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At least 955 records · Page 53Linked to original sources
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↗
PubMedDate not supplied

[Decrease in the activity of cerebral gamma-aminobutyric acid metabolism enzymes under the influence of kynurenines possessing convulsive activity].

Content of gamma-aminobutyric acid (GABA) was unaltered in mouse brain and cerebellum after administration of D,L-kynurenine (50 mcg), quinolinic acid (5 mcg) and nicotinic acid (50 mcg) into brain ventricles. At the same time, after administration of kinurenine, quinolinic acid and nicotinic acid activity of GABA-transaminase in brain was decreased by 39%, 40% and 48, respectively; activity of glutamate decarboxylase was decreased by 27% and 36%, respectively, in this case nicotinic acid affected only slightly. Strong clonic convulsions occurred in 60% of mice after administration of kynurenine and quinolinic acid and only in 7% of mice after treatment with nicotinic acid. Deceleration in the GABA turnover and the subsequent weakening of the brain inhibitory systems were apparently essential in development of convulsions caused by the kynurenines.

4-Aminobutyrate Transaminase↗
PubMed1984

Stimulation of [3H]gamma-aminobutyric acid release by calcium chelators in synaptosomes.

The effect of EGTA on the release of labeled gamma-aminobutyric acid (GABA), glutamate, acetylcholine, and dopamine was studied in superfused synaptosomes from mouse brain. In the absence of both Ca2+ and Mg2+, EGTA and also EDTA at 50 microM or higher concentrations induced a 2.5-5-fold stimulation of [3H]GABA release, similar to that produced by potassium depolarization, whereas only a slight effect, or no effect at all, was observed on the release of the other transmitters studied. The GABA-releasing action of EGTA was practically abolished in the presence of Mg2+. In contrast, the effect of EDTA was also observed when the medium contained Mg2+. Studies on the ionic dependence showed that the stimulation of GABA release by EGTA was abolished in a Na+-free medium. Li+ did not substitute Na+ for the EGTA effect, which was also independent of chloride. This Na+ dependence does not seem to involve voltage-sensitive channels, since tetrodotoxin did not affect the GABA-releasing action of EGTA, whereas in parallel superfusion chambers it blocked over 80% the stimulation of GABA release by veratridine. In contrast, two calcium channel blockers in synaptosomes, La3+ and the cationic dye ruthenium red, greatly inhibited the GABA-releasing effect of EGTA. L-2,4-Diaminobutyric acid, an inhibitor of the Na+-dependent GABA carrier, did not affect the releasing action of EGTA, whereas in a parallel experiment this drug inhibited by more than 90% the exchange of labeled GABA with unlabeled GABA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

[The contents of gamma-aminobutyric acid and glutamic acid in brain affected by coriaria lactone].

Capillary chromatography was applied to studying the contents of gamma-aminobutyric acid (GABA) and glutamic acid (Glu) in brain affected by coriaria lactone. The results showed that there was a significant increase in the content of Glu whereas no significant change in the content of GABA was noted. The precisions for GABA and Glu were 3.3% and 4.98% and the recoveries of them were 80.5% and 85.2%, respectively. Capillary chromatography is a good method for determining the contents of GABA and Glu in brain, which has the characteristics of rapid and high sensitivity.

Animals↗
PubMed1982

Comparison of the antinociceptive effect of gamma-aminobutyric acid (GABA) agonists: evidence for a cholinergic involvement.

The antinociceptive action of three classes of gamma-aminobutyric acid (GABA) agonists was examined in mice using the hot-plate and tail-immersion tests. A significant increase in reaction time was noted in the hot-plate test after treatment with the direct-acting GABA receptor agonists, kojic amine or 4,5,6,7-tetrahydroisoxazolo[5,4-C] pyridin-3-ol, with gamma-vinyl GABA, an inhibitor of GABA degradation, or with nipecotic acid ethyl ester, an inhibitor of high-affinity GABA transport. Studies with naloxone indicated that the increase in pain threshold was not mediated through the brain opiate system, although it was possible to reverse the antinociceptive effect of these drugs with atropine. Receptor binding experiments indicated that except for the ethyl ester of nipecotic acid, the GABA agonists have little affinity for the cholinergic muscarinic receptor site. Atropine, at a dose that completely blocked the antinociceptive action of kojic amine, was unable to attenuate the sedative effects of this drug. These findings suggest that, regardless of their mechanism, the three types of GABA agonists tested are capable of inducing an antinociceptive response in mice and that this action is apparently secondary to a GABA-mediated increase in brain cholinergic function.

Analgesics↗
PubMed1985

[Anxiolytic action of sodium valproate (possible role of gamma-aminobutyric acid in affective disorders)].

An experimental and clinico-pharmacological study of sodium valproate, a GABA-ergic drug, was conducted to elucidate the role of gamma-aminobutyric acid in the mechanisms responsible for affective disturbances, in particular for anxiety. A tranquilizing effect of the drug, comparable with the action of diazepam, was established in a conflict situation model in experimental animals. Using clinico-psychological methods the authors showed a distinct tranquilizing action of valproate in patients suffering from neurotic and neurosis-like disorders with manifestations of anxiety in the structure of the psychopathological syndrome. It was established that this action was accompanied by no manifestations of myorelexation, ataxia or somnolence characteristic of tranquilizers of the benzodiazepine series. The presence of tranquilizing properties in the GABA-ergic drug sodium valproate confirms the suggestion that a certain relationship exists between the GABA system and anxiety.

Adult↗
PubMed1997

Agonist-induced closure of constitutively open gamma-aminobutyric acid channels with mutated M2 domains.

Ligand-gated ion channels display a fundamental property-channels remain virtually closed at rest and open upon agonist binding. Here we show that substituting alanines for either of two amino acid residues (T314 or L317) in the M2 region of the gamma-aminobutyric acid (GABA) rho1 subunit results in spontaneous channel opening in the absence of ligand. Surprisingly, for two single point mutants (T314A or L317A), application of very low concentrations of agonist partially suppressed this spontaneous current, while higher concentrations re-activated the receptors. When both of these sites were mutated (T314A/L317A), GABA nearly completely suppressed the constitutive current and did not re-activate the current even at very high concentrations. This study provides important new insights into the structure-function relationship of ligand-gated ion channels, where modification of the structure of the channel pore region not only alters the allosteric transition of the receptor protein but also reverses the polarity of agonist regulation of channel gating. Our results suggest that the sites where these two residues are located are structurally critical for channel gating.

Amino Acid Sequence↗
PubMed1978

Distribution of gamma-aminobutyric acid, glycine, glutamate and aspartate in the cochlear nucleus of the rat.

The distributions of gamma-aminobutyric acid (GABA), glycine, glutamate and aspartate were measured in cochlear nuclei of two rats by quantitative histochemical mapping procedures. The levels and distributions in the two rats were comparable, and resembled those previously reported for cat cochlear nucleus. The results are consistent with a concept that these putative transmitter amino acids have similar levels and distributions in the cochlear nucleus among mammals.

Aminobutyrates↗
PubMed2002

The human gamma-aminobutyric acid A receptor delta (GABRD) gene: molecular characterisation and tissue-specific expression.

Terminal deletions of 1p36 result in a specific and common syndrome characterised by the following: growth delay, distinctive facial anomalies, hearing and visual deficits, heart defects, body asymmetry, moderate to severe psychomotor retardation, epilepsy, and self-abusive behaviour. The human gamma-aminobutyric acid A receptor delta-subunit gene (GABRD) encodes for one of at least 15 ligand-gated chloride channels for gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain. Recently we have mapped this gene by radiation hybrid mapping to the critical region of gene loss of the 1p36 deletion syndrome within 1p36.33. The complete complementary DNA (cDNA) sequence of GABRD was generated using assembled sequence of cDNA fragments already available, and 5'-rapid amplification of cDNA ends products. Fine physical mapping of the GABRD gene within this genomic interval was performed by screening bacterial artificial chromosome contigs spanning the critical region of the 1p36 deletion syndrome. The GABRD gene maps immediately proximal to the PRKCZ gene that is located between marker D1S243 and cosmid D1Z2--a region thought to be critical for cognition and speech development. The GABRD gene is expressed most abundantly in brain and has three alternative exons (1A-C) with alternative start codons at the 5'-end. Genomic localisation, function, and expression would suggest that the GABRD gene represents a good candidate for the neurodevelopmental and neuropsychiatric anomalies seen in the 1p36 deletion syndrome.

Amino Acid Sequence↗
PubMed1993

Plasticity of astroglial glutamate and gamma-aminobutyric acid uptake in cell cultures derived from postnatal mouse cerebellum.

The plasticity of astroglial glutamate and gamma-aminobutyric acid (GABA) uptakes was investigated using mouse cerebellar cell cultures. The influence of external factors, such as different sera and/or the presence of neurons, was examined. Control autoradiography experiments showed that after short-term exposure to radioactive amino acids, granule cells took up neither glutamate nor GABA, and beta-alanine predominantly inhibited astroglial GABA uptake. Astroglial uptake was quantified by measuring the radioactivity taken up by the cells in the culture and relating this measurement to the number of glial fibrillary acidic protein-positive cells present. Glutamate uptake was investigated in astroglial cultures and subcultures and in neuronal-astroglial cultures derived from postnatal day 4 mouse cerebella. In the absence of neurons, glutamate uptake increased during the first 9 days after plating and then leveled off. At 14 days in vitro in horse serum, which favors the differentiation of fibrous-like astrocytes, glutamate uptake related to astrocyte number was twice as high as in fetal calf serum. In the presence of cerebellar neurons, this rate was even higher. The specificity of the responsiveness of astrocytes to neurons with respect to glutamate uptake was investigated by comparing GABA uptake in the different culture conditions. Neurons also increased the rate of GABA uptake by astrocytes. Another component of the astroglial plasma membrane, the density of beta-adrenergic receptors, was, however, not markedly affected by the presence of neurons. Hence, these results showed that in astrocytes plated from postnatal day 4 mouse cerebella, the level of neurotransmitter uptake can be regulated in vitro by factors present in sera and by cerebellar neurons in the culture. However, this plasticity declined during development because astrocytes plated from postnatal day 8 cerebella and cultured under identical conditions were less active in glutamate uptake and were insensitive to the presence of horse serum. The latter observation suggested that the metabolic plasticity of astrocytes is restricted to a period defined early in cerebellar development and is no longer evident by postnatal day 8.

Aging↗
PubMed1996

Nitric oxide-evoked [3H] gamma-aminobutyric acid release is mediated by two distinct release mechanisms.

Mechanisms underlying the release of [3H] gamma-aminobutyric acid (GABA) evoked by nitric oxide (NO) were investigated by use of primary cultured neurons prepared from the mouse cerebral cortex. NO generators such as sodium nitroprusside (SNP) and S-nitroso-N-a etylpenicillamine (SNAP) increased both [3H]GABA release from the neurons and [45Ca2+] influx into the neurons in a dose-dependent manner, which was significantly diminished by hemoglobin. The removal of Ca2+ significantly reduced the NO-induced [3H]GABA release by about 50%. Nipecotic acid and 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1, 2, 5, 6-tetrahydro-3- pyridinecarboxylic acid (NO-711), GABA uptake inhibitors dose-dependently inhibited the NO-evoked [3H]GABA release in either the presence or absence of Ca2+. The concentration of these GABA uptake inhibitors to suppress the NO-induced release of [3H]GABA was sufficiently lower than that to exhibit the inhibition of [3H]GABA transport into the neurons. In addition, the NO-evoked [3H]GABA release was reduced by approximately 50% when total Na+ in incubation buffer was replaced with equimolar choline, and was also completely abolished by the removal of both Ca2+ and Na+. These results indicate that the release of [3H]GABA evoked by NO is mediated by two release mechanisms, a Ca2+ -dependent release system and the reverse process of the Ca2+ -independent and Na+ -dependent carrier-mediated GABA uptake system.

Animals↗
PubMed1997

Initial development of gamma-aminobutyric acid immunoreactivity in the human cerebral cortex.

The development of cortical cells immunoreactive for gamma-aminobutyric acid (GABA) was studied in human cerebral cortex in the first trimester of gestation (from 4 to 13 gestational weeks; g.w.). The first GABA-immunoreactive (IR) cells were observed at 6.5 g.w., i.e., before the appearance of the cortical plate, which gives rise to a majority of the adult cortical layers. GABA-IR cells were found initially in the telencephalic wall, where a lateromedial gradient in the density of GABA-positive cells was observed at this early developmental time point, but not at later stages. At 7 g.w., as the cortical plate emerged in the ventrolateral region of the cerebral vesicle, GABA-immunoreactive cells were found dorsal and ventral to the developing cortical plate. At this stage, immunoreactivity was also observed in the other transient developmental zones of the cortical anlage: in the subplate layer and in the intermediate, subventricular and ventricular zones. From 8 to 9 g.w. and continuing throughout the end of the studied period (13 g.w.), GABA-IR cells were distributed throughout the full width of the telencephalic wall, and, at 13 g.w., the newly formed subpial granular layer contained GABA-immunoreactive cells, as well. However, the predominant sites for GABA immunoreactivity remained the prospective layer I and the subplate. The population of GABA-positive cells described here was not immunoreactive for glial fibrillary acidic protein (GFAP) at any gestational age examined and, therefore, probably represents GABA-containing neurons. The observation that GABA-IR neurons appear in human developing cortex slightly before the cortical plate formation and beginning of synaptogenesis (6.5 g.w.) suggests that GABA plays an important role in the initial organization of the developing human cerebral cortex.

Cerebral Cortex↗
PubMed1998

Substitutions of the highly conserved M2 leucine create spontaneously opening rho1 gamma-aminobutyric acid receptors.

All members of the receptor-operated ion channel family that includes gamma-aminobutyric acid (GABA), glycine, nicotinic acetylcholine, and serotonin type 3 receptors have a conserved leucine near the center of the presumed second membrane-spanning domain. This leucine has been postulated to play a role in the gating of the pore. In this study, we examined the effects of mutating this leucine (L301) on the function of human homomeric rho1 GABA receptors. Oocytes expressing rho1 GABA receptors in which this leucine was substituted with alanine (A), glycine (G), serine (S), threonine (T), valine, or tyrosine, but not isoleucine or phenylalanine, demonstrated larger-than-normal resting conductances in the absence of GABA. This resting conductance had a reversal potential (and shifted reversal potential with chloride substitution) indistinguishable from that of the wild-type rho1 GABA-activated current. This resting conductance was antagonized by picrotoxin and, in the case of the A, G, S, and T substitutions, by GABA itself. Although the rho1 competitive antagonist 3-aminopropyl(methyl)-phosphinic acid did not block the resting conductance, this compound did competitively inhibit the GABA-mediated antagonism of the resting conductance. At higher concentrations, both 3-aminopropyl(methyl)-phosphinic acid and GABA directly activated the A, G, S, and T mutant receptors. Taken together, these data suggest that substitution of this highly conserved leucine with either small or polar residues produced rho1 GABA receptors that can open in the absence of GABA and support the hypothesis that this leucine may play a key role in the gating of the pore.

Animals↗
PubMed1983

Uptake and stimulus-evoked release of [3H]-gamma-aminobutyric acid by myenteric nerves of guinea-pig intestine.

1--Following preloading with [3H]-gamma-aminobutyric acid ([3H]-GABA), in the presence of beta-alanine to inhibit glial uptake of the label, electrical stimulation caused a frequency-dependent release of tritium as [3H]-GABA from isolated longitudinal-muscle myenteric-plexus preparations of the guinea-pig ileum and colon. 2--The electrically evoked efflux of [3H]-GABA was Ca2+-dependent, virtually abolished by preventing neuronal conduction with tetrodotoxin, and markedly reduced by preloading with [3H]-GABA in the presence of nipecotic acid which is an inhibitor of high affinity GABA-uptake. Veratridine and KCl were less effective than electrical stimulation in evoking [3H]-GABA release. 3--It is concluded that the electrically stimulated efflux of [3H]-GABA originated from GABAergic neurones of the myenteric plexus which had taken up the label. 4--These results provide further evidence to support the suggestion that GABA is a transmitter in the mammalian enteric nervous system.

Animals↗