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

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

The homospecific activity of GABA-transaminase (EC 2.6.1.19; GABA-T) in brain or neurons was determined as a function of development in vivo or in culture by measuring the enzyme activity together with the relative amount of GABA-T apoenzyme by the aid of a monospecific anti-GABA-T antibody. It was observed that both in cerebral cortex and cerebellum in vivo and in neurons cultured from these brain regions the homospecific activity of GABA-T changed during development. By incubation of tissue extracts with similar extracts in which GABA-T activity had been selectively and irreversibly destroyed with gamma-vinyl GABA (Vigabatrin) it was established that this change in homospecific activity was at least partly due to the presence of an endogenous activator of GABA-T. The results point towards a rather complex endogenous regulation of GABA-T during development in vivo and in vitro.
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PMID:Development of homospecific activity of GABA-transaminase in the mouse cerebral cortex and cerebellum and in neurons cultured from these brain areas. 271 65

1. The interactions of three GABAergic compounds, gamma-acetylenic GABA, gamma-vinyl GABA and ethylenediamine with the analgesic effects of morphine and pentazocine were examined in mice using the hot plate and tail immersion tests. 2. A significant increase in reaction time induced by morphine was noted in the tail immersion test after pretreatment with the drugs acting through GABA functions. 3. The inhibitors of GABA transaminase, gamma-acetylenic GABA and gamma-vinyl GABA, and the GABAmimetic ethylenediamine did not significantly change the analgesic action induced by pentazocine. 4. In the hot plate test the three GABAergic compounds antagonized the analgesic effects of pentazocine in contraposition with previous results indicating that morphine-induced analgesia is increased by pretreatment with those agents. 5. These findings suggest that GABAergic and opiopeptidergic systems are interconnected through mu receptors, whereas the kappa opiate systems seem to be unrelated to GABA functions.
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PMID:A comparison of GABAergic influences on the analgesic responses to morphine and pentazocine. 271 13

The effects of three drugs, namely gamma-vinyl GABA (vigabatrin), gamma-acetylenic GABA, and aminooxyacetic acid, which increase brain GABA concentrations by irreversible inhibition of GABA degradation, were studied in amygdala-kindled rats. Vigabatrin 800 or 1,200 mg/kg i.p. 4 h after its administration, caused prolongation of behavioural seizures and electrographic afterdischarges recorded from the stimulated amygdala. One to three days after administration it dose dependently reduced seizure severity, seizure duration and afterdischarge duration in most animals. Determination of GABA levels in synaptosomes isolated from 12 brain regions of kindled rats 4 or 48 h after injection of 1,200 mg/kg vigabatrin indicated that the variable effects of this drug at different times after its administration could be related to differences in the time course of nerve terminal GABA increases in selective brain regions such as amygdala and corpus striatum. In contrast to vigabatrin, gamma-acetylenic GABA, 100 mg/kg i.p., reduced seizure severity in kindled rats as early as 4 h after its administration but afterdischarge duration increased significantly on subsequent days. Similar late increases in afterdischarge duration (and limbic seizure activity) after the time of maximum anticonvulsant effect had elapsed were also observed with vigabatrin, which could suggest that the anticonvulsant effect of such drugs is followed by withdrawal hyperexcitability. Aminooxyacetic acid, 20 mg/kg i.p., exerted no significant anticonvulsant effect in kindled rats but prolonged afterdischarge duration in several of the animals studied. The data suggest that GABA-T inhibitors, such as vigabatrin, differ from most antiepileptic drugs previously tested in the kindling model in that they may produce both anticonvulsant and proconvulsant effects at the same dose in the same animal as a function of time after administration.
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PMID:Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model. 274 84

This study better defines the way in which the thalamus controls expression of experimental generalized seizures. The effects of small intrathalamic injections of the direct GABA agonist muscimol on the thresholds of pentylenetetrazol (PTZ)-induced seizures and on spontaneous behavior were determined in the rat and compared with the effects of injections of gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase. Muscimol injections produced neuronal inhibition in a relatively small area of thalamus, whereas GVG injections produced inhibition in a much larger area. Muscimol injections in the midline thalamus in the vicinity of the paraventricular, paratenial, interanteromedial, intermediodorsal, and central medial nuclei facilitated PTZ myoclonic and clonic seizures and also produced sedation. These effects on seizure thresholds were attributable both to a lower PTZ threshold dose for initiation of electroencephalographic (EEG) seizure activity and to an increased probability of this EEG activity being expressed as behavioral seizures. Midline injections located more posteriorly in the thalamus also inhibited tonic seizures. Muscimol injections placed laterally, dorsally, or ventrally to this midline thalamic region had much less effect on behavior or seizures. In contrast, GVG injections in the anterior medial thalamus elevated the threshold for all PTZ seizure types and for associated EEG seizure activity but had little effect on spontaneous behavior. These findings demonstrate the existence of an important seizure regulatory system in the midline of the thalamus and a direct anatomic link between the mechanisms for regulating arousal and seizure production which may help explain the association between sleep and seizure facilitation in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a median thalamic system regulating seizures and arousal. 275 1

By using a radioreceptor assay GABA was detectable in rat interscapular brown adipose tissue (IBAT), the levels being 1% those of CNS and 10-fold those of peripheral plasma. Injection of the glutamic acid decarboxylase (GAD) inhibitor 3-mercaptopropionic acid lowered IBAT GABA levels by about half while injection of the GABA transaminase inhibitor gamma-acetylenic GABA increased them by 230%. Rats kept at 4 degrees C for 14 days exhibited IBAT GABA levels that were about half those found at 22 degrees C. Accumulation of IBAT GABA after gamma-acetylenic GABA increased by 2-fold in cold-exposed rats. Sympathetic denervation of IBAT prevented the effect of the cold environment on GABA content and impaired that on GABA accumulation. GAD activity was detectable in IBAT homogenates and isolated brown adipocytes. Exposure of rats to cold increased Vmax of GAD without modifying its Km, regardless of intactness of innervation. In binding studies with 3H-GABA as a ligand, two types of sites were uncovered of KD = 14 and 146 nM, respectively. In the presence of 2.5 mM Ca2+ bicuculline and baclofen were 57 and 46% as effective as GABA to displace 3H-GABA from IBAT binding sites. The results indicate existence, possible synthesis and type A and B receptors of GABA in rat IBAT.
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PMID:GABA and its neural regulation in rat brown adipose tissue. 275 28


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