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At least 775 records · Page 43Linked to original sources
PubMed1990

Mechanisms of [3H] gamma-aminobutyric acid release by chromaffin cells in primary culture.

The basal and evoked [3H] gamma-aminobutyric acid (GABA) release from chromaffin cells in primary cultures was studied and compared with that of [3H]NA. [3H]GABA was found to be released, in a dose-dependent fashion, by different secretagogues known to induce noradrenaline (NA) release, that is, the cholinergic agonist nicotine, high-potassium chloride, veratridine, and calcium ionophores. In general, there was a parallelism between percentages of release of both [3H]GABA and [3H]NA, although in all circumstances the former were lower. The nicotine- and high-potassium-evoked [3H]GABA release was absolutely calcium dependent, thus indicating the existence of a exocytotic-like mechanism, whereas in the veratridine-induced release, a calcium-independent component was also detected. This latter component was sodium dependent, as it showed an absolute requirement for extracellular sodium and was enhanced by ouabain. Moreover, it was inhibited by known GABA uptake inhibitors, which indicate that this component of [3H]GABA release induced by veratridine could be due to GABA outflow through the membrane carrier. The above results, together with that obtained from studies about subcellular localization of [3H]GABA taken up by chromaffin cells, seem to support the existence of two mechanisms for [3H]GABA release by chromaffin cells: one calcium-dependent, exocytotic-like, and another calcium-independent and sodium-dependent, possibly mediated by the GABA carrier. Both processes could have a functional role on the regulation of extracellular GABA levels and so in the control of catecholamine release by chromaffin cells.

Adrenal Medulla↗
PubMed1999

Influence of gamma-aminobutyric acid on retinal cells excitotoxicity upon glucose deprivation.

The role of extracellular endogenous gamma-aminobutyric acid (GABA) in rescuing retinal cells in culture from the decrease in viability induced by Glu under metabolic inhibition is analyzed. Glutamate (10 microM-10 mM) dose-dependently decreased the intracellular GABA content, but increased the extracellular accumulation of GABA. In the absence of glucose, Glu (10-100 microM) decreased the intracellular GABA (2-fold), whereas the extracellular accumulation of GABA was increased by about 4-fold. Glu-mediated decrement in cell survival was not affected by inhibiting the GABA(A) receptors with bicuculline (1 or 10 microM) or by blocking the Na+ -dependent release of GABA with 1-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (SKF89976-A). Data suggest a non-protective role of endogenous GABA release after metabolic deprivation of retinal cells submitted to Glu.

Animals↗
PubMed1983

High-affinity, sodium-dependent gamma-aminobutyric acid uptake by slices of rat ovary.

The high concentration of gamma-aminobutyric acid (GABA) recently demonstrated in rat ovary prompted us to examine the capacity of ovarian slices to take up [3H]GABA. Active uptake, dependent on temperature and sodium concentration, was observed and a kinetic constant (Km) of 1.0 microM found for the uptake process. Ouabain (100 microM) reduced the rate of accumulation of [3H]GABA. Uptake was inhibited only partially by 100 microM d,l-nipecotic acid, but more strongly by 100 microM beta-alanine. These results suggest that the uptake system in ovary possesses properties similar to those of high-affinity GABA transport systems in the brain.

Animals↗
PubMed1985

Action and localization of gamma-aminobutyric acid in the cat retina.

The effects of iontophoretically applied GABA (gamma-aminobutyric acid) and bicuculline on retinal ganglion cells were studied in the optically intact eye of the anaesthetized cat. GABA suppressed both the spontaneous activity and light-evoked discharge of all retinal ganglion cells, regardless of their type and regardless of the visual stimulus used. Bicuculline antagonized the action of iontophoretically applied GABA. Bicuculline enhanced the spontaneous activity of on-centre cells, but suppressed the spontaneous activity of most off-centre cells. The light-evoked response of on-centre cells was increased by bicuculline. A more complicated picture emerged for off-centre cells. Weak light responses were suppressed by bicuculline, but during strong light responses the initial transient phase of the response was dramatically enhanced. Amacrine cells of the inner nuclear layer and displaced amacrine cells of the ganglion cell layer were labelled, using glutamic acid decarboxylase (GAD) immunohistochemistry and [3H]muscimol uptake. GAD-positive dendrites were found throughout the inner plexiform layer and no sign of dendritic stratification was detected.

Action Potentials↗
PubMed1994

The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit.

Type A gamma-aminobutyric acid (GABAA) receptors of the mammalian nervous system are a family of ligand-gated ion channels probably formed from the coassembly of different subunits (alpha 1-6, beta 1-3, gamma 1-3, delta) in the arrangement alpha beta gamma or alpha beta delta. The activation of these receptors by GABA can be modulated by a range of compounds acting at distinct allosteric sites. One such compound is the broad-spectrum anticonvulsant loreclezole, which we have recently shown to act via a specific modulatory site on the beta subunit of the GABAA receptor. The action of loreclezole depends on the type of beta subunit present in the receptor complex; receptors containing beta 2 or beta 3 subunits have > 300-fold higher affinity for loreclezole than receptors containing a beta 1 subunit. We have used this property to identify the amino acid residue in the beta subunit that determines the subunit selectivity of loreclezole. Chimeric beta 1/beta 2 human GABAA receptor subunits were constructed and coexpressed in Xenopus oocytes with human alpha 1 and gamma 2s subunits. The chimera beta 1/beta 2Lys237-Gly334 conferred sensitivity to 1 microM loreclezole. Within this region there are four amino acids that are conserved in beta 2 and beta 3 but differ in beta 1. By mutating single amino acids of the beta 1 subunit to the beta 2/beta 3 equivalent, only the beta 1 mutation of Ser-290-->Asn conferred potentiation by loreclezole. Similarly, mutation of the homologous residue in the beta 2 and beta 3 subunits to the beta 1 equivalent (Asn-->Ser) resulted in loss of sensitivity to loreclezole. The affinity for GABA and the potentiation by flunitrazepam were unchanged in receptors containing the mutated beta subunits. Thus, a single amino acid, beta 2 Asn-289 (beta 3 Asn-290), located at the carboxyl-terminal end of the putative channel-lining domain TM2, confers sensitivity to the modulatory effects of loreclezole.

Allosteric Site↗
PubMed1992

Beta-lactams: a new class of conformationally-rigid inhibitors of gamma-aminobutyric acid aminotransferase.

A structural similarity of several monobactams (2-4), 3-aminonocardicinic acid (6), 6-aminopenicillanic acid (7), 7-aminocephalosporanic acid (8), and 7-aminodesacetoxycephalosporanic acids (9, 10) to gamma-aminobutyric acid (GABA) and to known inhibitors and substrates of GABA aminotransferase is described. Because of this, the above-mentioned compounds were tested as competitive inhibitors and as inactivators of pig brain GABA aminotransferase. All of the compounds were competitive inhibitors of GABA aminotransferase. On the basis of the inhibitory potency of these conformationally-rigid GABA analogues it is hypothesized that GABA is bound at the active site with its amino and carboxylate groups in a syn orientation. None of the compounds inactivates GABA aminotransferase. These beta-lactam analogues represent the first examples of a new class of inhibitors of GABA aminotransferase.

4-Aminobutyrate Transaminase↗
PubMed1997

Analysis of the transmembrane topology and membrane assembly of the GAT-1 gamma-aminobutyric acid transporter.

The transmembrane topology of the Na+- and Cl--dependent gamma-aminobutyric acid transporter GAT-1 has been studied using protein chimeras in Xenopus oocytes. A series of COOH-terminal truncations was generated to which a prolactin epitope was fused. Following expression of transporter-prolactin chimeras in Xenopus oocytes, the transmembrane orientation of each chimera was determined by testing for protease sensitivity in an oocyte membrane preparation. Data from protease protection assays with GAT-1-prolactin chimeras has shown that residues in the loops connecting hydrophobic domain (HD)3 and HD4 and HD7 and HD8 are accessible to protease in the cytoplasm and suggest the presence of pore loop structures which extend into the membrane from the extracellular face. Such pore loop structures may be involved in the formation of the substrate-binding pocket. Studies presented herein confirm that the NH2 and COOH termini are cytosolic and hydrophobic domains span the membrane in a manner consistent with the predicted hydropathy model for Na+- and Cl--dependent transporters. These data also provide insight into GAT-1 transmembrane assembly and suggest that a complex series of topogenic sequences directs this process. A potential pause-transfer sequence has been identified and may be responsible for the translocational pausing observed in this study.

Amino Acid Sequence↗
PubMed1997

Unsaturated phosphinic analogues of gamma-aminobutyric acid as GABA(C) receptor antagonists.

The phosphinic and methylphosphinic analogues of gamma-aminobutyric acid (GABA) are potent GABA(C) receptor antagonists but are even more potent as GABA(B) receptor agonists. Conformationally restricted unsaturated phosphinic and methylphosphinic analogues of GABA and some potent GABA(B) receptor phosphonoamino acid antagonists were tested on GABA(C) receptors in Xenopus oocytes expressing human retinal rho1 mRNA. 3-Aminopropyl-n-butyl-phosphinic acid (CGP36742), an orally active GABA(B) receptor antagonist, was found to be a moderately potent GABA(C) receptor antagonist (IC50 = 62 microM). The unsaturated methylphosphinic and phosphinic analogues of GABA were competitive antagonists of the GABA(C) receptors, the order of potency being [(E)-3-aminopropen-1-yl]methylphosphinic acid (CGP44530, IC50 = 5.53 microM) > [(E)-3-aminopropen-1-yl]phosphinic acid (CGP38593, IC50 = 7.68 microM) > [(Z)-3-aminopropen-1-yl]methylphosphinic acid (CGP70523, IC50 = 38.94 microM) > [(Z)-3-aminopropen-1-yl]phosphinic acid (CGP70522, IC50 > 100 microM). This order of potency differs from that reported for these compounds as GABA(B) receptor agonists, where the phosphinic acids are more potent than the corresponding methylphosphinic acids.

Animals↗
PubMed1981

Substantia nigra gamma-aminobutyric acid receptors in Huntington's disease.

The specific binding of [3H]gamma-aminobutyric acid (GABA) to nigral GABA receptors has been studied in postmortem brains from controls and patients with Huntington's disease (HD). A specific increase in the number of high-affinity binding sites for [3H]GABA was observed in HD patients, analogous to changes observed in rat substantia nigra [3H]GABA binding after striatal kainic acid (KA) lesion. The results provide further support for the striatal KA lesion in the rat as an animal model of HD. The implications of the results for the proposed therapeutic potential of GABA agonists in HD are discussed.

Aged↗
PubMedDate not supplied

[Study of gamma-aminobutyric acid (GABA) concentration in blood plasma of alcoholism patients].

Concentration of gamma-aminobutyric acid (GABA) was estimated in the plasma of 104 patients with alcoholism during 2 month treatment course in addiction hospital and in 29 healthy volunteers. Highly distinct differences in content of GABA were detected in the plasma of the volunteers and patients with alcoholism, which remained within 60 days of alcohol withdrawal.

Alcoholism↗
PubMed1988

Colocalization of substance P and gamma-aminobutyric acid in amacrine cells of the cat retina.

Substance P and gamma-aminobutyric acid (GABA) were colocalized by immunocytochemistry in two subpopulations of amacrine cells in the cat retina. All of the cells which stained for substance P also showed GABA reactivity. However, there were many GABA-immunoreactive cells which did not stain for substance P. The presence of neuropeptides provides a basis for additional neurochemical characterization of the multiple populations of GABA immunoreactive cells.

Animals↗
PubMed1983

Depolarizing action of GABA (gamma-aminobutyric acid) on myelinated fibers of peripheral nerves.

The inhibitory neurotransmitter GABA (gamma-aminobutyric acid) has been shown to have a depolarizing action on myelinated axons of both mammalian and amphibian peripheral nerves. In initial in vivo observations intravenous injections of GABA caused an increase in the excitability of the low-threshold, fast conducting fibers of the superficial radial and median nerves of the cat. Similar, graded, reversible effects were confirmed (using changes in the amplitude/integral of the stimulus-evoked A-fiber submaximal compound action potential to assess excitability) in in vitro studies with the isolated, desheathed frog sciatic nerve. GABA caused a mean maximal increase in half-maximal action potential of 29.8% (S.E. +/- 2.7), with an ED50 value of 0.09 mM and Hill coefficient of 0.70. This effect did not appear to desensitize, and could be reversibly antagonized by both bicuculline and picrotoxin. Comparison of agonist sensitivities showed a rank order of potency with muscimol greater than 3-aminopropanesulfonic acid greater than GABA greater than beta-guanidinopropionic acid greater than imidazole-acetic acid greater than guanidoacetic acid greater than delta-aminovaleric acid. With structure activity analysis the maximal activity was found to be related to N+-C separation near the 5 A value. Partial substitution of chloride ions in the superfusate by isethionate reversibly depressed the effect of GABA. These observations support the conclusion that extrasynaptic receptors for GABA are present on the myelinated axons of peripheral nerves.

Animals↗
PubMed1992

Release of gamma-aminobutyric acid by visual stimulation in the kitten visual cortex.

Release of gamma-aminobutyric acid (GABA) was measured by brain microdialysis and high-performance liquid chromatography (HPLC) in the visual cortex of anesthetized kitten. The basal level of endogenous GABA release was 0.25 +/- 0.02 pmol/30 microliters dialysate (n = 8), which was near the lower limit of resolution of the present measuring system. When nipecotic acid, a GABA uptake inhibitor, was infused, release was increased 5-10 fold. The nipecotic acid-induced GABA output was not affected by the infusion of tetrodotoxin (TTX), a sodium channel blocker. Visual stimulation presented to one eye led to a marked increase in GABA output over the basal level. This effect was completely suppressed by TTX administration. These results suggest that the increase in GABA output in response to visual stimulation is due to an increase in GABAergic neuronal activity in the kitten visual cortex.

Animals↗
PubMed1994

Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice.

Three genes (Gabrg3, Gabra5, and Gabrb3) encoding the gamma 3, alpha 5, and beta 3 subunits of the type A gamma-aminobutyric acid receptor, respectively, are known to map near the pink-eyed dilution (p) locus in mouse chromosome 7. This region shares homology with a segment of human chromosome 15 that is implicated in Angelman syndrome, an inherited neurobehavioral disorder. By mapping Gabrg3 on a panel of p-locus deletions, we have determined that the order of genes within this cluster is centromere-p(D15S12h)-Gabrg3-Gabra5-Gabrb3-telom ere. Like Gabrb3, neither the Gabra5 nor Gabrg3 gene is functionally imprinted in adult mouse brain. Mice deleted for all three subunits die at birth with a cleft palate, although there are rare survivors (approximately 5%) that do not have a cleft palate but do exhibit a neurological abnormality characterized by tremor, jerky gait, and runtiness. We have previously suggested that deficiency of the beta 3 subunit may be responsible for the clefting defect. Most notably, however, in this report we describe mice carrying two overlapping, complementing p deletions that fail to express the gamma 3 transcript, as well as mice from another line that express neither the gamma 3 nor alpha 5 transcripts. Surprisingly, mice from both of these lines are phenotypically normal and do not exhibit any of the neurological symptoms characteristic of the rare survivors that are deleted for all three (gamma 3, alpha 5, and beta 3) subunits. These mice therefore provide a whole-organism type A gamma-aminobutyric-acid receptor background that is devoid of any receptor subtypes that normally contain the gamma 3 and/or alpha 5 subunits. The absence of an overt neurological phenotype in mice lacking the gamma 3 and/or alpha 5 subunits also suggests that mutations in these genes are unlikely to provide useful animal models for Angelman syndrome in humans.

Angelman Syndrome↗
PubMed1978

alpha-Hydroxy-beta-keto-gamma-aminobutyric acid in human urine.

A new amino acid has been isolated from the normal human urine. The chemical structure of the amino acid was determined to be alpha-hydroxy-beta-keto-gamma-aminobutyric acid based on its physical properties involving NMR, infrared and mass spectra, as well as chemical degradation and synthesis. In six healthy adults the urinary contents of the new amino acid were 3.2--4.5 mumol/24 h.

Aminobutyrates↗
PubMed2004

Role of calcium and kinases on the neurotrophic effect induced by gamma-aminobutyric acid.

An increasing body of evidence supports a trophic action of gamma-aminobutyric acid (GABA) during nervous system development. The purported mediator of these trophic effects is a depolarizing response triggered by GABA, which elicits a calcium influx in immature CNS cells. This Mini-Review focuses on the neurotrophic role of neural activity and GABA and some of the most common intracellular cascades activated by depolarization and trophic factors. Several biological effects induced by GABA in the developing nervous system are reviewed, with particular emphasis on what is known about calcium-dependent neurotrophic effects induced by GABA and its intracellular mechanisms.

Animals↗
PubMed1989

gamma-Aminobutyric acid uptake and localization in bovine chromaffin cells in primary culture.

gamma-Aminobutyric acid (GABA) uptake was studied in bovine chromaffin cells maintained in primary culture. Uptake was found to be dependent on Na+, but not on K+ and Ca2+ ions; it was found that 2 Na+ ions were necessary for each molecule of GABA transported. 2,4-Dinitrophenol, ouabain and vanadate inhibited GABA uptake showing the energy dependency of the system. Two affinity sites were demonstrated, a high affinity site and a low affinity site with Km values of 10 microM and 170 microM, respectively. While the low affinity site did not show large variations with culture age, the Km of the high affinity site increased from 1 microM in freshly isolated cells to 10 microM in 3-9 day-old cells. GABA uptake was unaffected by glutamic acid, aspartic acid, glycine and catecholamines, while taurine, beta-alanine, nipecotic acid and L-2,4 diaminobutyric acid inhibited GABA uptake. Nipecotic acid and L-2,4 diaminobutyric acid acted as competitive inhibitors modifying Km values of the high affinity site. Subcellular studies performed on [3H]GABA-loaded chromaffin cells showed that GABA was not in secretory granules but was recovered in the 100,000 g soluble fraction. The GABA uptake process associated with chromaffin cells may be an important mechanism for regulating the modulation of catecholamine secretion. In addition, the presence of GABA in the cytosol indicates that this molecule may be an effector of chromaffin cell activity in addition to modulating catecholamine secretion.

Adrenal Medulla↗
PubMed1978

[Conformation of gamma-aminobutyric acid and its receptors].

The preferable conformations of the inhibitory transmitter gamma-aminobutyric acid (GABA) and its specific inhibitor bicuculline are due to the occupation of the GABAreceptor by a part of the bicuculline molecule that is isosteric with the biologically active conformation of GABA. In the present review are described characteristics of sodium-independence receptor sites and evaluated the regional distribution of postsynaptic receptor binding for GABA in the central nervous system. The postsynaptic GABA receptor has been labeled by direct binding of 3H-GABA. The structural analogues and antagonists of GABA were investigated for inhibition of GABA binding. The developmental changes in the activity of glutamic acid decarboxylase, the GABA uptake mechanism and GABA receptor binding in embryo brain were examined. Different models for the GABA-receptor interaction are considered. Data of the stoichiometry of GABA-receptor interactions indicate that the interaction is probabilistic and that 3 molecules of GABA are needed to activate the receptor probabilistically. It was found that 1 molecule of picrotoxin was capable of blocking the interaction with 3 GABA molecules. The hypothetical model of cooperative action of GABA-recepto-inophore complexes involving membrane mobility is also discussed. The transitive complex GABA with ligand binding of Na+, Cl- and the conformational changes of GABA-receptor is proposed.

Aminobutyrates↗