Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P80404 (GABA transaminase)
 786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Slices of rat temporo-parietal cortex were prelabeled with gamma-[3H]aminobutyric acid ([3H]GABA), in the presence of the glial GABA uptake inhibitor beta-alanine. The slices were then superfused with a medium containing the GABA transaminase inhibitor aminooxyacetic acid and stimulated electrically (5 min, 2 msec, 36 mA at 5 or 10 Hz), in the presence of the neuronal GABA reuptake inhibitor SK&F 89976A [N-(4,4-diphenyl-3-butenyl)-nipecotic acid] and of beta-alanine. Representative experiments showed that the tritium released could be accounted for almost entirely by authentic [3H]GABA. The electrically evoked overflow of [3H]GABA was tetrodotoxin sensitive and largely calcium-dependent. Exogenous GABA, added to the superfusion medium at 3 to 30 microM, reduced in a concentration-dependent manner the electrically evoked (5 Hz) release of [3H]GABA. The GABAB receptor agonist (-)-baclofen, but not the GABAA receptor agonist muscimol, mimicked GABA and produced a concentration-inhibition curve almost superimposable to that of the natural transmitter. The effects of GABA and of (-)-baclofen were much more pronounced at 5 than at 10 Hz. The GABA-induced inhibition of [3H]GABA release was sensitive to the novel GABAB receptor antagonist beta-(p-chlorophenyl)-3-amino propyl phosphonic acid which, by itself, increased the [3H]GABA overflow. The inhibitory effect of GABA was not counteracted by the GABAA receptor antagonists bicuculline or SR 95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide]. The results are compatible with the presence in the rat cerebral cortex of autoreceptors mediating inhibition of GABA release and belonging to the GABAB type. These autoreceptors may be activated tonically under physiological conditions.
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PMID:Release of gamma-[3H]aminobutyric acid (GABA) from electrically stimulated rat cortical slices and its modulation by GABAB autoreceptors. 254 42

Agents modifying GABAergic neurotransmission were administered to ovariectomized rats treated with different doses of estradiol benzoate (EB) + progesterone (P) or with EB alone. Hormone treatments were designed to induce an intermediate level of receptivity in order to be able to observe both stimulatory and inhibitory effects on lordosis behavior. Both the GABAA receptor agonist THIP and the GABAB receptor agonist baclofen inhibited lordosis behavior at doses from 20 and 5 mg/kg, respectively. The GABA transaminase inhibitor gamma-acetylen GABA (GAG) and the GABA agonist 3-aminopropanesulfonic acid had no effects, even when high doses were administered. The GABAA receptor antagonist bicuculline had no effect by itself nor did it block the effects of THIP. It is therefore suggested that the GABAA receptor is of slight importance in the control of lordosis behavior. No evidence could be found supporting the hypothesis that an interaction between P and GABA is important for hormone-induced receptivity. It does not appear likely that motor disturbances are responsible for the inhibitory effects of baclofen and THIP. The exact mechanism by which these drugs inhibit lordosis behavior is not clear at present.
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PMID:GABAergic drugs and lordosis behavior in the female rat. 255 11

We carried out the forced swimming test in mice to investigate the antidepressant potentials of GABA transaminase (GABA-T) inhibitors including aminooxyacetic acid, ethanolamine-O-sulfate, gamma-vinyl GABA (GVG) and valproic acid (VPA). In acute experiments only GVG reduced immobility. Following chronic oral administration via drinking water containing the drugs, immobility was significantly reduced at days 5 and 10 in all of the GABA-T inhibitors examined. The tolerance of the anti-immobility effect, however, occurred at day 20. Brain GABA contents showed moderate to marked increase during the session with the exception of VPA, which did not alter GABA contents. These results suggest that subchronic GABA-T inhibitors possess antidepressant properties, though the anti-immobility effect of GABA-T inhibitors did not directly correlate with the increase in brain GABA.
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PMID:Potential antidepressant properties of subchronic GABA transaminase inhibitors in the forced swimming test in mice. 255 61

The hypothetical modulation by GABAergic neurons of yawning behavior in the rat was explored with GABA-active drugs. Gamma-acetylenic-GABA, a specific inhibitor of GABA-T, increases yawning frequency when injected at a dose of 7 mg/kg. Baclofen, a GABAB agonist (3 mg/kg), inhibits yawning completely; GABA antagonists, bicuculline and picrotoxin, at subconvulsant doses, also decrease yawning. All drugs were injected intraperitoneally with the exception of apomorphine, which was injected subcutaneously. It is suggested that GABAB receptors play a role in yawning behavior by modulating ACh release, and that GABAA receptors may modify yawning frequency by modulating inhibitory influences on ACh neurons.
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PMID:GABAergic modulation of yawning behavior. 256 Feb 2

In astrocytes grown in primary cultures from cerebral cortex of neonatal rats, alpha 1-adrenoceptors regulate the active uptake of glutamate followed by an activation of glutamic oxaloacetate transaminase (GOT; EC 2.6.1.1.) and a slight activation of glutamine synthetase (GS; EC 6.3.1.2.) activity. The beta-adrenoceptors regulate the active uptake of GABA, and this is followed by an activation of gamma-aminobutyric acid alpha-ketoglutarate transaminase (GABA-T; EC 2.6.1.19.). The data suggest that astrocyte adrenoceptors may modulate neurotransmitter induced neuronal excitability.
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PMID:Regulation of glutamate and GABA transport by adrenoceptors in primary astroglial cell cultures. 256 1

The effects of specific D1 and D2 agonists and antagonists on GABA turnover in four brain structures have been studied. GABA turnover was estimated by measuring the accumulation of GABA after GABA-T inhibition with gabaculine. Stimulation of DA receptors by apomorphine, a mixed D1 and D2 agonist or by (+/-)2-(N-phenylethyl-N-propyl)amino-5-hydroxytetraline, a selective agonist of D2 receptors, dose-dependently reduced GABA turnover. Both agonists had no effect on GABA levels. S(-)sulpiride, a selective D2 antagonist, had no effect on either GABA levels or GABA turnover. However, sulpiride antagonized the reduction of GABA turnover produced by apomorphine or (+/-)2-(N-phenylethyl-N-propyl)amino-5-hydroxytetraline. By contrast, SKF 38393, a selective D1 agonist, did not appear to influence GABA-mediated inhibitory neurotransmission. SCH 23390, a D1 antagonist, which by itself had no effect on GABA levels and only slightly decreased GABA turnover, did not antagonize the effect of apomorphine. On the contrary, SCH 23390, slightly, but significantly increased the reduction in GABA turnover produced by apomorphine. Furthermore, idaxozan, an alpha 2-antagonist, antagonized the reduction of GABA turnover produced by the alpha 2-agonist clonidine, but did not prevent the effect of apomorphine on GABA turnover. Thus, the tonic inhibition exerted by DA on GABA-mediated neurotransmission seems to be mainly controlled by D2 receptors.
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PMID:[Interactions of GABAergic and catecholaminergic neurotransmissions. Effects of dopaminergic and noradrenergic agonists and antagonists on GABA turnover]. 257 14

The present study investigates whether clonazepam exerts its antimyoclonic action through a GABA independent mechanism. We have studied the antimyoclonic effect of clonazepam and compared it with that of aminooxyacetic acid (AOAA), a GABA transaminase inhibitor, against myoclonus induced by picrotoxin, a GABA receptor antagonist and allylglycine, a drug which inhibits synthesis and release of GABA. We have also investigated the effect of clonazepam against picrotoxin-induced myoclonus in rats pretreated with either AOAA or submyoclonic dose of allylgylycine. Clonazepam pretreatment inhibited both picrotoxin and allylglycine-induced myoelonus whereas AOAA was effective in inhibiting only picrotoxin-induced myoclonus. The protective effect of clonazepam against picrotoxin-induced myoclonus was potentiated by AOAA pretreatment. Moreover, clonazepam afforded protection against picrotoxin-induced myoclonus in rats pretreated with a submyoclonic GABA reducing dose of allylglycine. These findings indicate that a GABA independent mechanism may also be involved in the antimyoclonic action of clonazepam.
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PMID:The antimyoclonic action of clonazepam through a GABA--independent mechanism. 262 Sep 67

The role of GABAergic neurons in the differential sensitivity to ethanol between the AT (Alcohol Tolerant) and ANT (Alcohol Nontolerant) rat lines developed for low and high degree of motor impairment from ethanol, was studied by comparing the effect of ethanol (2 or 4 g/kg, IP) on GABA turnover in different regions of the brain in these rat lines. GABA turnover was estimated from the accumulation of GABA after inhibition of GABA aminotransferase with aminooxyacetic acid (AOAA, 50 mg/kg, IP) given 10 min after administration of ethanol. The rats were killed two hours after the AOAA treatment with focused microwaves. The concentrations of GABA, aspartate, glutamate, glutamine and taurine were analyzed with HPLC. The saline-treated ANT rats were found to have a higher concentration of GABA in the striatum and a higher rate of GABA accumulation in the cerebellum than the AT rats. Ethanol suppressed the accumulation of GABA in both lines, but the suppression was significantly greater in the AT rats than in the ANT rats. In specific regions, this line difference was significant in the cerebral cortex and cerebellum with the higher ethanol dose. No line differences were found in the brain or tail blood ethanol concentration. AOAA increased the concentration of glutamine, decreased that of aspartate and glutamate, and did not modify that of taurine. The AOAA-induced changes in the concentrations of these amino acids were, however, minor relative to those found in the concentrations of GABA. The results that GABAergic mechanisms are involved in the differential sensitivity to the motor-impairing effects of ethanol between the AT and ANT rats.
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PMID:GABA turnover in the brain of rat lines developed for differential ethanol-induced motor impairment. 262 44

GABA-T (4-aminobutyrate-2-ketoglutarate aminotransferase) has been found in human hair follicle. Kinetics experiments with hair follicle homogenate supported a ping-pong type of enzymatic mechanism. Extrapolated Km values were 1.02 mmol/l for GABA and 0.45 mmol/l for alpha-ketoglutarate. Hair follicle GABA-T activity was completely inhibited by preincubation of the samples with either 5 x 10(-8) mol/l aminooxyacetic acid or 5 x 10(-4) mol/l gamma-vinyl GABA. The radioenzymatic assay presented is both sensitive enough (only 10 hair follicles are needed for one assay) and economical, making it suitable for clinical practice. Hair follicle GABA-T activity determination could be useful in the study of GABA deficiency diseases (such as epilepsy), congenital GABA-T deficiencies or the control of GABA-T inhibitors treatment.
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PMID:4-aminobutyrate-2-ketoglutarate aminotransferase (GABA-T) in human hair follicle. 263 Nov 56

Because of the importance of the inactivation of GABA aminotransferase to the design of anticonvulsant agents, a seemingly wide variety of inactivators has been investigated; all of the compounds, however, are analogues of GABA, beta-alanine, or delta-aminovaleric acid, which are substrates for the enzyme. Relatively minor modifications in the inactivator structures result in major differences in inactivation mechanisms and enzyme adduct structures. Compounds that inactivate GABA aminotransferase by a Michael addition mechanism, leading to modification of an active-site residue are Class I inactivators. Those that proceed by an enamine mechanism and give ternary adducts are Class II inactivators. Class III inactivators modify only the PLP cofactor; if the inactivation involves aromatization of the inactivator, it is a Class IIIA inactivation, and if no aromatization is involved, then it is a Class IIIB inactivation. The last class of inactivators (Class IV) are not classified on the basis of the mechanism, but, rather, that they require the enzyme to be in the PMP form. There appears to be no trend in partition ratio values when comparing Class I with Class II inactivators. Class III inactivations alter only the cofactor, so it may be possible for these adducts to diffuse slowly out of the active site; reactivation of the apoenzyme would require additional PLP. These inactivators also inactivate a variety of other PLP-dependent enzymes. At this point there does not seem to be a therapeutic advantage of one class of inactivators over another, although the only current example of these inactivators to be useful clinically is gamma-vinyl GABA (vigabatrin), a Class I inactivator recently approved for the drug market in France and the U.K. There is a mechanistic significance, however, for one class over another. If labeling of an active-site amino acid residue is desired, then Class I inactivators should be selected; desire for attachment of the inactivator to both the protein and the cofactor or just to the cofactor would determine whether Class II or Class III inactivators would be chosen. The classification presented here should allow us to think about inactivator structures in terms of their mechanistic potential and, as a result of this, should afford us the opportunity to be able to make predictions regarding inactivation mechanisms for hypothetical new structural classes of inactivators. Since the different mechanistic pathways lead to different types of enzyme adducts, inactivator design may be driven by the class of adduct that is desired.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Design of potential anticonvulsant agents: mechanistic classification of GABA aminotransferase inactivators. 268 82


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