Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.19 (GABA transaminase)
808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An isocratic high-performance liquid chromatographic technique was developed to measure levels of gamma-aminobutyric acid (GABA), glutamate, and taurine in the brain and pituitary of goldfish. Accuracy of this procedure for quantification of these compounds was established by evaluating anesthetic and postmortem effects and by selectively manipulating GABA concentrations by intraperitoneal administration of the glutamic acid decarboxylase (GAD) inhibitor 3-mercaptopropionic acid or the GABA transaminase inhibitor gamma-vinyl GABA. The technique provided a simple, rapid, and reliable method for evaluating the concentrations of these amino acids without the use of complex gradient chromatographic systems. To investigate the relationship between neurotransmitter amino acids and the control of pituitary secretion of gonadotropin, the effects of injection of taurine, GABA, or monosodium glutamate on GABA, glutamate, taurine, and, in some instances, monoamine concentrations in the brain and pituitary were evaluated and related to serum gonadotropin levels. Injection of taurine caused an elevation in serum gonadotropin concentrations. In addition, injection of the taurine precursor hypotaurine but not the taurine catabolite isethionic acid elevated serum gonadotropin levels. Intracerebroventricular injection of either GABA or taurine also elevated serum gonadotropin concentrations. Pretreatment of recrudescent fish with alpha-methyl-p-tyrosine reduced pituitary dopamine concentrations and also potentiated the serum gonadotropin response to taurine. Injection of monosodium glutamate caused an increase of glutamate content in the pituitary at 24 h; this was followed by a decrease at 72 h after administration. Pituitary GABA, taurine, and dopamine concentrations underwent a transient depletion after monosodium glutamate administration, and this was associated with an elevation of serum gonadotropin content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amino acid neurotransmitters and dopamine in brain and pituitary of the goldfish: involvement in the regulation of gonadotropin secretion. 134 46

The effects of fengabine (a novel benzylidene derivative possessing clinically demonstrated antidepressant action) on neurochemical parameters related to norepinephrine, serotonin and gamma-aminobutyric acid (GABA) neurons have been investigated in the rat and mouse brain. When given acutely, fengabine (50-1000 mg/kg i.p.) does not alter norepinephrine uptake but accelerates the turnover rate of norepinephrine in the rat brain as demonstrated by the enhancement of: the alpha-methyl-p-tyrosine-induced disappearance of norepinephrine in the hypothalamus; 3,4-dihydroxyphenylacetic acid levels in noradrenergic cell body areas; the pargyline-induced accumulation of normetanephrine in the hypothalamus; and 3,4-dihydroxyphenylethyleneglycol levels in the hypothalamus, septum and spinal cord. No tolerance to the effect of fengabine on the latter biochemical parameter was observed after repeated treatment for 2 weeks at doses of 100 or 200 mg/kg i.p., b.i.d. Fengabine (100 or 200 mg/kg i.p., b.i.d.), given for 14 days, causes a desensitization of isoprenaline-stimulated adenylate cyclase in septal and cortical slices of the rat but fails to modify cortical beta, alpha-1 or alpha-2 adrenoceptor binding sites. Fengabine (up to 400 mg/kg i.p.) has no effect on rat cerebral serotonin uptake, synthesis or metabolism. Moreover, when given subacutely (100 or 200 mg/kg i.p., b.i.d. for 2 weeks), it fails to alter rat cortical serotonine receptors or [3H]imipramine binding sites. Fengabine (up to 50-100 microM) is also inactive in vitro on [3H] GABA binding to GABAA or GABAB receptors in the rat brain or on GABA transaminase activity in the mouse brain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fengabine, a novel antidepressant GABAergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABAergic transmission in the rat. 303 4

Tryptophan hydroxylase (TPH) activity was measured in various rat brain regions after administering large doses of methamphetamine (METH). After four sequential doses of METH (15 mg/kg), given every 6 hr, TPH activity was decreased (to approximately 10% of control) in both the neostriatum and hippocampus. The depression of enzyme activity persisted for at least 30 days. When compared with the depression of neostriatal tyrosine hydroxylase activity, the depression of neostriatal and hippocampal TPH activity occurred sooner and was more pronounced. The depression of TPH activity was dependent on the number of doses and the amount of drug administered. Five days after one to two doses of METH, a transient recovery was observed but when four doses were given, the enzyme was depressed. No decrease in TPH activity was observed in brain areas containing serotonergic cell bodies. Agents which prevent the METH-induced decrease of neostriatal tyrosine hydroxylase activity, i.e., haloperidol, alpha-methyl-p-tyrosine and gamma-aminobutyric acid transaminase inhibitors also prevented the decrease in TPH activity caused by METH. In addition, fluoxetine, an inhibitor of 5-hydroxytryptamine re-uptake, prevented the METH-induced decrease in neostriatal and hippocampal TPH activity but did not alter the decrease in nenostriatal tyrosine hydroxylase activity.
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PMID:Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. 610 22

A single high oral dose of 1,3-bis(tetrahydro-2-furanyl)-5-fluoro-2, 4-pyrimidinedione (FD-1) (486.0-729.0 mg/kg) followed by daily administration of lower doses of FD-1 (121.5 mg/kg) for 2-4 weeks increased the concentration of striatal dopamine (DA) in rats. The decrease in striatal DA following an injection of alpha-methyl-p-tyrosine methyl ester (alpha-MT) was lessened by a dose of FD-1 (364.8 mg/kg, p.o.) given immediately before the alpha-MT. This may indicate a decrease in striatal DA utilization by FD-1. The increase in striatal DA after FD-1 was inhibited by two antagonists of gamma-aminobutyric acid (GABA) which act on postsynaptic receptors: bicuculline (0.5-2.0 mg/kg, i.p.) and picrotoxin (2.0 mg/kg, i.p.). The increase of DA induced by the GABA transaminase inhibitor aminooxyacetic acid (AOAA) was enhanced by FD-1. These results suggest that the action of FD-1 is mediated by GABA. FD-1 probably causes inhibition of DA release from nerve terminals resulting in an accumulation of DA in the corpus striatum.
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PMID:Effects of 1,3-bis(tetrahydro-2-furanyl)-5-fluoro-2,4-pyrimidinedione (FD 1) on the central nervous system: (2) Effects on nigro-striatal dopaminergic neurons. 611 4

Bilateral ablation of the olfactory bulbs caused marked changes in the 'turnover' of several neurotransmitters in the amygdaloid cortex and the mid-brain areas of the rat brain. Following tyrosine and tryptophan hydroxylase inhibition, the decrease in the concentration of noradrenaline and serotonin respectively in the amygdaloid cortex was not so marked in the bulbectomized rats as in their controls. This suggests that the 'turnover' of these biogenic amines is reduced following bulbectomy. Following GABA transaminase inhibition, the increase in the concentration of GABA in this region was increased compared to the controls thereby suggesting that the 'turnover' of the inhibitory neurotransmitter was enhanced, glutamate decarboxylase activity was also increased in the amygdaloid cortex. No changes were found in the 'turnover' of noradrenaline or serotonin in the mid-brain but that of dopamine was decreased as was the activity of glutamate decarboxylase. It is concluded that changes in neurotransmitter 'turnover' in these brain regions are attributable to the destruction of the olfactory bulbs and may contribute to the behavioural deficits which we, and others, have reported elsewhere.
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PMID:Changes in neurotransmitter metabolism following olfactory bulbectomy in the rat. 620 59

Behavioural effects following bilateral intranigral administration of GABA antagonists have been investigated. Bicuculline methiodide (BMI), picrotoxin and isopropylbicyclophosphate all induced biting behaviour, teeth-chattering and chewing. Sub-threshold doses for biting induced locomotor activity and sniffing. The strongest response was observed after injection into the caudal pars reticulata, whereas weaker effects were seen after injection into the rostral pars reticulata or the pars compacta. The biting induced by intranigral BMI was not antagonized by prior catecholamine depletion with reserpine plus alpha-methyl-p-tyrosine or by dopamine receptor blockade with haloperido. Concomitant intranigral injection of the GABA agonists muscimol and THIP, however, completely antagonized biting. Systemic GABAergic drugs also antagonized the BMI-induced biting: the benzodiazepine, diazepam and the GABA transaminase inhibitor, gamma-acetylenic GABE, were most effective, whereas muscimol was only partially effective and THIP was without effect. It is suggested that this animal model may be used for the evaluation of antidyskinetic drugs.
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PMID:Intranigral GABA antagonists produce dopamine-independent biting in rats. 718 66

When gamma-aminobutyric acid aminotransferase (GABA-T) activity was measured in vitro in rat brain, neither isoniazid (INH) nor for of its known metabolites (isonicotinic acid, acetylisoniazid, acetylhydrazine, diacetylhydrazine) inhibited the enzyme in concentrations (5 mM) far higher than those likely to be achieved when INH is administered to man. In contrast, hydrazine (5 micrometers) caused a 50% inhibition of GABA-T without inhibiting glutamic acid decarboxylase (GAD). Rats were injected daily for 109 days with hydrazine (0.08 or 0.16 mmol/kg/day), after which amino acid contents and enzyme activities were measured in their brains. Both hydrazine doses caused significant elevations of whole brain GABA content and reductions of GABA-T activity, but did not affect GAD activity. Chronic administration of hydrazine at these doses did not reduce weight gain or alter rat behavior, nor did it produce any irreversible pathologic changes in liver or alterations in hepatic aryl hydrocarbon hydroxylase activity. However, hydrazine treatment caused changes in the contents of many brain amino acids besides GABA, and markedly increased concentrations of ornithine, tyrosine, and alpha-aminoadipic acid in rat plasma. Inhibition of GABA-T activity and the other biochemical alterations observed in patients given high doses of INH probably result from hydrazine formed in the metabolic degradation of INH. Thus administration of hydrazine might be a more direct means of elevating brain GABA content in patients where this seems indicated, and might not entail a greater risk of adverse effects.
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PMID:Elevation of brain GABA content by chronic low-dosage administration of hydrazine, a metabolite of isoniazid. 725 11

It is known that norepinephrine (NE) is important in the neuroendocrine control of pituitary gonadotropin II (GTH-II) and growth hormone (GH) release but very little is known about the factors regulating NE neurons in the goldfish brain. Female gonad-intact goldfish were implanted intraperitoneally (100 micrograms/g) with testosterone (T) or estradiol (E2) to elevate serum steroid levels. High-performance liquid chromatography measurements showed that steroid implantation had no effect on NE content in the telencephalon, including preoptic area (TEL-POA), or the hypothalamus (HYP). The turnover rate of NE was estimated from the rate of depletion of NE content from tissues following inhibition of tyrosine hydroxylase by alpha-methyl-p-tyrosine (240 micrograms/g). The present study demonstrates that E2 can decrease NE turnover rates in TEL-POA and HYP of sexually regressed goldfish (August). The results in recrudescent fish (November), however, indicate a more complex interaction of E2 with NE neurons since E2 increased NE turnover in TEL-POA and HYP in these animals. Testosterone (T) has less prominent effects on NE turnover rates in TEL-POA and HYP; the only significant effect of T-implantation was a small reduction of NE turnover in the TEL-POA of sexually recrudescent fish. Elevation of endogenous brain GABA concentrations by injection of the GABA transaminase inhibitor, gamma-vinyl-GABA (300 micrograms/g), significantly reduced NE turnover in TEL-POA. These data demonstrate that goldfish NE neurons in the TEL-POA are sensitive to regulation by changes in circulating sex steroids and by increases in brain GABA.
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PMID:Norepinephrine turnover in the goldfish brain is modulated by sex steroids and GABA. 825 2

It is established that dopamine inhibits while GABA stimulates LH release in goldfish. In this study, we examine dopaminergic regulation of GABAergic activity in the hypothalamus of early recrudescent female goldfish (Carassius auratus). We utilize a unique technique that permits concomitant quantification and correlation of in vivo GAD65 and GAD67 mRNA with GABA synthesis rate in response to decreased dopamine levels. Catecholamine depletion was achieved by treatment with alpha-methyl-para-tyrosine methyl ester (alphaMPT; 240 microg/g body weight), an inhibitor of tyrosine hydroxylase. Endogenous GABA levels were increased by intraperitoneal administration of gamma-vinyl GABA (GVG; 300 microg/g body weight), an inhibitor of the GABA catabolic enzyme GABA transaminase. Dual treatment of GVG+alphaMPT increased serum LH levels 4-fold. However, LH mRNA levels in the pituitary remained stable, suggesting that treatments affected secretion and not synthesis. In the hypothalamus, GABA synthesis rates increased 30% in response to alphaMPT treatment. This was correlated (r=0.61; p<0.05) to increased levels of GAD67 mRNAs but not GAD65 (r=0.14; p>0.05). These observations suggest that catecholamines inhibit GABA synthesis in the goldfish hypothalamus through isoform specific regulation of GAD67.
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PMID:Catecholamine depletion modulates serum LH levels, GAD67 mRNA, and GABA synthesis in the goldfish. 1563 45

Ornithine aminotransferase and 4-aminobutyrate aminotransferase are related pyridoxal phosphate-dependent enzymes having different substrate specificities. The atomic structures of these enzymes have shown (i) that active site differences are limited to the steric positions occupied by two tyrosine residues in ornithine aminotransferase and (ii) that, uniquely among related, structurally characterized aminotransferases, the conserved arginine that binds the alpha-carboxylate of alpha-amino acids interacts tightly with a glutamate residue. To determine the contribution of these residues to the specificities of the enzymes, we analyzed site-directed mutants of ornithine aminotransferase by rapid reaction kinetics, x-ray crystallography, and 13C NMR spectroscopy. Mutation of one tyrosine (Tyr-85) to isoleucine, as found in aminobutyrate aminotransferase, decreased the rate of the reaction of the enzyme with ornithine 1000-fold and increased that with 4-aminobutyrate 16-fold, indicating that Tyr-85 is a major determinant of specificity toward ornithine. Unexpectedly, the limiting rate of the second half of the reaction, conversion of ketoglutarate to glutamate, was greatly increased, although the kinetics of the reverse reaction were unaffected. A mutant in which the glutamate (Glu-235) that interacts with the conserved arginine was replaced by alanine retained its regiospecificity for the delta-amino group of ornithine, but the glutamate reaction was enhanced 650-fold, whereas only a 5-fold enhancement of the ketoglutarate reaction rate resulted. A model is proposed in which conversion of the enzyme to its pyridoxamine phosphate form disrupts the internal glutamate-arginine interaction, thus enabling ketoglutarate but not glutamate to be a good substrate.
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PMID:Determinants of substrate specificity in omega-aminotransferases. 1609 75


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