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)

Kainic acid-induced seizures cause a marked increase in the expression of glutamate decarboxylase 67 (GAD67) in granule cells of the dentate gyrus. To determine the possible modes of sequestration of newly formed gamma-aminobutyric acid (GABA), we used in situ hybridization and immunocytochemistry to investigate the expression of several proteins related to GABA in dentate granule cells of rats 4 h to 60 days after kainic acid-induced status epilepticus and in controls. GAD67 and GAD65 mRNA levels were increased by up to 300% and 800%, respectively, in the granule cell layer 6-24 h after kainate injection. Subsequently, increased GAD and GABA immunoreactivity was observed in the terminal field of mossy fibers and in presumed dendrites of granule cells. mRNA of both known plasma membrane GABA transporters (GAT-1 and GAT-3) was expressed in granule cells of control rats. GAT-1 mRNA levels increased (by 30%) 9 h after kainate injection but were reduced by about 25% at later intervals. GAT-3 mRNA was reduced (by 35-75%) in granule cells 4 h to 30 days after kainic acid injection. In contrast, no expression of the mRNA or immunoreactivity of the vesicular GABA transporter was detected in granule cells or in mossy fibers, respectively. GABA transaminase mRNA was only faintly expressed in granule cells, and its levels were reduced (by 60-65%) 12 h to 30 days after kainate treatment. The results indicate that GABA can be taken up and synthesized in granule cells. No evidence for the expression of the vesicular GABA transporter (VGAT) in granule cells was obtained. After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells. It is suggested that, during epileptic seizures, elevated intracellular GABA and sodium concentration could then result in nonvesicular release of GABA from granule cell dendrites. GABA could then act on GABA-A receptors, protecting granule cells from overexcitation.
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PMID:Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures. 1462 Aug 76

We have carried out a detailed examination of L-glutamine metabolism in rat islets in order to elucidate the paradoxical failure of L-glutamine to stimulate insulin secretion. L-Glutamine was converted by isolated islets into GABA (gamma-aminobutyric acid), L-aspartate and L-glutamate. Saturation of the intracellular concentrations of all of these amino acids occurred at approx. 10 mmol/l L-glutamine, and their half-maximal values were attained at progressively increasing concentrations of L-glutamine (0.3 mmol/l for GABA; 0.5 and 1.0 mmol/l for Asp and Glu respectively). GABA accumulation accounted for most of the 14CO2 produced at various L-[U-14C]glutamine concentrations. Potentiation by L-glutamine of L-leucine-induced insulin secretion in perifused islets was suppressed by malonic acid dimethyl ester, was accompanied by a significant decrease in islet GABA accumulation, and was not modified in the presence of GABA receptor antagonists [50 micromol/l saclofen or 10 micromol/l (+)-bicuculline]. L-Leucine activated islet glutamate dehydrogenase activity, but had no effect on either glutamate decarboxylase or GABA transaminase activity, in islet homogenates. We conclude that (i) L-glutamine is metabolized preferentially to GABA and L-aspartate, which accumulate in islets, thus preventing its complete oxidation in the Krebs cycle, which accounts for its failure to stimulate insulin secretion; (ii) potentiation by L-glutamine of L-leucine-induced insulin secretion involves increased metabolism of L-glutamate and GABA via the Krebs cycle (glutamate dehydrogenase activation) and the GABA shunt (2-oxoglutarate availability for GABA transaminase) respectively, and (iii) islet release of GABA does not seem to play an important role in the modulation of the islet secretory response to the combination of L-leucine and L-glutamine.
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PMID:Conversion into GABA (gamma-aminobutyric acid) may reduce the capacity of L-glutamine as an insulin secretagogue. 1476

Cellular GABA levels are determined by the dynamic balance between synthesis and catabolism and are regulated at the level of glutamate decarboxylase, precursor availability (e.g., glutamate and glutamine), and possibly GABA degradation. GABA levels rise and stabilize within hours in human cortex following orally administered vigabatrin, an irreversible inhibitor of GABA-T, suggesting potential product inhibition of GABA synthesis or enhanced GABA degradation through the non-inhibited GABA-T fraction. In this study time courses of the rise in cortical GABA were measured in anesthetized rats in vivo after vigabatrin treatment using localized (1)H magnetic resonance spectroscopy and the times to reach steady-state for a given dose were determined. Rates of GABA synthesis were estimated for the period of constant GABA level from the accumulation of [2-(13)C]GABA following a short intravenous infusion (20 min) of either [1,6-(13)C(2)]glucose or [2-(13)C]acetate. No evidence of product inhibition of glutamate decarboxylase by the increased GABA concentration or reduced synthesis from [1,6-(13)C(2)]glucose (control, 0.031+/-0.010; vigabatrin-treated, 0.037+/-0.004 micromol/g/min, P=0.30) or [2-(13)C]acetate (control, 0.078+/-0.010; vigabatrin-treated, 0.084+/-0.006 micromol/g/min, P=0.42) was found. Fractional changes in steady-state GABA levels and GABA-T activities 5-6 h after vigabatrin treatment were approximately equal. The lack of change in GABA synthesis (and GABA catabolic flux for constant GABA levels) suggests that GABA-T has a near-zero flux control coefficient in vivo-capable of greatly altering the steady-state GABA concentration but exerting little or no control on GABA synthesis or GABA/glutamine cycling flux. The findings are consistent with a Michaelis-Menten kinetic model whereby cellular GABA levels increase until flux through the remaining (uninhibited) transaminase equals the rate of GABA synthesis. The findings suggest that astroglia may be the site of continuing GABA catabolism after acute vigabatrin treatment.
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PMID:Acute regulation of steady-state GABA levels following GABA-transaminase inhibition in rat cerebral cortex. 1651 19

During germination the chestnut (Castanea sativa L.) var ecotype 33 accumulates a large amount of asparagine in the cotyledons. This compound also accumulates in the growing axis:shoots and roots. In the cotyledons, gamma-aminobutyrate (GABA) represents a major amino compound during germination and early seedling growth. In young seedlings, 35 days old, arginine predominates over the other soluble amino acids, particularly in roots. Five enzymic activities involved in arginine and GABA have been measured in the storage organ of the seed: arginase and ornithine carbamyltransferase decrease during germination indicating the slowing down of the urea cycle. In contrast, ornithine aminotransferase increases. Glutamate decarboxylase is particularly active about 21 days after imbibition and GABA aminotransferase activity decreases during germination. These two activities are in good agreement with the likely transport of GABA from cotyledons to growing axis. Asparagine, arginine, and GABA are the three amino compounds obviously involved in the mobilization of nitrogen reserves in the germinating chestnut seeds Castanea sativa.
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PMID:Amino Acids Content in Germinating Seeds and Seedlings from Castanea sativa L. 1666 82

GABA receptor activation in central nervous white matter may be protective during white matter hypoxia in the adult, and it may modify axonal conduction, especially in the developing brain. GABA uptake is important for the shaping of the GABA signal, but quantitative data are lacking for GABA uptake and GABA-metabolizing enzymes in central nervous white matter. We report that high-affinity uptake of GABA in adult pig corpus callosum, fimbria, subcortical pyramidal tracts, and occipital white matter is approximately 20% of that in temporal cortex gray matter. Tiagabine (0.1 microM), an antiepileptic drug that specifically inhibits the GAT-1 GABA transporter inhibited GABA uptake 50% in temporal cortex and 60-68% in white structures. This finding indicates that GAT-1 is an important GABA transporter in white matter and suggests that white matter GABA uptake is inhibited during tiagabine therapy. GABA transaminase activity in white structures was approximately 20% of neocortical values. Glutamate decarboxylase (GAD) activity in white structures was only 4% of that in neocortex (7-12 pmol/mg tissue x min(-1) versus approximately 200 pmol/mg tissue x min(-1)). Since white matter activity of citrate synthase of the tricarboxylic acid cycle was approximately 25% of neocortical values ( approximately 0.4 nmol/mg tissue x min(-1) versus approximately 1.5 nmol/mg tissue x min(-1)), the low GAD activity suggests a slower metabolic turnover of GABA in white than in gray matter.
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PMID:High-affinity GABA uptake and GABA-metabolizing enzymes in pig forebrain white matter: a quantitative study. 1706 32

Recent studies have suggested that the globus pallidus may be a particularly sensitive target of manganese (Mn), however, in vitro studies of the effects of Mn on GABAergic neurons have been restricted by the lack of a cell model expressing GABAergic properties. Here, we investigated the effects of low-level Mn treatment on cellular GABA and glutamate metabolism using the newly characterized AF5 rat neural-derived cell line, which displays GABAergic properties during culture in vitro. Intracellular GABA and glutamate levels were measured along with measurement of the release of GABA and glutamate into the culture medium, glutamine uptake from the culture medium, and the specific effects of Mn on the enzymes directly responsible for the synthesis and degradation of GABA, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T). Our results demonstrate that Mn had no effect on the activities of GAD or GABA-T. Similarly, low-level Mn treatment of AF5 cultures had only a small effect on intracellular GABA levels (114% of control) and no effect on the release of GABA. In contrast, intracellular and extracellular glutamate levels were enhanced to 170 and 198% of control during Mn treatment, respectively, while extracellular glutamine decreased to 73% of controls. Together, these results suggest that glutamate homeostasis may be preferentially affected over GABA in AF5 cells during low-level Mn treatment, suggesting a novel mechanism by which Mn-induced excitotoxicity might arise.
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PMID:Low-level manganese exposure alters glutamate metabolism in GABAergic AF5 cells. 1732 Jan 82

When subjected to low oxygen stress, plants accumulate alanine and gamma-aminobutyric acid (GABA). To investigate the function of GABA metabolism under hypoxia and its contribution to alanine accumulation, we studied the genes that encode the two key enzymes of the GABA shunt, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T). Among the five homologous GAD genes found in Arabidopsis thaliana, GAD1 expression was predominantly found in roots, while GAD2 expression was evident in all organs. Expression of the other three GAD genes was generally weak. In response to hypoxia, transcriptional induction was observed for GAD4 only. For GABA-T1, its expression was detected in all organs, but there was no significant transcriptional change under hypoxic conditions. Moreover, we have isolated and characterized Arabidopsis mutants defective in GAD1 and GABA-T1. In gad1 mutants, GAD activity was significantly reduced in roots but was not affected in shoots. In the gaba-t1 mutant, GABA-T activity was decreased to negligible levels in both shoots and roots. These mutants were phenotypically normal under normal growth conditions except for the reduced seed production of the pop2 mutants as described previously. However, metabolite analysis revealed significant changes in GABA content in gad1 and gaba-t1 mutants. The levels of alanine under hypoxic conditions were also affected in the roots of gad1 and gaba-t1 mutants. The partial inhibition of the hypoxia-induced alanine accumulation in roots of these mutants suggests that the GABA shunt is, in part, responsible for the alanine accumulation under hypoxia.
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PMID:Contribution of the GABA shunt to hypoxia-induced alanine accumulation in roots of Arabidopsis thaliana. 1807 64

A large amount of gamma-aminobutyric acid (GABA) was found to accumulate in tomato (Solanum lycopersicum) fruits before the breaker stage. Shortly thereafter, GABA was rapidly catabolized after the breaker stage. We screened the GABA-rich tomato cultivar 'DG03-9' which did not show rapid GABA catabolism after the breaker stage. Although GABA hyperaccumulation and rapid catabolism in fruits is well known, the mechanisms are not clearly understood. In order to clarify these mechanisms, we performed comparative studies of 'Micro-Tom' and 'DG03-9' fruits for the analysis of gene expression levels, protein levels and enzymatic activity levels of GABA biosynthesis- and catabolism-related enzymes. During GABA accumulation, we found positive correlations among GABA contents and expression levels of SlGAD2 and SlGAD3. Both of these genes encode glutamate decarboxylase (GAD) which is a key enzyme of GABA biosynthesis. During GABA catabolism, we found a strong correlation between GABA contents and enzyme activity of alpha-ketoglutarate-dependent GABA transaminase (GABA-TK). The contents of glutamate and aspartate, which are synthesized from GABA and glutamate, respectively, increased with elevation of GABA-TK enzymatic activity. GABA-TK is the major GABA transaminase form in animals and appears to be a minor form in plants. In 'DG03-9' fruits, GAD enzymatic activity was prolonged until the ripening stage, and GABA-TK activity was significantly low. Taken together, our results suggest that GAD and GABA-TK play crucial roles in GABA accumulation and catabolism, respectively, in tomato fruits.
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PMID:Biochemical mechanism on GABA accumulation during fruit development in tomato. 1871 63

The gamma-aminobutyrate (GABA) shunt, an alternative route for the conversion of alpha-ketoglutarate to succinate, involves the glutamate decarboxylase Gad1p, the GABA transaminase Uga1p and the succinate semialdehyde dehydrogenase Uga2p. This pathway has been extensively described in plants and animals, but its function in yeast remains unclear. We show that the flux through Gad1p is insignificant during fermentation in rich sugar-containing medium, excluding a role for this pathway in redox homeostasis under anaerobic conditions or sugar stress. However, we found that up to 4 g of exogenous GABA/liter was efficiently consumed by yeast. We studied the fate of this consumed GABA. Most was converted into succinate, with a reaction yield of 0.7 mol/mol. We also showed that a large proportion of GABA was stored within cells, indicating a possible role for this molecule in stress tolerance mechanisms or nitrogen storage. Furthermore, based on enzymatic and metabolic evidence, we identified an alternative route for GABA catabolism, involving the reduction of succinate-semialdehyde into gamma-hydroxybutyric acid and the polymerization of gamma-hydroxybutyric acid to form poly-(3-hydroxybutyric acid-co-4-hydroxybutyric acid). This study provides the first demonstration of a native route for the formation of this polymer in yeast. Our findings shed new light on the GABA pathway and open up new opportunities for industrial applications.
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PMID:New insights into {gamma}-aminobutyric acid catabolism: Evidence for {gamma}-hydroxybutyric acid and polyhydroxybutyrate synthesis in Saccharomyces cerevisiae. 1941 12

A new quinoline derivative, QUAN-0806 (7-hexyloxy-5-phenyl-1,2,4-triazolo[4,3-alpha]quinoline) was tested for anticonvulsant activity using the maximal electroshock seizure (MES) and the rotarod neurotoxicity (Tox) tests in mice. The MES test showed that QUAN-0806 exhibited higher activity (ED50 = 6.5 mg/kg) and lower toxicity (TD50 = 228.2 mg/kg), resulting in a higher protective index (PI = 35.1) than the reference drugs phenytoin, carbamazepin, phenobarbital, and valproate. In addition, QUAN-0806 was found to exhibit significant oral activity against MES-induced seizures with low oral neurotoxicity in mice. QUAN-0806 was tested in chemically induced models (pentylenetetrazole, PTZ; isoniazid, ISO; 3-mercaptopropionic acid, 3-MPA; and strychnine, STRYC) to further investigate the anticonvulsant activity. QUAN-0806 produced significant antagonistic activity against seizures induced by PTZ, 3-MPA, and ISO, suggesting that QUAN-0806 influences GABAergic neurotransmission by activating glutamate decarboxylase (GAD) or inhibiting (GABA)-a-oxoglutarate aminotransferase (GABA-T) in the brain.
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PMID:Evaluation of anticonvulsant activity of QUAN-0806 in various murine experimental seizure models. 1943 43


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