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At least 19 recordsLinked to original sources
PubMed1992

gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid rho 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes.

Xenopus oocyte expression of the recently cloned gamma-aminobutyric acid (GABA) rho 1 receptor subunit cDNA yields a pharmacologic profile characteristic of the GABAc responses described by Johnston [Benzodiazepine/GABA Receptors and Chloride Channels. Receptor Biochemistry and Methodology (R. W. Olsen and J. C. Venter, eds), Vol. 5. Alan R. Liss, New York, 57-71 (1986)] and the responses to retinal mRNA recently reported in the Xenopus expression system [Proc. Natl. Acad. Sci. USA 88:4318-4322 (1991)]. A rationale for defining GABA rho 1 as forming a GABAc receptor is discussed.

Animals↗
PubMed1993

Characterization of bicuculline/baclofen-insensitive (rho-like) gamma-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of gamma-aminobutyric acidA and gamma-aminobutyric acidB receptor agonists and antagonists.

Poly(A)+ RNA from mammalian retina expresses bicuculline/baclofen-insensitive gamma-aminobutyric acid (GABA) receptors in Xenopus oocytes with properties similar to those of homooligomeric GABA rho 1 receptors. The pharmacological profile of these rho-like receptors was extended by measuring sensitivities to various GABAA and GABAB receptor ligands. For direct comparison the same compounds were also assayed with GABAA receptors expressed by rat brain RNA. The potency sequence for heterocyclic GABA analogues at the GABA rho-like receptors was GABA (1.3) > muscimol (2.3) > isoguvacine (100) (approximate EC50 in parentheses; all EC50 and Kb values given in microM). Both muscimol and isoguvacine were partial agonists at the rho-like receptors. 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol (Kb congruent to 32), piperidine-4-sulfonic acid (Kb congruent to 85), and isonipecotic acid (Kb congruent to 1000) acted primarily as competitive antagonists, showing little or no activity as agonists. The sulfonic acid GABA analogue 3-aminopropanesulfonic acid was also a competitive antagonist (Kb congruent to 20). Conformationally restricted GABA analogues trans- and cis-4-aminocrotonic acid (TACA and CACA) were agonists at the rho-like receptors. TACA (EC50 congruent to 0.6) had twice the potency of GABA and was 125 times more potent than CACA (EC50 congruent to 75). Z-3-(Amidinothio)propenoic acid, an isothiouronium analogue of GABA, had little activity as an agonist but instead acted as a competitive antagonist (Kb congruent to 20). At concentrations of > 100 microM, bicuculline did have some weak competitive inhibitory effects on the GABA rho-like receptors (Kb congruent to 6000), but it was at least 5000 times more potent at GABAA receptors. Strychnine (Kb congruent to 70) and SR-95531 (Kb congruent to 35) also were competitive inhibitors of the rho-like receptors but were, respectively, 20 and 240 times more potent at GABAA receptors. The GABAB receptor ligands baclofen, phaclofen, and saclofen (1-100 microM) had no appreciable effects on the rho-like receptors. In contrast, 3-aminopropylphosphonic acid, the phosphonic acid analogue of GABA, acted as a competitive antagonist (Kb congruent to 10), and 3-aminopropylphosphinic acid and 3-aminopropyl(methyl)-phosphinic acid were moderately potent antagonists (Kb congruent to 1.7 and 0.8, respectively). delta-Aminovaleric acid was also an antagonist (Kb congruent to 20), whereas 4-aminobutylphosphonic acid, the phosphonic acid analogue of delta-aminovaleric acid, was only a weak inhibitor (Kb congruent to 600).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Overestimation of serum concentrations of gamma-aminobutyric acid in patients with hepatic encephalopathy by the gamma-aminobutyric acid-radioreceptor assay.

Sera of patients with hepatic encephalopathy strongly inhibit the specific binding of gamma-aminobutyric acid to synaptic membranes. In a previous study, this inhibition of specific gamma-aminobutyric acid binding was attributed to gamma-aminobutyric acid itself, and it was assumed that serum gamma-aminobutyric acid is increased 5- to 30-fold in patients with hepatic encephalopathy. The findings of that study, however, were not confirmed by other analytical methods. Therefore, the validity of the gamma-aminobutyric acid-radioreceptor assay was tested. In view of the increased serum concentrations of several amino acids in hepatic encephalopathy, the effects of L-alpha-amino acids on the assay were studied. Five amino acids inhibited specific gamma-aminobutyric acid binding at a concentration of 0.5 mM or lower: glutamine; glutamate; taurine; proline, and OH-proline. Equimolar amounts of aminooxyacetate prevented the inhibition of specific gamma-aminobutyric acid binding by glutamine and glutamate but had no effect on that of gamma-aminobutyric acid, taurine, proline and OH-proline. Aminooxyacetate had no effect on specific gamma-aminobutyric acid binding itself. The inhibitory activity of a serum sample from a patient with hepatic encephalopathy was inhibited by 0.5 mM aminooxyacetate. The gamma-aminobutyric acid binding inhibitory activity of a serum sample of a patient with hepatic encephalopathy was purified by gel chromatography and contained several amino acids at concentrations of about 0.1 mM, 3.5 mM glutamine but no detectable gamma-aminobutyric acid. Accordingly, the gamma-aminobutyric acid binding inhibitory activity is not mediated by gamma-aminobutyric acid alone and is most likely due to glutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1984

Presumptive gamma-aminobutyric acid pathways from the midbrain to the superior colliculus studied by a combined horseradish peroxidase-gamma-aminobutyric acid transaminase pharmacohistochemical method.

A pharmacohistochemical method for gamma-aminobutyric acid transaminase, the key enzyme for gamma-aminobutyric acid metabolism, has been combined with retrograde tracing by horseradish peroxidase, to a study of projections from the midbrain to the superior colliculus. The results indicate projections from the substantia nigra zona reticulata, the zona incerta and the reticular formation of the mesencephalon which are exclusively from neurons staining intensely for gamma-aminobutyric acid transaminase and presumptively gamma-aminobutyric acid as their transmitter. The projection from the ventral lateral geniculate body to the superior colliculus, on the other hand, comes from cells which do not stain for gamma-aminobutyric acid transaminase and therefore do probably not use gamma-aminobutyric acid as their transmitter.

4-Aminobutyrate Transaminase↗
PubMed1989

Entropy as a factor in the binding of gamma-aminobutyric acid and nipecotic acid to the gamma-aminobutyric acid transport system.

Nipecotic acid is one of the most potent competitive inhibitors and alternative substrates for the high-affinity gamma-aminobutyric acid transport system in neurons, but the structural basis of this potency is unclear. Because gamma-aminobutyrate is a highly flexible molecule in solution, it would be expected to lose rotational entropy upon binding to the transport system, a change which does not favor binding. Nipecotic acid, in contrast, is a much less flexible molecule, and one would expect the loss of conformational entropy upon binding to be smaller thus favoring the binding of nipecotic acid over gamma-aminobutyric acid. To investigate this possibility, the thermodynamic parameters, delta G degrees, delta H degrees, and delta S degrees, were determined for the binding of gamma-aminobutyrate and nipecotic acid to the high affinity GABA transport system in synaptosomes. In keeping with expectations, the apparent entropy change for nipecotic acid binding (112 +/- 13 J.K-1) was more favorable than the apparent entropy change for gamma-aminobutyric acid binding (61.3 +/- 6.6 J.K-1). The results suggest that restricted conformation per se is an important contributory factor to the affinity of nipecotic acid for the high-affinity transport system for gamma-aminobutyric acid.

Animals↗
PubMed1980

Regional distributions of gamma-aminobutyric acid (GABA), glutamate decarboxylase (GAD), and gamma-aminobutyrate transaminase (GABA-T) in the central nervous brains of C57/BR, C3H/He, and F1 hybrid mice.

The distributions of gamma-aminobutyric acid (GABA), glutamate decarboxylase (GAD), and gamma-aminobutyrate transaminase (GABA-T) have been studied in various brain areas of mice. These neurochemical markers, which are related to inhibitory neurotransmission, were investigated in different inbred strains of mice (C3H/He, C57/BR, and their F1 hybrids). The regional distributions of GABA, GAD activity, and GABA-T activity in adult mice of these three strains were quite similar. No significant differences were found in any brain area for GAD or GABA-T activity. However, significant differences in GABA level were found in several brain areas among these strains of mice, especially in hypothalamus, hippocampus, olfactory bulb, and occipital cortex. These results provide further information to the possible influence of the GABAergic system in these brain areas.

4-Aminobutyrate Transaminase↗
PubMed1983

4-aminobutyric acid methyl ester hydrochloride, a precursor of 4-aminobutyric acid.

4-Aminobutyric methyl ester hydrochloride (GME) is able to cross the blood-brain barrier after intracardiac administration to the rat. GME has an LD50 of 1300 mg/kg in mice and 950 mg/kg in rats, exhibits an antiaggressive effect and is able to decrease isoniazid-induced convulsions in the rat. GME is hydrolyzed to 4-aminobutyric acid (GABA) by brain homogenates, acts as an inhibitor of GABA binding to crude synaptic plasma membranes, activates the release and inhibits the uptake of GABA by rat synaptosomes and acts as a competitive inhibitor of the so-called GABAse system in vitro.

Animals↗
PubMed1994

Synthesis and photochemistry of photolabile derivatives of gamma-aminobutyric acid for chemical kinetic investigations of the gamma-aminobutyric acid receptor in the millisecond time region.

The gamma-aminobutyric acid (GABA) receptor is an abundant neuronal receptor in the mammalian and invertebrate nervous systems and is associated with an inhibitory chloride ion channel. GABA is the endogenous neurotransmitter for the receptor and can trigger both fast activation and a reversible desensitization of the receptor. A series of photolabile amine-linked o-nitrobenzyl derivatives of GABA were synthesized that photolyze rapidly to release free GABA. The photochemical properties of the GABA precursors were determined; the compounds undergo rapid photolysis, initiated with UV irradiation at 308 nm, and release free GABA on a millisecond time scale. The pH of the photolysis medium affects both the quantum yield and the rate of photolysis. For example, the quantum yield observed for N-(alpha-carboxy-2-nitrobenzyl)-gamma-aminobutyric acid increases from 0.06 at pH 5.0 to 0.1 at pH 10.5, and the half-life for the photolytic reaction decreases from 1.0 to 2.5 ms in the same pH range. Photolysis of the compounds induces rapid onset of transmembrane ion currents in mouse cortical neurons. The potential of the new compounds for use in rapid chemical kinetic investigations of the neuronal GABA receptor is demonstrated.

Animals↗
PubMed1973

Effect of inhibitors of -aminobutyrate aminotransferase on the accumulation of 3H- -aminobutyric acid by the retina.

1. Rat retinae pre-incubated and incubated at 37 degrees C in media containing amino-oxyacetic acid (AOAA) (0.1 muM to 1 mM) accumulated more (3)H-gamma-aminobutyric acid ((3)H-GABA) than control retinae incubated in the absence of AOAA. This increased accumulation of (3)H-GABA by tissue exposed to AOAA was not apparent at short incubation times (0-20 min), but became significant after incubations of 30 min, and maximal after incubation for 60 minutes.2. At a concentration of 10 muM, AOAA did not alter the apparent K(m) for (3)H-GABA uptake or V(max) for either the low or the high affinity GABA uptake systems present in retina.3. The potentiation of (3)H-GABA accumulation produced by AOAA appeared to parallel the inhibitory effect of this compound on 2-oxoglutarate-4-aminobutyrate aminotransferase (GABA-T). Similarly, hydrazinopropionic acid inhibited retinal GABA-T and potentiated the accumulation of (3)H-GABA, but hydroxylamine and thiosemicarbazide which did not affect GABA-T, were also without effect on the retinal accumulation of (3)H-GABA.4. In vitro incubation with AOAA did not increase the endogenous levels of GABA or other amino acids in the retina.5. AOAA did not significantly increase the retinal accumulation of radioactive L-glutamate, L-glutamine, taurine, glycine, alpha-aminoisobutyrate or dopamine: the accumulation of L-aspartate was increased by approximately 30%.6. The inhibition of retinal GABA-T by AOAA was time-dependent and was not reversed by pyridoxal-5'-phosphate or by repeated washing of the tissue with fresh medium.7. AOAA also inhibited glutamate decarboxylase (GAD) in retinae incubated in vitro. This inhibitory effect was partially reversed by pyridoxal-5'-phosphate.8. Efflux of radioactivity from the retina was strikingly reduced in the presence of AOAA at concentrations sufficient to inhibit GABA-T by 100%.9. These findings suggest that AOAA potentiates the accumulation of (3)H-GABA by isolated retina, not by increasing the exchange of (3)H-GABA with the endogenous GABA pools, but by reducing the metabolism of the amino acid and hence reducing the loss of radioactivity from the tissue in the form of tritiated metabolites.

Acetates↗
PubMed1993

Potentiation of gamma-aminobutyric acid-induced chloride currents by various benzodiazepine site agonists with the alpha 1 gamma 2, beta 2 gamma 2 and alpha 1 beta 2 gamma 2 subtypes of cloned gamma-aminobutyric acid type A receptors.

Previous studies with cloned gamma-aminobutyric acid type A receptors expressed in human embryonic kidney cells have indicated that the alpha 1 beta 2 gamma 2 and alpha 1 gamma 2 (but not alpha 1 beta 2) subtypes have benzodiazepine sites. We found in this study that even the beta 2 gamma 2 subtype displays gamma-aminobutyric acid-induced Cl- currents that are potentiated by triazolam (a triazolobenzodiazepine). The maximal efficacy of the drug among the subtypes was highest with the alpha 1 beta 2 gamma 2 subtype, followed by the alpha 1 gamma 2 and beta 2 gamma 2 subtypes. These observations led us to compare the ability of several benzodiazepine site agonists of diverse chemical structures to potentiate Cl- currents with these subtypes. With the alpha 1 gamma 2 subtype, diazepam, alpidem, zolpidem, Cl-218872, zopiclone, U-79098 (an imidazoquinoxaline derivative), and U-90167 (a diimidazoquinazoline derivative) at 5 microM potentiated Cl- currents to essentially similar levels (slightly lower for a few ligands), compared with those with the alpha 1 beta 2 gamma 2 subtype. With the beta 2 gamma 2 subtype, the type 1 ligands zolpidem, alpidem, and Cl-218872 showed no or very low levels of potentiation, whereas less selective ligands such as diazepam, zopiclone, U-78098, and U-90167 displayed levels of Cl- current potentiation comparable to those observed with the subtypes containing the alpha 1 and gamma 2 subunits. These data indicate that, in the presence of gamma 2, beta 2 may substitute for alpha 1 in forming the benzodiazepine site of limited sensitivity to the type 1 ligands. It appears that individual ligands for benzodiazepine sites have their own sets of interacting domains, which are distributed in alpha 1 and gamma 2, and the agonistic activity of type 1 ligands may be more dependent on the alpha 1-specific domains than is that of less selective ligands.

Anti-Anxiety Agents↗
PubMed1977

Antiseizure activity of gamma-acetylenic gamma-aminobutyric acid: a catalytic irreversible inhibitor of gamma-aminobutyric acid transaminase.

gamma-Acetylenic gamma-aminobutyric acid (gamma-acetylenic GABA) produces several-fold sustained elevations of brain GABA concentrations when administered intraperitoneally to mice. It protects mice against seizures induced by audiogenic stimuli, electroshock, thiosemicarbazide, isoniazid and strychnine. The duration and degree of audiogenic seizure protection appears to correlate with elevations in whole brain GABA levels. gamma-Acetylenic GABA does not protect against seizures induced by pentylenetetrazol or picrotoxin even at doses that increase brain GABA concentrations approximately 6-fold. This differential antiseizure activity suggests that the GABA system may play a role in some, but not all experimentally produced seizures.

4-Aminobutyrate Transaminase↗
PubMed2000

Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Chronic antipsychotic drug treatment may cause tardive dyskinesia (TD), a long-term movement disorder. The gamma-aminobutyric acid (GABA) agonist drugs have been trialed as a treatment for TD, but these drugs have intense sedative properties and can possibly exacerbate psychotic symptoms. OBJECTIVES: To determine the effects of GABA agonist drugs (baclofen, gamma-vinyl-GABA, gamma-acetylenic-GABA, progabide, muscimol, sodium valproate and tetrahydroisoxazolopyridine (THIP)) in people with neuroleptic-induced tardive dyskinesia (TD) and schizophrenia or other chronic mental illnesses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1998), The Cochrane Library CENTRAL (1998), Cochrane Schizophrenia Group's Register of Trials (1998), EMBASE (1980-1998), LILACS (1982-1996), MEDLINE (1966-1998), PsycLIT (1974-1998), and SCISEARCH were undertaken. References of all identified studies were searched for further trial citations. First authors of each included trial were contacted. SELECTION CRITERIA: The inclusion criteria for all relevant randomised studies were that they should focus on people with schizophrenia or other chronic mental illnesses, with neuroleptic-induced TD and compare the use of GABA agonist drugs to placebo or no intervention. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and the odds ratio (OR) and its 95% confidence interval (CI) or the weighted mean difference with 95% CI were estimated. The reviewers assumed that people who dropped out had no improvement. MAIN RESULTS: Eight studies were able to be included. Results were equivocal, showing only a tendency for clinical improvement for those using GABA agonist drugs but, when analysis of any improvement (rather than clinical improvement) was performed, a significant reduction was noted in the GABA group (OR 0.36 CI 0.15-0.85). This suggests that for every 10 people treated with GABA drugs one person would benefit with a reduction in TD symptoms. People using the interventions had more confusion (OR 7.4 CI 1.3-40.9) and sedation (OR 3.0 CI 1.2-7.6). The numbers of people needed to treat to cause one extra person to experience these side effects were three and six, respectively. Tendency for more deterioration of the TD symptoms (OR 1.72 CI 0. 54-5.5), deterioration of the mental state (OR 3.07 CI 0.78-12.05), and to drop out before the end of the trial (OR 2.05 CI 0.8-5.21) were also observed in those using GABA agonists. REVIEWER'S CONCLUSIONS: No clear statement about the efficacy of GABA agonist drugs could be provided. From the combined data, GABA agonist drugs tend to be associated with some degree of improvement in TD symptoms, but also with side effects such as confusion and sedation and a deterioration of the person's mental state.

Antipsychotic Agents↗
PubMed1998

4-Aminobutyrate (GABA) transporters from the amine-polyamine-choline superfamily: substrate specificity and ligand recognition profile of the 4-aminobutyrate permease from Bacillus subtilis.

A previous study [Ferson, Wray and Fisher (1996) Mol. Microbiol. 22, 693-701] has shown that transposon-mediated disruption of a protein 47% identical to the Escherichia coli GABA (4-aminobutyrate) transporter abolishes the ability of nitrogen-limited culture conditions to induce expression of a GABA transport activity in Bacillus subtilis. Here it is demonstrated directly that the B. subtilis GABA permease (gabP) gene can complement the transport defect in the gabP-negative E. coli strain. Unexpectedly, the ligand-recognition profile of the B. subtilis GabP was found to differ substantially from that of the highly homologous E. coli GabP. Unlike the E. coli GabP, the B. subtilis GabP: (i) exhibits approx. equal preference for the 3-carbon (beta-alanine, Km=9.6 microM) and the 4-carbon (GABA, Km=37 microM) amino acids, and (ii) resists inhibition by bulky, conformationally constrained compounds (e.g. nipecotic acid, guvacine), which are active against GABA transporters from brain. The present study shows additionally that the B. subtilis GabP can translocate several open-chain GABA analogues (3-aminobutyrate, 3-aminopropanoate, cis-4-aminobutenoate) across the membrane via counterflow against [3H]GABA. Thus, consistent with the idea that the ligand-recognition domain of the B. subtilis GabP is less spacious than that of the close homologue from E. coli, the former exhibits more stringent requirements than the latter for substrate recognition and translocation. These distinct functional characteristics of the E. coli and B. subtilis GABA transporters provide a basis by which to identify ligand-recognition domains within the amine-polyamine-choline transporter superfamily.

Amines↗
PubMed1987

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

The release of [3H]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 [3H]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 [3H]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 [3H]GABA release were not identical in the presence and absence of either inhibitor.

4-Aminobutyrate Transaminase↗
PubMed1986

Autoradiographic study of the distribution of [3H]gamma-aminobutyrate-accumulating neural elements in guinea-pig intestine: evidence for a transmitter function of gamma-aminobutyrate.

High affinity uptake, and the distribution of 3H-radiolabelled gamma-aminobutyrate (GABA), cis-3-aminocyclohexanecarboxylic acid, beta-alanine, proline, and leucine have been examined autoradiographically in laminar preparations of the myenteric plexus from the guinea-pig intestine. Following labelling with [3H]proline and [3H]leucine, which are incorporated into neurons, silver grains were concentrated over recognisable perikarya in the ganglia and meshworks of the plexus, whilst [3H]GABA labelled a smaller proportion of neurons and their processes. Specificity of labelling in the sites of [3H]GABA-uptake was established using combinations of labelled and unlabelled GABA, beta-alanine, and cis-3-aminocyclohexanecarboxylic acid, substrates for glial or neuronal high affinity GABA uptake systems. Only myenteric neurons and their processes were labelled significantly by [3H]GABA and its analogue cis-3-[3H]aminocyclohexanecarboxylic acid. Using autoradiographs of laminar preparations and paraffin sections, [3H]GABA labelling was found over nerve fibre bundles that could be traced from their ganglionic origins through the interconnecting meshworks of the myenteric plexus into the innervation of the deep muscular plexus of the circular muscle layer where GABA is evidently concerned with prejunctional modulation of transmitter release. The extensive but selective distribution of [3H]GABA high affinity uptake sites in neural elements of the guinea-pig myenteric plexus is consistent with GABA being an enteric neurotransmitter.

Alanine↗