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PubMed2000

Changes in gamma-aminobutyric acid content during beni-koji making.

The changes in the gamma-aminobutyric acid (GABA) content during the making of beni-koji prepared with Monascus pilosus IFO 4520 vs. the difference in the rate of tomo koji (10%, 30%, and 50%) were examined. The increased proportion of tomo koji would increase the GABA production and the productions of GABA peaked on the fifth day and thereafter declined. The glutamate decarboxylase activity during beni-koji making with 50% tomo koji steadily increased after the start of the koji making, reaching its peak on the fifth day. The succinic acid content increased after the sixth day. The mycelial growth was in the stationary phase after the sixth day. Therefore, the GABA content increases with an increase in the proportion of tomo koji. It is presumed that the maximum amount of GABA reached on the fifth day was the cause of the increasing amount of conversion of GABA into succinic acid, in addition to the decline in the GAD activity after the fifth day of koji making.

Ascomycota↗
PubMed1972

Gamma-aminobutyric acid: role in primary afferent depolarization.

The effects of putative transmitters on the primary afferent terminals were studied in the magnesium-treated, isolated spinal cord of the frog. Gamma-aminobutyric acid and glutamic acid reversibly depolarized primary afferent terminals and increased their excitability, whereas glycine produced weak and variable effects. Bicuculline and picrotoxin, which reduce primary afferent depolarization, reversibly antagonized the gamma-aminobutyric acid-mediated responses but had little effect on those produced by either glutamic acid or glycine. The glutamic acid- and the gamma-aminobutyric acid-induced depolarizations remained in the absence of external chloride but disappeared in the absence of external sodium. These results support the hypotheses that gamma-aminobutyric acid is the transmitter mediating the synaptic depolarization of primary afferent terminals and that sodium is the predominant ion involved.

Action Potentials↗
PubMed1987

gamma-Aminobutyric acid stimulates acid secretion from the isolated guinea pig stomach.

gamma-Aminobutyric acid (GABA) content was measured, and the effect of GABA on acid secretion was studied using the everted preparation of isolated guinea pig stomachs. GABA contents in the mucosa layer and the remaining layer were 20-24 nmol/g tissue and 34-42 nmol/g tissue, respectively. GABA at 10(-6) to 3 X 10(-5) M induced acid secretion, and the maximum secretion was obtained at 3 X 10(-5) M, that is approximately 1.6-fold of the spontaneous secretion and approximately half of the amount secreted by histamine at 3 X 10(-4) M. The GABA-induced acid secretion was inhibited by bicuculline, scopolamine, pirenzepine, proglumide, and tetrodotoxin, but not by cimetidine. Muscimol (3 X 10 to 10(-5) M), but not baclofen, induced acid secretion in a concentration-dependent manner. The responses to GABA and muscimol were antagonized by bicuculline. Scopolamine and tetrodotoxin completely inhibited the acid secretion induced by low concentrations of GABA and muscimol and to some extent the response induced by high concentrations of muscimol. All these results indicate that GABA induces acid secretion via the A type of GABA receptor, probably located mainly on the cholinergic neurons and partially on the nonneuronal cells in the guinea pig stomach.

Animals↗
PubMed1991

Distinct muscarinic receptors inhibit release of gamma-aminobutyric acid and excitatory amino acids in mammalian brain.

Intracellular recordings were made from neurons of rat lateral amygdala, nucleus accumbens, and striatum in vitro. Synaptic potentials mediated by gamma-aminobutyric acid and by excitatory amino acids were isolated pharmacologically by using receptor antagonists, and their amplitudes were used as a measure of transmitter release. Muscarine and acetylcholine inhibited the release of both gamma-aminobutyric acid and excitatory amino acids, but measurements of the dissociation equilibrium constants for the antagonists pirenzepine, 11-(2-[(diethylamino)methyl]-1-piperidinyl)acetyl-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepine-6-one, methoctramine, and hexahydrosiladifenidol indicated clearly that different muscarinic receptors were involved (M1 and probably M3, respectively). The differential localization of distinct muscarinic receptor subtypes on terminals releasing the major inhibitory and excitatory transmitters of the brain could be exploited therapeutically in some movement disorders and Alzheimer disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1977

gamma-Aminobutyric acid (Gaba) and the dopamine hypothesis of schizophrenia.

gamma-Aminobutyric acid (Gaba) has been shown to influence dopamine activity in the brain. The author suggests that Gaba could be involved in the hypothesized dopamine hyperactivity in schizophrenia. He discusses pharmacological interventions that may raise Gaba-mediated function in the brain and states that further development of Gaba analogues seems clearly indicated. It is conceivable, he concludes, that these compounds could enhance the antipsychotic activity of dopamine receptor blockers, which could lead to the use of lower doses and therefore fewer extrapyramidal side effects.

Aminobutyrates↗
PubMed1982

[Seasonal changes in the gamma-aminobutyric acid system of the mouse brain].

Dynamics of gamma-aminobutyric acid (GABA) content, the level of glutamate and total content of dicarboxylic amino acids and their amides as well as glutamate decarboxylase and GABA-alpha-ketoglutarate aminotransferase activities in the brain of F1CBAXC57BL/6 hybrid mice were determined during a year. The content of GABA and adicarboxylic acids in the brain in autumn-winter is higher than in summer. An analogous regularity is observed in the activity of basic enzymes of the GABA metabolism. Against a background of the common regularity (higher values of these indices in winter and autumn and comparatively low in summer) a particularly pronounced significant increase (as compared with the minimum level) is found in March for the activity of GABA-shunt enzymes, the content of GABA and dicarboxylic amino acids. The data obtained testify to the fact that in autumn-winter the brain tissue is characterized by a comparatively high content of dicarboxylic amino acids, their amides and GABA as well as by a more intensive functioning of the GABA-shunt, which is confirmed by the activation of the enzymes of GABA production and utilization in the corresponding seasons.

4-Aminobutyrate Transaminase↗
PubMed1989

Release of gamma-[3H]aminobutyric acid from rat olfactory bulb and substantia nigra: differential modulation by glutamic acid.

We have studied the glutamate modulation of gamma-[3H]aminobutyric acid ([3H]GABA) release from GABAergic dendrites of the external plexiform layer of the olfactory bulb and from GABAergic axons of the substantia nigra. In the olfactory bulb, [3H]GABA release was induced by high K+ and kainate, and not by aspartate and glutamate alone. However, when the tissue was conditioned by a previous K+ depolarization, glutamate and aspartate caused [3H]GABA release. The effect of glutamate was significantly enhanced when the GABA uptake mechanism was blocked by nipecotic acid. N-Methyl-D-aspartate and quisqualate did not cause [3H]GABA release under the same conditions. The acidic amino acid receptor antagonist 2-amino-4-phosphonobutyric acid and the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovaleric acid significantly inhibited the K+-glutamate- and the kainate-induced [3H]GABA release. Mg2+ (5 mM), which blocks the N-methyl-D-aspartate receptors, significantly inhibited the K+-glutamate-induced but not the kainic acid-induced [3H]GABA release. The K+-glutamate-stimulated release, but not the K+-stimulated [3H]GABA release, was strongly inhibited by Na+-free solutions or by 300 nM tetrodotoxin. Apparently the glutamate-induced release of [3H]GABA occurs through an interneuron because it is dependent on the presence of nerve conduction. In the substantia nigra no [3H]GABA release was elicited by any of the glutamate agonists tested. The present results clearly differentiate between the effects of glutamate on the release of [3H]GABA from the substantia nigra and from the olfactory bulb.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1993

Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain [corrected].

Two novel gamma-aminobutyric acid (GABA) transporters, GAT3 and GAT4, were cloned from the mouse neonatal brain cDNA library and expressed in Xenopus oocytes. Sequence analysis indicated they were members of the Na(+)-dependent neurotransmitter transporter family. The GABA uptake activities were measured in cRNA injected Xenopus oocytes. The Km for GABA uptake by GAT3 was 18 microM and by GAT4 was 0.8 microM. GAT3 also transports beta-alanine and taurine with Km of 28 and 540 microM, respectively. Similarly, GAT4 transports beta-alanine with Km of 99 microM and taurine with a Km of 1.4 mM. The newly cloned GABA transporters were compared with two previously cloned GABA transporters, GAT1 and GAT2, in terms of molecular and pharmacological properties. While GAT1 and GAT4 gene expression were neural specific, GAT2 and GAT3 mRNAs were detected in other tissues such as liver and kidney, in which GAT3 mRNA was especially abundant. The expression of GAT3 mRNA in mouse brain is developmentally regulated, and its mRNA is abundant in neonatal brain but not in adult brain. High affinity GABA transporters GAT1 and GAT4 were more sensitive to inhibition by nipecotic acid. Low affinity GABA transporters GAT2 and GAT3 were inhibited most effectively by betaine and beta-alanine, respectively. The differential tissue distribution and distinct pharmacological properties of those four GABA transporters suggest functional specialization in the mechanisms of GABA transmission termination.

Amino Acid Sequence↗
PubMed1984

Antibodies against gamma-aminobutyric acid: specificity studies and immunocytochemical results.

Antibodies against gamma-aminobutyric acid (GABA)-glutaraldehyde-lysine were obtained by using a procedure based upon (i) a high yield of coupling of GABA to protein carriers, (ii) the reduction of the resulting immunoreactive double bonds, and (iii) a protocol of alternative immunizations using different immunogens having in common only the GABA-glutaraldehyde-lysine segment. This strategy led to the use of the resulting GABA antiserum without further purification. Specificity controls have been carried out with a radiolabeled ligand, [3H]GABA-glutaraldehyde- prolylphenylalanyl -lysine , which mimicked the structure of the immunogen and the fixed hapten in the tissue. Displacement curves showed that the nearest coupled analogs, beta-alanine and glycine, cross-react poorly with GABA, requiring 175-fold or 795-fold higher concentrations, respectively. Immunocytochemical results indicated that the localization obtained with this GABA antiserum largely corresponds with that reported after glutamate decarboxylase immunocytochemistry. The approach may have general applicability to other small molecules such as amino acids.

Animals↗
PubMed2001

Linkage disequilibrium of HLA-A11 and A1 with one of the polymorphisms of the gamma-aminobutyric acid receptor type B.

The gamma-aminobutyric acid receptor type B 1 (GABA(B) R1) is located approximately at 200 kb telomeric to HLA-A on chromosome 6. It has 11 single-nucleotide polymorphisms (SNPs). We studied the most common of its SNPs (T1974C) in a panel of 118 normal Caucasians from New England and 161 epileptic patients of Caucasian ancestry residing in USA. The frequency of the polymorphism did not differ between patients and controls. Here, we report that the allele C of this SNP in the GABA(B) R1 gene is in linkage disequilibrium with HLA-A11 (P<0.00001) and to a lesser extent with HLA-A1 (P<0.01).

Alleles↗
PubMed2002

Zirconium-mediated intramolecular ester transfer reaction: synthesis of alpha-substituted gamma-aminobutyric acid (GABA) derivatives.

[reaction: see text]. The zirconium-mediated intramolecular ester transfer reaction of N-alkenyl carbamate derivatives proceeded to give alpha-substituted gamma-aminobutyric acid (GABA) derivatives in good to excellent yields. Quenching experiments of the reaction mixture with iodine or O2 indicated the presence of a cyclopropane intermediate. The resulting iodide was converted to 2-substituted pyrrolidine-3-carboxylate and/or alpha-alkylidene-gamma-aminobutyric acid derivatives in a stereospecific manner.

Esters↗
PubMed1986

Release of previously incorporated gamma-[3H]aminobutyric acid in rabbit caudate nucleus slices.

The release of gamma-aminobutyric acid (GABA) was studied in slices of the head of the rabbit caudate nucleus. The slices were preincubated with [3H]GABA and then superfused. Aminooxyacetic acid was present throughout. Both the tritium in the slices and that in the superfusate consisted practically entirely of [3H]GABA. Stimulation for 2 min by electrical field pulses of 3 ms width and 9 V/cm voltage drop (36 mA current strength) at 5 or 20 Hz elicited an overflow of [3H]GABA that amounted to 0.23 or 0.47% of the tritium content of the tissue, respectively, and was diminished by 85% in the presence of tetrodotoxin. At higher current strength, less of the stimulation-evoked overflow was tetrodotoxin-sensitive. cis-1,3-Aminocyclohexane carboxylic acid diminished the uptake of [3H]GABA into the tissue but did not change the percentage released by electrical stimulation. Ca2+ withdrawal greatly accelerated basal [3H]GABA efflux and almost abolished the response to stimulation. Nipecotic acid 10-1,000 microM enhanced both the basal and (up to eightfold) the stimulation-evoked overflow. The method described allows us to elicit electrically a quasiphysiological, i.e., Ca2+-dependent and tetrodotoxin-sensitive, neuronal release of [3H]GABA. Nipecotic acid diverts released [3H]GABA from reuptake to overflow.

Amino Acids↗
PubMed2005

Endogenous gamma-aminobutyric acid can excite gonadotropin-releasing hormone neurons.

gamma-Aminobutyric acid (GABA) provides a major synaptic input to GnRH neurons. GnRH neurons maintain high intracellular chloride levels and respond to exogenous GABA with depolarization and action potential firing. We examined the role of synaptic GABA type A receptor (GABA(A)R) activation on the firing activity of GnRH neurons. Targeted extracellular recordings were used to detect firing activity of GnRH neurons in brain slices from adult female mice. Because the brain slice preparation preserves both glutamatergic and GABAergic neuronal networks, the effects of GABA(A)Rs on GnRH neurons were isolated by blocking ionotropic glutamatergic receptors (iGluR). With iGluR blocked, many GnRH neurons remained spontaneously active. Consistent with an excitatory role for GABA, subsequent blockade of GABA(A)Rs suppressed the firing rate in active cells from diestrous females by approximately 40% (P < 0.05; n = 10). GABA(A)R blockade did not affect inactive cells (n = 7), indicating that GABA(A)R-mediated inhibition was not responsible for the lack of firing. In prenatally androgenized females, GnRH neurons exhibit larger, more frequent GABAergic postsynaptic currents than control females. Most cells from prenatally androgenized animals fired spontaneously, and the firing rate was suppressed approximately 80% after GABA(A)R blockade (P < 0.01; n = 8). Blocking GABA(A)R without blocking iGluRs increased the firing rate in GnRH neurons from diestrous females (P < 0.05; n = 6), perhaps attributable to hyperexcitability within the slice network. Our results indicate that GABAergic inputs help generate a portion of action potentials in GnRH neurons; this fraction depends on the level of GABA transmission and postsynaptic responsiveness. The complexities of the GnRH neuron response to GABA make this a potentially critical integration point for central regulation of fertility.

Action Potentials↗
PubMed1971

The uptake of ( - 3 H) aminobutyric acid in the goldfish retina.

After goldfish retinas had been incubated for 1 hr with [gamma-(3)H]aminobutyric acid, we found by autoradiography that the label was localized to a few restricted types of retinal cells. In particular, external and internal horizontal cells from light-stimulated retinas were more heavily labeled than corresponding cells from retinas kept in darkness. Some other cells and tissues in the retina also incorporated the labeled acid. Light stimulation, however, did not cause a pronounced change in the amount of label associated with these cells. Among these were some heavily labeled cells on the vitreal side of the inner nuclear layer, and scattered grains associated with the ganglion cell and optic nerve layers. Electrophoresis of retinal extracts after incubation with the labeled acid also showed that light-stimulated retinas contained about 40-100% more radioactivity than retinas kept in darkness, and that 90% of this activity remained as [gamma-(3)H]aminobutyric acid. The role of the acid in the retina is not known; it is not clear if horizontal cells normally synthesize or store it. The stimulation-dependent accumulation of the labeled acid into horizontal cells suggests that it plays a functional role in these cells.

Aminobutyrates↗
PubMed1993

Concordance between isolated cleft palate in mice and alterations within a region including the gene encoding the beta 3 subunit of the type A gamma-aminobutyric acid receptor.

Genetic and molecular analyses of a number of radiation-induced deletion mutations of the pink-eyed dilution (p) locus in mouse chromosome 7 have identified a specific interval on the genetic map associated with a neonatally lethal mutation that results in cleft palate. This interval, closely linked and distal to p, and bracketed by the genes encoding the alpha 5 and beta 3 subunits of the type A gamma-aminobutyric acid receptor (Gabra5 and Gabrb3, respectively), contains a gene(s) (cp1; cleft palate 1) necessary for normal palate development. The cp1 interval extends from the distal breakpoint of the prenatally lethal p83FBFo deletion to the Gabrb3 locus. Among 20 p deletions tested, there was complete concordance between alterations at the Gabrb3 transcription unit and inability to complement the cleft-palate defect. These mapping data, along with previously described in vivo and in vitro teratological effects of gamma-aminobutyric acid or its agonists on palate development, suggest the possibility that a particular type A gamma-aminobutyric acid receptor that includes the beta 3 subunit may be necessary for normal palate development. The placement of the cp1 gene within a defined segment of the larger D15S12h (p)-D15S9h-1 interval in the mouse suggests that the highly homologous region of the human genome, 15q11-q13, be evaluated for a role(s) in human fetal facial development.

Animals↗
PubMed1977

Net uptake of gamma-aminobutyric acid by a high affinity synaptosomal transport system.

Reuptake of gamma-aminobutyric acid (GABA) by a high affinity transport system in nerve endings in the central nervous system is thought to terminate the action of this postulated neurotransmitter. This hypothesis has been challenged since the demonstration of exchange between synaptosomal and exogenous GABA (G. Levi and M. Raiteri, Nature 250: 735, 1974). In our studies, rat cortical synaptosomes were incubated (25 degrees C) in various media containing 10 muM 14C-GABA. After the synaptosomes were removed by centrifugation, 14C and total GABA (fluorometric assay) in the resulting supernatant were measured. Uptake of labeled GABA, detected by a decrease in medium radioactivity, is Na+- and K+-dependent. Net GABA uptake, however, does not parallel 14C-GABA translocation. Exchange accounts for 20 to 70% of radiolabeled GABA accumulation depending upon the experimental conditions. On the other hand, GABA-deficient synaptosomes (prepared by treatment with 56 mM KCl and 1 mM CaCl2) show equivalent net and radiolabeled GABA uptake in Ringer's solution containing 1 to 4 mM KCl and 60 to 150 mM NaCl (average 4.6 nmol of GABA accumulated per mg of synaptosomal protein). Net and 14C-GABA uptake by GABA-deficient synaptosomes are identical at various pH values (6.0-8.5), synaptosomal protein concentrations (0.4-3.5 mg/ml) and temperatures (5-37 degrees C). Although GABA homoexchange may contribute significantly to radiolabel accumulation by synaptosomes containing higher GABA levels (9.5-9.9 nmol/mg), homoexchange is limited in GABA-depleted synaptosomes. Our results are consistent with the proposal that presynaptic GABA capture by a high affinity system in vivo may terminate the action of this neuroactive amino acid.

Aminobutyrates↗
PubMed1988

gamma-Aminobutyric acid in synovial membrane of rat knee joint.

gamma-Aminobutyric acid (GABA) content was measured, and the release of GABA was studied in the synovial membrane of the rat knee joint. GABA content of the synovial membrane was 20.1 nmol/g tissue. Ten days after unilateral dissection of the sciatic nerve, femoral nerve or both nerves, the GABA contents of the ipsilateral membrane were 13.8, 14.6 and 7.8 nmol/g tissue, respectively. High K+ evoked the Ca2+-dependent release of [3H] GABA from the synovial membranes of intact rats preloaded with [3H] GABA, but did not evoke release from the membrane ipsilateral to the dissection of both sciatic and femoral nerves. Evoked release of [3H] GABA was obtained in the synovial membrane preloaded with [3H] GABA in the presence of beta-alanine, but not in the presence of 2,4-L-diaminobutyric acid. These results indicate that GABA is present in the neuronal elements of the synovial membrane of the rat knee joint.

Animals↗
PubMed1994

gamma-Aminobutyric acid type A receptor antagonists picrotoxin and bicuculline alter acetylcholine channel kinetics in cultured embryonic rat skeletal muscle.

The effects of the classical gamma-aminobutyric acid type A receptor antagonists picrotoxin and bicuculline on nicotinic acetylcholine receptors in cultured embryonic rat skeletal muscle were examined with whole-cell and cell-attached single-channel recording methods. Up to 600 microM picrotoxin had little or no effect on the amplitude of the whole-cell current, whereas bicuculline dose-dependently blocked it, with an IC50 value of 101.2 +/- 8.9 microM. Bicuculline reduced the maximum inducible acetylcholine current without changing the Kd value, suggesting that bicuculline uncompetitively blocked the binding of acetylcholine to its receptor. The elementary nicotinic acetylcholine receptor currents recorded in the cell-attached single-channel recording configuration exhibited properties typical of those recorded in embryonic muscle (approximately 36 pS and approximately 6 msec). Picrotoxin dramatically transformed individual channel openings into briefly interrupted bursts, so that the number of openings increased while the mean open time markedly decreased. Bicuculline decreased mean open time to a lesser but statistically significant degree. The dominant component of the closed time histogram in control recordings occurred at 17 msec, whereas that recorded with picrotoxin occurred at 0.5 msec. Bicuculline prolonged the closed time, with a dominant closed time component at 52 msec. Elementary conductance was not altered by either agent. In conclusion, we found that the gamma-aminobutyric acid type A channel antagonists picrotoxin and bicuculline were also blockers of embryonic nicotinic acetylcholine receptor channels in cultured rat muscle.

Animals↗