A) receptor subunits are located primarily at symmetrical synapses formed by GABAergic boutons, where they display a several-hundred-fold enrichment over extrasynaptic sites. In contrast, GABA(B) receptors are widely distributed at synaptic and extrasynaptic sites on both presynaptic and postsynaptic membranes. Presynaptic GABA(B) receptors are localized on striatopallidal, striatonigral and pallidonigral afferent terminals, as well as glutamatergic terminals derived from the cortex, thalamus and subthalamic nucleus. It is concluded that fast GABA transmission mediated by GABA(A) receptors in the basal ganglia occurs primarily at synapses whereas GABA transmission mediated by GABA(B) receptors is more complex, involving receptors located at presynaptic, postsynaptic and extrasynaptic sites. PMID:17499117

Boyes, Justin; Bolam, J Paul



Vibrational Spectra of ?-Aminobutyric Acid  

NASA Astrophysics Data System (ADS)

The NIR-FT Raman, FT-IR spectral analysis of ?-Aminobutyric acid (GABA) a simple amino acid is carried out by density functional computations. The vibrational spectra confirm the existence of NH3+ in GABA. Hydroxyl groups H-bonded to the different extents are analysed, supported by computed results.

Suresh, D. M.; Sajan, D.; Laladas, K. P.; Joe, I. Hubert; Jayakumar, V. S.



GABA uptake by rabbit restiform body homogenates.  


Restiform body (inferior cerebellar peduncle) preparations were obtained from rabbit brain stem slices and homogenized. When challenged with labelled GABA, these homogenates took it up briskly. We have characterized pharmacologically this uptake which resulted almost equally neuronal and glial. The neuronal component of the GABA uptake might be due to the adjacent cochlear nuclei coming along in the preparations, whereas the glial component probably belongs to the restiform body proper. Another possibility is that actually both components are due to the myelinated fibers and glia which make up the restiform body. PMID:11328685

Hydèn, H; Cupello, A; Rapallino, M V; Scarrone, S; Seitun, A



The Role of Gamma-Aminobutyric Acid in the Inhibitory Mechanism of Mammalian Central Nervous System.  

National Technical Information Service (NTIS)

Since nerve cells of large sizes were isolated from various nuclei of cat brain stem; for each isolated nerve cell, its gamma aminobutyric acid (GABA) content was measured and the GABA concentration calculated. In two cats, cerebellar vermis was removed, ...

M. Otsuka



Identification of the minimal promoter for specific expression of the GABA?1 receptor in retinal bipolar cells.  


?-aminobutyric acid (GABA)? receptors regulate rapid synaptic ion currents in the axon end of retinal ON bipolar neurons, acting as a point of control along the visual pathway. In the GABA?1 subunit knock out mouse, inhibition mediated by this receptor is totally eliminated, showing its role in neural transmission in retina. GABA?1 mRNA is expressed in mouse retina after post-natal day 7, but little is known about its transcriptional regulation. To identify the GABA?1 promoter, in silico analyses were performed and indicated that a 0.290-kb fragment, flanking the 5'-end of the GABA?1 gene, includes putative transcription factor-binding sites, two Inr elements, and lacks a TATA-box. A rapid amplification of cDNA ends (RACE) assay showed three transcription start sites (TSS) clustered in the first exon. Luciferase reporter assays indicated that a 0.232-kb fragment upstream from the ATG is the minimal promoter in transfected cell lines and in vitro electroporated retinae. The second Inr and AP1 site are important to activate transcription in secretin tumor cells (STC-1) and retina. Finally, the 0.232-kb fragment drives green fluorescent protein (GFP) expression to the inner nuclear layer, where bipolar cells are present. This first work paves the way for further studies of molecular elements that control GABA?1 transcription and regulate its expression during retinal development. PMID:23106649

Machuca-Parra, Arturo Israel; Miledi, Ricardo; Martínez-Torres, Ataúlfo



Enhancement of muscle contraction in the stomach of the crab Cancer borealis: a possible hormonal role for GABA.  


Gamma-aminobutyric acid (GABA) is best known as an inhibitory neurotransmitter in the mammalian central nervous system. Here we show, however, that GABA has an excitatory effect on nerve-evoked contractions and on excitatory junctional potentials (EJPs) of the gastric mill 4 (gm4) muscle from the stomach of the crab Cancer borealis. The threshold concentration for these effects was between 1 and 10 micromol l(-1). Using immunohistochemical techniques, we found that GABA is colocalized with the vesicle-associated protein synapsin in nearby nerves and hence is presumably released there. However, since these nerves do not innervate the muscle directly, we conclude that these release sites are not the likely source of the GABA responsible for muscle modulation. We also extracted hemolymph from the crab pericardial cavity, which contains the pericardial organs, a major neurosecretory structure. Through reversed-phase liquid chromatography-mass spectrometry analysis we determined the concentration of GABA in the hemolymph to be 3.3 +/- 0.7 micromol l(-1), high enough to modulate the muscle. These findings suggest that the gm4 muscle could be modulated by GABA produced by and released from a distant neurohemal organ. PMID:20570852

Suljak, Steven W; Rose, Christopher M; Sabatier, Christelle; Le, Thuc; Trieu, Quoc; Verley, Derek R; Lewis, Alexandra M; Birmingham, John T



Seizure suppression in kindling epilepsy by intracerebral implants of GABA- but not by noradrenaline-releasing polymer matrices.  


Gamma-aminobutyric acid (GABA)-releasing polymer matrices were implanted bilaterally, immediately dorsal to the substantia nigra, in rats previously kindled in the amygdala. Two days after implantation, rats with GABA-releasing matrices exhibited only focal limbic seizures in response to electrical stimulation, whereas animals with control matrices devoid of GABA had generalized convulsions. GABA release from the polymer matrices was high during the first days after implantation, as demonstrated both in vitro and, using microdialysis, in vivo. The anticonvulsant effect was no longer observed at 7 and 14 days at which time GABA release was found to be low. In a parallel experiment, polymer matrices containing noradrenaline (NA) were implanted bilaterally into the hippocampus of rats with extensive forebrain NA depletion induced by an intraventricular 6-hydroxydopamine injection. No effect on the development of hippocampal kindling was observed, despite extracellular NA levels exceeding those of rats with intrahippocampal locus coeruleus grafts that have previously been shown to retard kindling rate. The results indicate that GABA-releasing implants located in the substantia nigra region can suppress seizure generalization in epilepsy, even in the absence of synapse formation and integration with the host brain. In contrast, the failure of NA-releasing polymer matrices to retard the development of seizures in NA-depleted rats suggests that such an effect can only be exerted by grafts acting through a well-regulated, synaptic release of NA. PMID:7813677

Kokaia, M; Aebischer, P; Elmér, E; Bengzon, J; Kalén, P; Kokaia, Z; Lindvall, O



A detailed analysis of localized J-difference GABA editing: theoretical and experimental study at 4 T.  


The problem of low signal-to-noise ratio for gamma-aminobutyric acid (GABA) in vivo is exacerbated by inefficient detection schemes and non-optimal experimental parameters. To analyze the mechanisms for GABA signal loss of a MEGA-PRESS J-difference sequence at 4 T, numerical simulations were performed ranging from ideal to realistic experimental implementation, including volume selection and experimental radio frequency (RF) pulse shapes with a macromolecular minimization scheme. The simulations were found to be in good agreement with phantom and in vivo data from human brain. The overall GABA signal intensity for the simulations with realistic conditions for the MEGA-PRESS difference spectrum was calculated to be almost half of the signal simulated under ideal conditions (~43% signal loss). In contrast, creatine was reduced significantly less then GABA (~19% signal loss). The 'four-compartment' distribution due to J-coupling in the PRESS-based localization was one of the most significant sources of GABA signal loss, in addition to imperfect RF profiles for volume selection and editing. An alternative strategy that reduces signal loss due to the four-compartment distribution is suggested. In summary, a detailed analysis of J-difference editing is provided with estimates of the relative amounts of GABA signal losses due to various mechanisms. The numerical simulations presented in this study should facilitate both implementation of the more efficient acquisition and quantification process of J-coupled systems. PMID:17377933

Kaiser, L G; Young, K; Meyerhoff, D J; Mueller, S G; Matson, G B



Potentiation of GABA(A) receptor-mediated Cl-current by urotensin peptides in identified Aplysia neurons.  


Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the vertebrate and invertebrate central nervous systems, including those of molluscs. The effects of extracellularly applied urotensin peptides (urotensin I (UI) and urotensin II (UII)) on the GABA-induced Cl- current recorded from identified neurons (R9 and R12) of Aplysia kurodai were investigated using voltage-clamp and pressure ejection techniques. Focal application of 100 nM UI and UII potentiated the GABA-induced Cl- current without affecting the resting membrane conductance and holding current. The increase was completely reversible. The GABA-induced Cl- current also was potentiated by bath-applied UI and UII (5-10 nM). The potentiating effects of UI and UII on the GABA-induced Cl- current were concentration-dependent and completely reversible. These results suggest that neurotensin peptides may decrease neuronal excitability by potentiating the GABA(A) receptor-mediated Cl- current in the neurons of mammalian and invertebrate central nervous systems. PMID:10369221

Sawada, M; Ichinose, M



The role of GABA A receptors in the subsensitivity of Purkinje neurons to GABA in genetic epilepsy prone rats  

Microsoft Academic Search

The GABA receptor subtype mediating responses of cerebellar Purkinje neurons to the neurotransmitter was evaluated and compared in GEPR-9 vs. nonepileptic, genetic control GEPR-NE rats. Quantitative analysis of responses to microiontophoretically applied GABA, muscimol and baclofen indicated that the inhibitory action of GABA on cerebellar Purkinje neurons was mediated by GABAA receptors since muscimol produced responses similar to those of

Errol M. Gould; Karen A. Curto; Charles R. Craig; William W. Fleming; David A. Taylor



GABA(A) receptors in visual and auditory cortex and neural activity changes during basic visual stimulation.  


Recent imaging studies have demonstrated that levels of resting ?-aminobutyric acid (GABA) in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABA(A) receptors, in the changes in brain activity between the eyes closed (EC) and eyes open (EO) state in order to provide detail at the receptor level to complement previous studies of GABA concentrations. We conducted an fMRI study involving two different modes of the change from EC to EO: an EO and EC block design, allowing the modeling of the haemodynamic response, followed by longer periods of EC and EO to allow the measuring of functional connectivity. The same subjects also underwent [(18)F]Flumazenil PET to measure GABA(A) receptor binding potentials. It was demonstrated that the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex predicted the degree of changes in neural activity from EC to EO. This same relationship was also shown in the auditory cortex. Furthermore, the local-to-global ratio of GABA(A) receptor binding potential in the visual cortex also predicted the change in functional connectivity between the visual and auditory cortex from EC to EO. These findings contribute to our understanding of the role of GABA(A) receptors in stimulus-induced neural activity in local regions and in inter-regional functional connectivity. PMID:23293594

Qin, Pengmin; Duncan, Niall W; Wiebking, Christine; Gravel, Paul; Lyttelton, Oliver; Hayes, Dave J; Verhaeghe, Jeroen; Kostikov, Alexey; Schirrmacher, Ralf; Reader, Andrew J; Northoff, Georg



In Vivo Measurement of Brain GABA Concentrations by Magnetic Resonance Spectroscopy in Smelters Occupationally Exposed to Manganese  

PubMed Central

Background Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable. Objectives Our goal was to determine whether in vivo brain levels of ?-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure. Methods We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)]. Results Seven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = ?0.93; p < 0.001). Conclusions We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.

Dydak, Ulrike; Jiang, Yue-Ming; Long, Li-Ling; Zhu, He; Chen, Jian; Li, Wen-Mei; Edden, Richard A.E.; Hu, Shuguang; Fu, Xue; Long, Zaiyang; Mo, Xue-An; Meier, Dieter; Harezlak, Jaroslaw; Aschner, Michael; Murdoch, James B.; Zheng, Wei



GABA receptors in the dorsal motor nucleus of the vagus influence feline lower esophageal sphincter and gastric function  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA) antagonist (bicuculline methiodide, BIC; picrotoxin, PIC) or agonist (muscimol, MUS) microinjections were made into the dorsal motor nucleus of the vagus nerve (DMV), and effects on lower esophageal sphincter pressure (LESP), gastric motility, and gastric acid secretion were determined in chloralose-anesthetized cats. Right or left DMV sites were microinjected with BIC, PIC, MUS, or isotonic saline (140

Robert J. Washabau; Melinda Fudge; William J. Price; Frank C. Barone



Effect of Oxidative Stress on the Uptake of GABA and Glutamate in Synaptosomes Isolated from Diabetic Rat Brain  

Microsoft Academic Search

It has been suggested that increased oxidative stress might be involved in the pathophysiology of diabetic complications. In this study, we investigated the effect of diabetes on the susceptibility of synaptosomes to oxidative stress (induced by the oxidizing pair ascorbate\\/Fe2+) and on the uptake of the amino acid neurotransmitters ?-aminobutyric acid (GABA) and glutamate. We found a lower susceptibility of

Ana Duarte; Maria Santos; Raquel Seiça; Catarina Resende de Oliveira



Spinal cord GABA receptors modulate the exercise pressor reflex in decerebrate rats.  


Neurotransmitters and neuromodulators released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Whether ?-aminobutyric acid (GABA), a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of dorsal horn remains to be determined. We performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to investigate the effect of GABA receptor blockade on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots, passive stretch, or hindlimb arterial injection of capsaicin (0.1 ?g/0.2 ml) in decerebrate rats. Microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to all stimuli. Microinjection of either bicuculline or CGP 52432 into the L5 dorsal horn significantly increased the pressor and cardioaccelerator responses to direct microinjection of l-glutatmate (10 mM, 100 nl) into this spinal segment. The disinhibitory effect of both GABA receptor antagonists on the EPR was abolished by microinjection of the broad-spectrum glutamate receptor antagonist kynurenate (10 mM/100 nl). These data suggest that 1) GABA exerts a tonic inhibition of the EPR at the level of dorsal horn; and 2) that an interaction between glutamatergic and GABAergic inputs exist at the level of dorsal horn, contributing to spinal control of the EPR. PMID:23637133

Wang, Han-Jun; Wang, Wei; Patel, Kaushik P; Rozanski, George J; Zucker, Irving H



Ionotropic glutamate and GABA receptors in human epileptic neocortical tissue: quantitative in vitro receptor autoradiography  

Microsoft Academic Search

Since a disturbed balance between excitatory and inhibitory amino acid receptors is suggested to be an important condition for epileptogenic cortical activity, the present study has focused on the analysis of the densities of (±)-?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl-d-aspartate, kainate and GABA subtype A receptors in neocortical tissue surgically removed from patients with focal epilepsy. The mean densities (collapsed over cortical

K. Zilles; M. S. Qü; R. Köhling; E.-J. Speckmann



Detection of the inhibitory neurotransmitter GABA in macrophages by magnetic resonance spectroscopy  

Microsoft Academic Search

Macrophages are key components of the inflammatory response to tissue injury, but their activities can exacerbate neuropathology. High-resolution magnetic resonance spectroscopy was used to identify metabolite levels in perchloric acid extracts of cultured cells of the RAW 264.7 murine macrophage line under resting and lipo- polysaccharide-activated conditions. Over 25 me- tabolites were identified including -aminobutyric acid (GABA), an inhibitory neurotransmitter

D. J. Stuckey; D. C. Anthony; J. P. Lowe; J. Miller; W. M. Palm; V. H. Perry; A. M. Blamire; N. R. Sibson



The benzodiazepine site of the GABA A receptor: an old target with new potential?  

Microsoft Academic Search

The gamma-aminobutyric acid-A (GABAA) receptors is the target for the most widely prescribed sleep medicines. It is a ligand-gated ion channel, activated by the amino acid neurotransmitter GABA, which normally results in hyperpolarization of neurons leading to reduced action potential firing, and thereby a reduction in neuronal activity. It has a rich pharmacology with a number of separate modulator binding

Alan N Bateson



Demonstration of GABA-like immunoreactivity in myenteric plexus of frog stomach  

Microsoft Academic Search

The GABAergic innervation of the frog stomach was studied by means of an indirect immunohistochemical method. Whole mount preparations were obtained from frog stomachs after the animals had been perfused with a mixture of picric acid, glutaraldehyde and glacial acetic acid. Samples were incubated with an antiserum specific for GABA coupled to BSA with glutaraldehyde. Anti-rabbit IgG-HRP was processed by

R. Gfibriel; M. Eckert



Effects of Valeriana Officinalis Extracts on [ 3 H]Flunitrazepam Binding, Synaptosomal [ 3 H]GABA Uptake, and Hippocampal [ 3 H]GABA Release  

Microsoft Academic Search

Extracts of Valeriana officinalis have been used in folkloric medicine for its sedative, hypnotic, tranquilizer and anticonvulsant effects, and may interact with ?-aminobutyric acid (GABA) and\\/or benzodiazepine sites. At low concentrations, valerian extracts enhance [3H]flunitrazepam binding (EC50 4.13 × 10-10 mg\\/ml). However, this increased [3H]flunitrazepam binding is replaced by an inhibition at higher concentrations (IC50 of 4.82 × 10-1 mg\\/ml).

José G. Ortiz; Jennifer Nieves-Natal; Pedro Chavez



Generation of a 3D model for human GABA transporter hGAT-1 using molecular modeling and investigation of the binding of GABA  

Microsoft Academic Search

A three-dimensional model of the human Na+\\/Cl?-dependent ?-aminobutyric acid (GABA) transporter hGAT-1 was developed by homology modeling and refined by subsequent molecular\\u000a modeling using the crystal structure of a bacterial homologue leucine transporter from Aquifex aeolicus (LeuTAa) as the template. Protein structure quality checks show that the resulting structure is particularly suited for the analysis\\u000a of the substrate binding pocket

Thomas Wein; Klaus T. Wanner



Distribution and ultrastructure of neurons in opossum piriform cortex displaying immunoreactivity to GABA and GAD and high-affinity tritiated GABA uptake  

SciTech Connect

GABAergic neurons have been identified in the piriform cortex of the opossum at light and electron microscopic levels by immunocytochemical localization of GABA and the GABA-synthesizing enzyme glutamic acid decarboxylase and by autoradiographic visualization of high-affinity /sup 3/H-GABA uptake. Four major neuron populations have been distinguished on the basis of soma size, shape, and segregation at specific depths and locations: large horizontal cells in layer Ia of the anterior piriform cortex, small globular cells with thin dendrites concentrated in layers Ib and II of the posterior piriform cortex, and multipolar and fusiform cells concentrated in the deep part of layer III in anterior and posterior parts of the piriform cortex and the subjacent endopiriform nucleus. All four populations were well visualized with both antisera, but the large layer Ia horizontal cells displayed only very light /sup 3/H-GABA uptake, thus suggesting a lack of local axon collaterals or lack of high-affinity GABA uptake sites. The large, ultrastructurally distinctive somata of layer Ia horizontal cells receive a very small number of symmetrical synapses; the thin, axonlike dendrites of small globular cells are exclusively postsynaptic and receive large numbers of both symmetrical and asymmetrical synapses, in contrast to somata which receive a small number of both types; and the deep multipolar and fusiform cells receive a highly variable number of symmetrical and asymmetrical synapses on somata and proximal dendrites. Labeled puncta of axon terminal dimensions were found in large numbers in the neuropil surrounding pyramidal cell somata in layer II and in the endopiriform nucleus. Moderately large numbers of labeled puncta were found in layer I at the depth of pyramidal cell apical dendrites with greater numbers in layer Ia at the depth of distal apical segments than in layer Ib.

Haberly, L.B.; Hansen, D.J.; Feig, S.L.; Presto, S.



Frontal GABA levels change during working memory.  


Functional neuroimaging metrics are thought to reflect changes in neurotransmitter flux, but changes in neurotransmitter levels have not been demonstrated in humans during a cognitive task, and the relationship between neurotransmitter dynamics and hemodynamic activity during cognition has not yet been established. We evaluate the concentration of the major inhibitory (GABA) and excitatory (glutamate + glutamine: Glx) neurotransmitters and the cerebral perfusion at rest and during a prolonged delayed match-to-sample working memory task. Resting GABA levels in the dorsolateral prefrontal cortex correlated positively with the resting perfusion and inversely with the change in perfusion during the task. Further, only GABA increased significantly during the first working memory run and then decreased continuously across subsequent task runs. The decrease of GABA over time was paralleled by a trend towards decreased reaction times and higher task accuracy. These results demonstrate a link between neurotransmitter dynamics and hemodynamic activity during working memory, indicating that functional neuroimaging metrics depend on the balance of excitation and inhibition required for cognitive processing. PMID:22485128

Michels, Lars; Martin, Ernst; Klaver, Peter; Edden, Richard; Zelaya, Fernando; Lythgoe, David J; Lüchinger, Rafael; Brandeis, Daniel; O'Gorman, Ruth L



Acoustic Immunosensor for Detecting Neurotransmitter GABA.  

National Technical Information Service (NTIS)

Acoustic impedance immunosensors are disclosed that are capable of real-time measurement of GABA in a buffer solution. Several embodiments include a bio-specific recognition layer on a quartz crystal surface, where the bio-recognition layer is formed by m...

A. Zhou J. Muthuswamy



Activation of VTA GABA neurons disrupts reward consumption  

PubMed Central

The activity of Ventral Tegmental Area (VTA) dopamine (DA) neurons promotes behavioral responses to rewards and environmental stimuli that predict them. VTA GABA inputs synapse directly onto DA neurons and may regulate DA neuronal activity to alter reward-related behaviors, however, the functional consequences of selective activation of VTA GABA neurons remains unknown. Here, we show that in vivo optogenetic activation of VTA GABA neurons disrupts reward consummatory behavior, but not conditioned anticipatory behavior in response to reward-predictive cues. In addition, direct activation of VTA GABA projections to the nucleus accumbens (NAc) resulted in detectable GABA release, but did not alter reward consumption. Furthermore, optogenetic stimulation of VTA GABA neurons directly suppressed the activity and excitability of neighboring DA neurons, as well as the release of DA in the NAc, suggesting that the dynamic interplay between VTA DA and GABA neurons can control the initiation and termination of reward-related behaviors.

van Zessen, Ruud; Phillips, Jana L.; Budygin, Evgeny A.; Stuber, Garret D.



Immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 in the Meninges and the Choroid Plexus: Implications for Non-Neuronal Sources for GABA in the Developing Mouse Brain  

PubMed Central

Neural progenitors in the developing neocortex, neuroepithelial cells and radial glial cells, have a bipolar shape with a basal process contacting the basal membrane of the meninge and an apical plasma membrane facing the lateral ventricle, which the cerebrospinal fluid is filled with. Recent studies revealed that the meninges and the cerebrospinal fluid have certain roles to regulate brain development. ?-aminobutyric acid (GABA) is a neurotransmitter which appears first during development and works as a diffusible factor to regulate the properties of neural progenitors. In this study, we examined whether GABA can be released from the meninges and the choroid plexus in the developing mouse brain. Immunohistochemical analyses showed that glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67), both of which are GABA-synthesizing enzymes, are expressed in the meninges. The epithelial cells in the choroid plexus express GAD65. GABA immunoreactivity could be observed beneath the basal membrane of the meninge and in the epithelial cells of the choroid plexus. Expression analyses on Bestrophin-1, which is known as a GABA-permeable channel in differentiated glial cells, suggested that the cells in the meninges and the epithelial cells in the choroid plexus have the channels able to permeate non-synaptic GABA into the extracellular space. Further studies showed that GAD65/67-expressing meningeal cells appear in a manner with rostral to caudal and lateral to dorsal gradient to cover the entire neocortex by E14.5 during development, while the cells in the choroid plexus in the lateral ventricle start to express GAD65 on E11–E12, the time when the choroid plexus starts to develop in the developing brain. These results totally suggest that the meninges and the choroid plexus can work as non-neuronal sources for ambient GABA which can modulate the properties of neural progenitors during neocortical development.

Tochitani, Shiro; Kondo, Shigeaki



Immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 in the meninges and the choroid plexus: implications for non-neuronal sources for GABA in the developing mouse brain.  


Neural progenitors in the developing neocortex, neuroepithelial cells and radial glial cells, have a bipolar shape with a basal process contacting the basal membrane of the meninge and an apical plasma membrane facing the lateral ventricle, which the cerebrospinal fluid is filled with. Recent studies revealed that the meninges and the cerebrospinal fluid have certain roles to regulate brain development. ?-aminobutyric acid (GABA) is a neurotransmitter which appears first during development and works as a diffusible factor to regulate the properties of neural progenitors. In this study, we examined whether GABA can be released from the meninges and the choroid plexus in the developing mouse brain. Immunohistochemical analyses showed that glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67), both of which are GABA-synthesizing enzymes, are expressed in the meninges. The epithelial cells in the choroid plexus express GAD65. GABA immunoreactivity could be observed beneath the basal membrane of the meninge and in the epithelial cells of the choroid plexus. Expression analyses on Bestrophin-1, which is known as a GABA-permeable channel in differentiated glial cells, suggested that the cells in the meninges and the epithelial cells in the choroid plexus have the channels able to permeate non-synaptic GABA into the extracellular space. Further studies showed that GAD65/67-expressing meningeal cells appear in a manner with rostral to caudal and lateral to dorsal gradient to cover the entire neocortex by E14.5 during development, while the cells in the choroid plexus in the lateral ventricle start to express GAD65 on E11-E12, the time when the choroid plexus starts to develop in the developing brain. These results totally suggest that the meninges and the choroid plexus can work as non-neuronal sources for ambient GABA which can modulate the properties of neural progenitors during neocortical development. PMID:23437266

Tochitani, Shiro; Kondo, Shigeaki



GABA-agonists induce the formation of low-affinity GABA-receptors on cultured cerebellar granule cells via preexisting high affinity GABA receptors  

Microsoft Academic Search

The kinetics of specific GABA-binding to membranes isolated from cerebellar granule cells, cultured for 12 days from dissociated cerebella of 7-day-old rats was studied using [3H]GABA as the ligand. The granule cells were cultured in the presence of the specific GABA receptor agonist 4, 5, 6, 7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 150 µM) or THIP plus the antagonist bicuculline methobromide (150 µM of

Bo Belhage; Eddi Meier; Arne Schousboe



GABA{sub A} receptor open-state conformation determines non-competitive antagonist binding  

SciTech Connect

The {gamma}-aminobutyric acid (GABA) type A receptor (GABA{sub A}R) is one of the most important targets for insecticide action. The human recombinant {beta}3 homomer is the best available model for this binding site and 4-n-[{sup 3}H]propyl-4'-ethynylbicycloorthobenzoate ([{sup 3}H]EBOB) is the preferred non-competitive antagonist (NCA) radioligand. The uniquely high sensitivity of the {beta}3 homomer relative to the much-less-active but structurally very-similar {beta}1 homomer provides an ideal comparison to elucidate structural and functional features important for NCA binding. The {beta}1 and {beta}3 subunits were compared using chimeragenesis and mutagenesis and various combinations with the {alpha}1 subunit and modulators. Chimera {beta}3/{beta}1 with the {beta}3 subunit extracellular domain and the {beta}1 subunit transmembrane helices retained the high [{sup 3}H]EBOB binding level of the {beta}3 homomer while chimera {beta}1/{beta}3 with the {beta}1 subunit extracellular domain and the {beta}3 subunit transmembrane helices had low binding activity similar to the {beta}1 homomer. GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold by increasing the open probability of the channel. Addition of the {alpha}1 subunit rescued the inactive {beta}1/{beta}3 chimera close to wildtype {alpha}1{beta}1 activity. EBOB binding was significantly altered by mutations {beta}1S15'N and {beta}3N15'S compared with wildtype {beta}1 and {beta}3, respectively. However, the binding activity of {alpha}1{beta}1S15'N was insensitive to GABA and {alpha}1{beta}3N15'S was stimulated much less than wildtype {alpha}1{beta}3 by GABA. The inhibitory effect of etomidate on NCA binding was reduced more than 5-fold by the mutation {beta}3N15'S. Therefore, the NCA binding site is tightly regulated by the open-state conformation that largely determines GABA{sub A} receptor sensitivity. - Graphical Abstract: Display Omitted Research Highlights: > The {beta}1 and {beta}3 subunits were compared by chimeragenesis, mutagenesis and modulators. > Low {beta}1 NCA binding was rescued by replacing its transmembrane helices with those of {beta}3. > GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold. > Mutation at 15' position in TM2 reduced GABA stimulation of NCA binding. > The open-state conformation largely determines GABAA receptor sensitivity to NCAs.

Chen Ligong [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States); Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Xue Ling [Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 (United States); Giacomini, Kathleen M. [Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Casida, John E., E-mail: [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States)



Taurine-like GABA aminotransferase inhibitors prevent rabbit brain slices against oxygen-glucose deprivation-induced damage.  


The activation of the GABAergic system has been shown to protect brain tissues against the damage that occurs after cerebral ischaemia. On the other hand, the taurine analogues (±)Piperidine-3-sulphonic- (PSA), 2-aminoethane phosphonic- (AEP), 2-(N-acetylamino) cyclohexane sulfonic-acids (ATAHS) and 2-aminobenzene sulfonate-acids (ANSA) have been reported to block GABA metabolism by inhibiting rabbit brain GABA aminotransferase and to increase GABA content in rabbit brain slices. The present investigation explored the neuroprotection provided by GABA, Vigabatrin (VIGA) and taurine analogues in the course of oxygen-glucose deprivation and reperfusion induced damage of rabbit brain slices. Tissue damage was assessed by measuring the release of glutamate and lactate dehydrogenase (LDH) during reperfusion and by determining final tissue water gain, measured as the index of cell swelling. GABA (30-300 ?M) and VIGA (30-300 ?M) significantly antagonised LDH and glutamate release, as well as tissue water gain caused by oxygen-glucose deprivation and reperfusion. Lower (1-10 ?M) or higher concentrations (up to 3,000 ?M) were ineffective. ANSA, PSA and ATAHS significantly reduced glutamate and LDH release and tissue water gain in a range of concentrations between 30 and 300 ?M. Lower (0-10 ?M) or higher (up to 3,000 ?M) concentrations were ineffective. Both mechanisms suggest hormetic ("U-shaped") effects. These results indicate that the GABAergic system activation performed directly by GABA or indirectly through GABA aminotransferase inhibition is a promising approach for protecting the brain against ischemia and reperfusion-induced damage. PMID:21667265

Ricci, Lorenzo; Valoti, Massimo; Sgaragli, Giampietro; Frosini, Maria



Dynamic regulation of glycine-GABA co-transmission at spinal inhibitory synapses by neuronal glutamate transporter.  


Fast inhibitory neurotransmission in the central nervous system is mediated by ?-aminobutyric acid (GABA) and glycine, which are accumulated into synaptic vesicles by a common vesicular inhibitory amino acid transporter (VIAAT) and are then co-released. However, the mechanisms that control the packaging of GABA + glycine into synaptic vesicles are not fully understood. In this study, we demonstrate the dynamic control of the GABA-glycine co-transmission by the neuronal glutamate transporter, using paired whole-cell patch recording from monosynaptically coupled cultured spinal cord neurons derived from VIAAT-Venus transgenic rats. Short step depolarization of presynaptic neurons evoked unitary (cell-to-cell) inhibitory postsynaptic currents (IPSCs). Under normal conditions, the fractional contribution of postsynaptic GABA or glycine receptors to the unitary IPSCs did not change during a 1 h recording. Intracellular loading of GABA or glycine via a patch pipette enhanced the respective components of inhibitory transmission, indicating the importance of the cytoplasmic concentration of inhibitory transmitters. Raised extracellular glutamate levels increased the amplitude of GABAergic IPSCs but reduced glycine release by enhancing glutamate uptake. Similar effects were observed when presynaptic neurons were intracellularly perfused with glutamate. Interestingly, high-frequency trains of stimulation decreased glycinergic IPSCs more than GABAergic IPSCs, and repetitive stimulation occasionally failed to evoke glycinergic but not GABAergic IPSCs. The present results suggest that the enhancement of GABA release by glutamate uptake may be advantageous for rapid vesicular refilling of the inhibitory transmitter at mixed GABA/glycinergic synapses and thus may help prevent hyperexcitability. PMID:23690564

Ishibashi, Hitoshi; Yamaguchi, Junya; Nakahata, Yoshihisa; Nabekura, Junichi



Proton modulation of recombinant GABAA receptors: influence of GABA concentration and the ? subunit TM2-TM3 domain  

PubMed Central

Regulation of GABAA receptors by extracellular pH exhibits a dependence on the receptor subunit composition. To date, the molecular mechanism responsible for the modulation of GABAA receptors at alkaline pH has remained elusive. We report here that the GABA-activated current can be potentiated at pH 8.4 for both ?? and ??? subunit-containing receptors, but only at GABA concentrations below the EC40. Site-specific mutagenesis revealed that a single lysine residue, K279 in the ? subunit TM2–TM3 linker, was critically important for alkaline pH to modulate the function of both ?1?2 and ?1?2?2 receptors. The ability of low concentrations of GABA to reveal different pH titration profiles for GABAA receptors was also examined at acidic pH. At pH 6.4, GABA activation of ??? receptors was enhanced at low GABA concentrations. This effect was ablated by the mutation H267A in the ? subunit. Decreasing the pH further to 5.4 inhibited GABA responses via ??? receptors, whereas those responses recorded from ?? receptors were potentiated. Inserting homologous ? subunit residues into the ?2 subunit to recreate, in ??? receptors, the proton modulatory profile of ?? receptors, established that in the presence of ?2H267, the mutation ?2T294K was necessary to potentiate the GABA response at pH 5.4. This residue, T294, is homologous to K279 in the ? subunit and suggests that a lysine at this position is an important residue for mediating the allosteric effects of both acidic and alkaline pH changes, rather than forming a direct site for protonation within the GABAA receptor.

Wilkins, Megan E; Hosie, Alastair M; Smart, Trevor G



Agonist- and antagonist-induced conformational changes of loop F and their contributions to the ?1 GABA receptor function  

PubMed Central

Binding of ?-aminobutyric acid (GABA) to its receptor initiates a conformational change to open the channel, but the mechanism of the channel activation is not well understood. To this end, we scanned loop F (K210–F227) in the N-terminal domain of the ?1 GABA receptor expressed in Xenopus oocytes using a site-specific fluorescence technique. We detected GABA-induced fluorescence changes at six positions (K210, K211, L216, K217, T218 and I222). At these positions the fluorescence changes were dose dependent and highly correlated to the current dose–response, but with lower Hill coefficients. The competitive antagonist 3-aminopropyl(methyl)phosphinic acid (3-APMPA) induced fluorescence changes in the same direction at the four middle or lower positions. The non-competitive antagonist picrotoxin blocked nearly 50% of GABA-induced fluorescence changes at T218 and I222, but only <20% at K210 and K217 and 0% at K211 and L216 positions. Interestingly, the picrotoxin-blocked fraction of the GABA-induced fluorescence changes was highly correlated to the Hill coefficient of the GABA-induced dose-dependent fluorescence change. The PTX-insensitive mutant L216C exhibited the lowest Hill coefficient, similar to that in binding. Thus, the PTX-sensitive fraction reflects the conformational change related to channel gating, whereas the PTX-insensitive fraction represents a binding effect. The binding effect is further supported by the picrotoxin resistance of a competitive antagonist-induced fluorescence change. A cysteine accessibility test further confirmed that L216C and K217C partially line the binding pocket, and I222C became more exposed by GABA. Our results are consistent with a mechanism that an outward movement of the lower part of loop F is coupled to the channel activation.

Zhang, Jianliang; Xue, Fenqin; Chang, Yongchang



Regulation of GABA and Glutamate Release from Proopiomelanocortin Neuron Terminals in Intact Hypothalamic Networks  

PubMed Central

Hypothalamic proopiomelanocortin (POMC) neurons and their peptide products mediate important aspects of energy balance, analgesia, and reward. In addition to peptide products, there is evidence that POMC neurons can also express the amino acid transmitters GABA and glutamate, suggesting these neurons may acutely inhibit or activate downstream neurons. However, the release of amino acid transmitters from POMC neurons has not been thoroughly investigated in an intact system. In the present study, the light-activated cation channel channelrhodopsin-2 (ChR2) was used to selectively evoke transmitter release from POMC neurons. Whole-cell electrophysiologic recordings were made in brain slices taken from POMC-Cre transgenic mice that had been injected with a viral vector containing a floxed ChR2 sequence. Brief pulses of blue light depolarized POMC-ChR2 neurons and induced the release of GABA and glutamate onto unidentified neurons within the arcuate nucleus, as well as onto other POMC neurons. To determine if the release of GABA and glutamate from POMC terminals can be readily modulated, opioid and GABAB receptor agonists were applied. Agonists for mu and kappa, but not delta, opioid receptors inhibited transmitter release from POMC neurons, as did the GABAB receptor agonist baclofen. This regulation indicates that opioids and GABA released from POMC neurons may act at presynaptic receptors on POMC terminals in an autoregulatory manner to limit continued transmission. The results show that in addition to the relatively slow and long-lasting actions of peptides, POMC neurons can rapidly affect the activity of downstream neurons via GABA and glutamate release.

Dicken, Matthew S.; Tooker, Ryan E.; Hentges, Shane T.



In vivo detection of GABA in human brain using a localized double-quantum filter technique.  


A proton MR spectral editing technique employing a spatially localized, double-quantum filter (DQF) was used to measure gamma-aminobutyric acid (GABA) in the human brain at 1.5 T. The double-quantum method provided robust, single-shot suppression of uncoupled resonances from choline, creatine, and NAA and allowed detection of the gamma CH2 GABA (3.0 ppm) resonance with 30% efficiency. Spatial localization of the GABA measurement was achieved by incorporating PRESS localization within the double-quantum excitation and detection sequence. A calibration technique was developed to adjust the relative phases of the RF pulses to maximize the in vivo double-quantum detection efficiency for an arbitrary voxel location. The sequence efficiency, degree of suppression of uncoupled reasonances, and characterization of the in vivo DQF technique was examined in phantom experiments and in a study of the occipital lobe of 10 normal subjects. The ratio of the 3.0-ppm GABA resonance to the 3.0-ppm creatine resonance was found to be 0.20 +/- 0.05 (SD). PMID:9055226

Keltner, J R; Wald, L L; Frederick, B D; Renshaw, P F



GABA and Glutamate are not colocalized in mossy fiber terminals of developing rodent hippocampus  

PubMed Central

It has been hypothesized that, in the developing rodent hippocampus, mossy fiber terminals release GABA together with glutamate. Here, we used transgenic glutamic acid decarboxylase-67 (GAD67)-GFP expressing mice and multi-label immunohistochemistry to address whether glutamatergic and GABAergic markers are colocalized. We demonstrate that in the dentate gyrus, interneurons positive for GABA/GAD are sparsely distributed along the edge of the hilus, in a different pattern than the densely packed granule cells. Co-staining for synaptophysin and vesicular glutamate transporter1 (VGLUT1) in postnatal day 14 brain sections from both mice and rats identified mossy fiber terminals as a group of large (2 – 5?m in diameter) VGLUT1-positive excitatory presynaptic terminals in the stratum lucidum of area CA3a/b. Furthermore, co-staining for synaptophysin and vesicular GABA transporter (VGAT) revealed a group of small-sized (~0.5?m in diameter) inhibitory presynaptic terminals in the same area where identified mossy fiber terminals were present. The two types of terminals appeared to be mutually exclusive, and showed no colocalization. Thus, our results do not support the hypothesis that GABA is released as a neurotransmitter from mossy fiber terminals during development.

Xiong, Guoxiang; Zhang, Lei; Mojsilovic-Petrovic, Jelena; Arroyo, Edguardo; Elkind, Jaclynn; Kundu, Suhali; Johnson, Brian; Smith, Colin J.; Cohen, Noam A.; Grady, Sean M.; Cohen, Akiva S.



GABA and glutamate specifically induce contractions in the sponge Tethya wilhelma.  


Sponges (Porifera) are nerve- and muscleless. Nevertheless, they react to external stimuli in a coordinated way, by body contraction, oscule closure or stopping pumping activity. The underlying mechanisms are still unknown, but evidence has been found for chemical messenger-based systems. We used the sponge Tethya wilhelma to test the effect of gamma-aminobutyric acid (GABA) and glutamate (L: -Glu) on its contraction behaviour. Minimal activating concentrations were found to be 0.5 microM (GABA) and 50 microM (L: -Glu), respectively. Taking maximum relative contraction speed and minimal relative projected body area as a measure of the sponge's response, a comparison of the dose-response curves indicated a higher sensitivity of the contractile tissue for GABA than for L: -Glu. The concentrations eliciting the same contractile response differ by about 100-fold more than the entire concentration range tested. In addition, desensitising effects and spasm-like reactions were observed. Presumably, a GABA/L: -Glu metabotropic receptor-based system is involved in the regulation of contraction in T. wilhelma. We discuss a coordination system for sponges based on hypothetical chemical messenger pathways. PMID:17021832

Ellwanger, Kornelia; Eich, Andre; Nickel, Michael



The effect of phencyclidine on the basal and high potassium evoked extracellular GABA levels in the striatum of freely-moving rats: an in vivo microdialysis study  

Microsoft Academic Search

The effect of phencyclidine (PCP) on the ?-aminobutyric acid-ergic (GABAergic) transmission in the striatum of freely-moving rats was investigated using an in vivo microdialysis. The high potassium (100 mM) increased the extracellular GABA level to 4000% of the basal level. Although the basal GABA level in the striatal dialysate did not show either calcium dependency or tetrodotoxin (TTX) sensitivity, the

Hisao Hondo; Tatsuo Nakahara; Kaoru Nakamura; Makoto Hirano; Hideyuki Uchimura; Nobutada Tashiro



GABA B receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL\\/6J mice  

Microsoft Academic Search

Rationale A growing number of studies suggest that ?-aminobutyric acid type-B (GABA B) receptor agonists reduce alcohol use and craving. Objectives This study was designed to further clarify behavioral mechanism(s) by which GABA B agonists may decrease alcohol reinforcement. Methods Male C57BL\\/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v\\/v) and water reinforcement during

Joyce Besheer; Veronique Lepoutre; Clyde W. Hodge



GABA Inhibition of Cyclic AMP Production in Immortalized GnRH Neurons Is Mediated by Calcineurin-Dependent Dephosphorylation of Adenylyl Cyclase 9  

Microsoft Academic Search

The neurotransmitter ?-aminobutyric acid (GABA) is an important modulator of gonadotropin-releasing hormone (GnRH), and consequently of reproduction. GABA, acting via ionotropic GABAA receptors, exerts a biphasic effect on GnRH secretion in immortalized GnRH cells. The initial increase in GnRH secretion is triggered by a sharp rise in [Ca2+]i, while the progressive decline of GnRH levels that follows is paralleled by

Cecilia Martin; Jessica S. Jacobi; Gabriel Nava; Michael C. Jeziorski; Carmen Clapp; Gonzalo Martínez de la Escalera



Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus  

Microsoft Academic Search

BACKGROUND: Excitatory amino acid release and subsequent biochemical cascades following traumatic brain injury (TBI) have been well documented, especially glutamate-related excitotoxicity. The effects of TBI on the essential functions of inhibitory GABA-A receptors, however, are poorly understood. METHODS: We used Western blot procedures to test whether in vivo TBI in rat altered the protein expression of hippocampal GABA-A receptor subunits

Cynthia J Gibson; Rebecca C Meyer; Robert J Hamm



Regulation of tonic GABA inhibitory function, presympathetic neuronal activity and sympathetic outflow from the paraventricular nucleus by astroglial GABA transporters  

PubMed Central

Neuronal activity in the hypothalamic paraventricular nucleus (PVN), as well as sympathetic outflow from the PVN, is basally restrained by a GABAergic inhibitory tone. We recently showed that two complementary GABAA receptor-mediated modalities underlie inhibition of PVN neuronal activity: a synaptic, quantal inhibitory modality (IPSCs, Iphasic) and a sustained, non-inactivating modality (Itonic). Here, we investigated the role of neuronal and/or glial GABA transporters (GATs) in modulating these inhibitory modalities, and assessed their impact on the activity of RVLM-projecting PVN neurons (PVN-RVLM neurons), and on PVN influence of renal sympathetic nerve activity (RSNA). Patch-clamp recordings were obtained from retrogradely labelled PVN-RVLM neurons in a slice preparation. The non-selective GAT blocker nipecotic acid (100–300 ?m) caused a large increase in GABAAItonic, and reduced IPSC frequency. These effects were replicated by ?-alanine (100 ?m), but not by SKF 89976A (30 ?m), relatively selective blockers of GAT3 and GAT1 isoforms, respectively. Similar effects were evoked by the gliotoxin l-?-aminodipic acid (2 mm). GAT blockade attenuated the firing activity of PVN-RVLM neurons. Moreover, PVN microinjections of nipecotic acid in the whole animal diminished ongoing RSNA. A robust GAT3 immunoreactivity was observed in the PVN, which partially colocalized with the glial marker GFAP. Altogether, our results indicate that by modulating ambient GABA levels and the efficacy of GABAAItonic, PVN GATs, of a likely glial location, contribute to setting a basal tone of PVN-RVLM firing activity, and PVN-driven RSNA.

Park, Jin Bong; Jo, Ji Yoon; Zheng, Hong; Patel, Kaushik P; Stern, Javier E



Dephosphorylation of endogenous GABA(B) receptor R2 subunit and AMPK ? subunits which were measured by in vitro method using transfer membrane.  


Protein phosphorylation can be regulated by changes in kinase activity, phosphatase activity, or both. GABA(B) receptor R2 subunit (GABA(B)R2) is phosphorylated at S783 by 5'-AMP-activated-protein kinase (AMPK), and this phosphorylation modulates GABA(B) receptor desensitization. Since the GABA(B) receptor is an integral membrane protein, solubilizing GABA(B)R2 is difficult. To circumvent this problem and to identify specific phosphatases that dephosphorylate S783, we employed an in vitro assay based on dephosphorylation of proteins on PVDF membranes by purified phosphatases. Our method allowed us to demonstrate that S783 in GABA(B)R2 is directly dephosphorylated by PP2A (but not by PP1, PP2B nor PP2C) in a dose-dependent and okadaic acid-sensitive manner. We also show that the level of phosphorylation of the catalytic subunit of AMPK at T172 is reduced by PP1, PP2A and PP2C. Our data indicate that PP2A dephosphorylates GABA(B)R2(S783) less efficiently than AMPK(T172), and that additional phosphatases might be involved in S783 dephosphorylation. PMID:23238131

Kuramoto, Nobuyuki; Ito, Machiko; Saito, Yukari; Niihara, Hiroki; Tanaka, Natsuki; Yamada, Ken-Ichi; Yamamura, Yusuke; Iwasaki, Kaname; Onishi, Yuki; Ogita, Kiyokazu



Specific targeting of the GABA-A receptor ?5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice  

PubMed Central

An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the ?5-subtype (?5IA). We demonstrate that ?5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, ?5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with ?5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with ?5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant ?5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals.

Braudeau, J; Delatour, B; Duchon, A; Pereira, P Lopes; Dauphinot, L; de Chaumont, F; Olivo-Marin, J-C; Dodd, RH; Herault, Y; Potier, M-C



Specific targeting of the GABA-A receptor ?5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice.  


An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the ?5-subtype (?5IA). We demonstrate that ?5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, ?5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with ?5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with ?5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant ?5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals. PMID:21693554

Braudeau, J; Delatour, B; Duchon, A; Pereira, P Lopes; Dauphinot, L; de Chaumont, F; Olivo-Marin, J-C; Dodd, R H; Hérault, Y; Potier, M-C



GABA, glycine, aspartate, glutamate and taurine in the vestibular nuclei: an immunocytochemical investigation in the cat.  


The distributions of five amino acids with well-established neuroexcitatory or neuroinhibitory properties were investigated in the feline vestibular complex. Consecutive semithin sections of plastic-embedded tissue were incubated with antisera raised against protein-glutaraldehyde conjugates of GABA, glycine, aspartate, glutamate and taurine. This approach allowed us to study the relative densities of the different immunoreactivities at the level of individual cell profiles. The results indicate that in the vestibular nuclei, neuronal colocalization of two or more neuroactive amino acids is the rule rather than an exception. Colocalization was found of immunoreactivities for GABA and glycine; glycine, aspartate and glutamate; glycine and aspartate, and glutamate and aspartate. GABA immunoreactive neurons were generally small and were found scattered throughout the vestibular complex. Glycine immunoreactive neurons were similarly distributed, except in the superior nucleus where the latter type of neuron could not be detected. Neuronal profiles colocalizing immunoreactivities for GABA and glycine occurred in all nuclei, but were most numerous in the lateral nucleus. The vast majority of the neurons showed noteworthy staining for glutamate and aspartate, although the level of immunoreactivities varied (e.g., the large neurons in the lateral and descending nuclei were more intensely aspartate immunoreactive than the smaller ones). Taurine-like immunoreactivity did not occur in neuronal cell bodies but appeared in Purkinje cell axons and in glial cell profiles. The functional significance of the complex pattern of amino acid colocalization remains to be clarified. In particular it needs to be distinguished between metabolic and transmitter pools of the different amino acids. The present results call for caution when attempts are made to conclude about transmitter identity on the basis of amino acid contents alone. PMID:1971225

Walberg, F; Ottersen, O P; Rinvik, E



Metabolism and functions of gamma-aminobutyric acid  

Microsoft Academic Search

Gamma-aminobutyric acid (GABA), a four-carbon non-protein amino acid, is a significant component of the free amino acid pool in most prokaryotic and eukaryotic organisms. In plants, stress initiates a signal-transduction pathway, in which increased cytosolic Ca2+ activates Ca2+\\/calmodulin-dependent glutamate decarboxylase activity and GABA synthesis. Elevated H+ and substrate levels can also stimulate glutamate decarboxylase activity. GABA accumulation probably is mediated

Barry J Shelp; Alan W Bown; Michael D McLean



Identification of gamma-aminobutyric acid and its binding sites in Caenorhabditis elegans  

SciTech Connect

Gamma-aminobutyric acid (GABA), glutamate decarboxylase and GABA-transaminase were identified in the nematode Caenorhabditis elegans. The concentration of GABA in C. elegans is approximately 10-fold lower than the concentration of GABA in rat brain. Glutamate decarboxylase and GABA-transaminase, the GABA anabolic and catabolic enzymes, are also present in C. elegans. Crude membrane fractions were prepared from C. elegans and used to study specific (/sup 3/H) GABA binding sites. GABA binds to C. elegans membranes with high affinity and low capacity. Muscimol is a competitive inhibitor of specific GABA binding with a K/sub I/ value of 120 nM. None of the other GABA agonists or antagonists inhibited greater than 40% of the specific GABA binding at concentrations up to 10/sup -4/M. Thirteen spider venoms were examined as possible GABA agonists or antagonists, the venom from Calilena agelenidae inhibits specific GABA binding with a K/sub I/ value of 6 nl/ml. These results suggest that GABA has a physiological role as a neurotransmitter in C. elegans.

Schaeffer, J.M.; Bergstrom, A.R.



GABA? expression in the medial nucleus of the trapezoid body.  


The Calyx of Held (CoH) synapse is the largest synapse in mammals. It is located in the medial nucleus of the trapezoid body (MNTB) and forms part of the auditory pathway. Modest GABAergic signaling is present in the CoH before hearing onset, when glutamatergic transmission predominates. In mice, after postnatal day 12, the absolute strength of glycinergic transmission increases markedly, while GABAergic signaling remains constant. The persistent GABAergic transmission in the MNTB is mediated by a slowly desensitizing component. In this study we recorded GABA-mediated responses from postsynaptic principal neurons (PPNs) of the MNTB and found that they are sensitive to TPMPA, suggesting the involvement of GABA? subunits. RT-PCR and immunohistofluorescence in the MNTB confirmed GABA? expression in PPNs. Interestingly, GABA?3 was present only before hearing onset, and there was a switch to GABA?1 and GABA?2 expression in adult animals. PMID:23123780

Reyes-Haro, Daniel; Rosas-Arellano, Abraham; González-González, María Alejandra; Mora-Loyola, Ernesto; Miledi, Ricardo; Martínez-Torres, Ataúlfo



Taurine, glutamate and GABA modulate the outgrowth from goldfish retinal explants and its concentrations are affected by the crush of the optic nerve  

Microsoft Academic Search

Summary The amino acid taurine plays an important trophic role during development and regeneration of the central nervous system. Other amino acid systems, such as those for glutamate and gamma-aminobutyric acid (GABA), are modified during the same physiological and pathological processes. After crushing the optic nerve, goldfish retinal explants were plated in the absence and in the presence of different

Lucimey Lima; F. Obregón; P. Matus



Stimulation of prolactin release in rats by GABA.  


Infusion of GABA into the lateral ventricle of intact female rats on the morning of proestrus and in ovariectomized rats significantly stimulated PRL release. This response apparently is not mediated through a direct action on the pituitary since injection of GABA into hypophysectomized rats with a pituitary transplant under the kindney capsule did not alter serum prolactin levels. These observations suggest that GABA may have a role in regulating prolactin secretion. PMID:1250855

Mioduszewski, R; Grandison, L; Meites, J



Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels  

PubMed Central

The aim of this study was to evaluate the effects of cocaine on ?-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25–0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0–2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25–2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25–2 mg/kg (IC50 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 ?m) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 ?m), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement.

Steffensen, Scott C.; Taylor, Seth R.; Horton, Malia L.; Barber, Elise N.; Lyle, Laura T.; Stobbs, Sarah H.; Allison, David W.



Differences between GABA levels in Alzheimer's disease and Down syndrome with Alzheimer-like neuropathology  

Microsoft Academic Search

Down syndrome (DS) is a genetic disease with developmental brain abnormalities resulting in early mental retardation and precocious, age-dependent Alzheimer-type neurodegeneration. Furthermore, non-cognitive symptoms may be a cardinal feature of functional decline in adults with DS. A number of amino acids [glutamate, aspartate, %-aminobutyrate (GABA), glycine, taurine, glutamine, serine, arginine] were investigated in post-mortem tissue samples from temporal, occipital cortex,

Rainer Seidl; Nigel Cairns; Nicolas Singewald; Stefan T. Kaehler; Gert Lubec



Two-color, two-photon uncaging of glutamate and GABA.  


We developed a caged GABA (gamma-aminobutyric acid), which, when combined with an appropriate caged glutamate, allows bimodal control of neuronal membrane potential with subcellular resolution using optically independent two-photon uncaging of each neurotransmitter. We used two-color, two-photon uncaging to fire and block action potentials from rat hippocampal CA1 neurons in brain slices with 720-nm and 830-nm light, respectively. Our method should be generalizable to other chemical messenger pairs. PMID:20037590

Kantevari, Srinivas; Matsuzaki, Masanori; Kanemoto, Yuya; Kasai, Haruo; Ellis-Davies, Graham C R



Columnar Architecture Sculpted by GABA Circuits in Developing Cat Visual Cortex  

PubMed Central

The mammalian visual cortex is organized into columns. Here, we examine cortical influences upon developing visual afferents in the cat by altering intrinsic ?-aminobutyric acid (GABA)–mediated inhibition with benzodiazepines. Local enhancement by agonist (diazepam) infusion did not perturb visual responsiveness, but did widen column spacing. An inverse agonist (DMCM) produced the opposite effect. Thus, intracortical inhibitory circuits shape the geometry of incoming thalamic arbors, suggesting that cortical columnar architecture depends on neuronal activity.

Hensch, Takao K.; Stryker, Michael P.



Characterization of the interaction between fenamates and hippocampal neuron GABA A receptors  

Microsoft Academic Search

Fenamate NSAIDs have several central effects, including anti-epileptic and neuroprotective actions. The underlying mechanism(s) of these actions are not presently understood. In this study, the effects of five members of the fenamate NSAID group were investigated on native ligand-gated ion channels expressed in cultured rat hippocampal neurons. All fenamates tested (1–100?M) dose-dependently potentiated GABA-evoked currents; mefenamic acid (MFA) was the

Leanne Coyne; Jiping Su; Debra Patten; Robert F. Halliwell



Steroid modulation of the GABA\\/benzodiazepine receptor-linked chloride lonophore  

Microsoft Academic Search

Recent findings suggest that steroids with sedative-hypnotic properties interact specifically with the ?-aminobutyric acidA\\/benzodiazepine receptor-chloride ionophore complex (GBRC). The