Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.19 (GABA transaminase)
 808 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The uptake of the inhibitory transmitter substance gamma-aminobutyric acid (GABA) into the adult rat pineal gland was studied autoradiographically using both light and electron microscopy. The sites of GABA uptake were shown to be exclusively present in the gliocyte cells of the gland following both in vitro incubation with tritiated GABA and after in vivo administration of the amino acid by intra-arterial injection. Both the pinealocyte cells and the numerous sympathetic axons in the gland were devoid of silver grains. Preliminary biochemical studies indicated that the gliocyte uptake process for GABA resembles that in the satellite glia of the sensory ganglia but differed from that in slices of the cerebral cortex. Evidence is also presented which shows the pineal gland to contain endogenous GABA and the enzymes directly associated with its in vivo metabolism, L-glutamate-1-carboxylase (EC 4.1.1.15) (GAD) and GABA-2-oxoglutarate aminotransferase (EC 2.6.1.19) (GABA-T). Furthermore, a 3-fold rise in endogenous GABA occurred in the pineal after inhibition of GABA-catabolism as would be expected if the GABA-shunt pathway was functionally active in the oxidative metabolism of the pineal gland.
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PMID:On GABA metabolism in the gliocyte cells of the rat pineal gland. 23 81

In the belief that homocysteine-induced convulsions might be related to alterations in brain gamma-aminobutyric acid metabolism, we have studied the action of this amino acid on the activity of glutamic decarboxylase (GAD, EC 4.1.1.15) and gamma-aminobutyrate aminotransferase (EC 2.6.1.19) of mouse brain in vitro DL-homocysteine competitively inhibited GAD with respect to both L-glutamate and pyridoxal 5'-phosphate. The respective Ki's were 3.8 mM and 0.3 mM. The activity of GABA-T also was altered in the presence of DL-homocysteine. A competitive inhibition (Ki = 6 mM) was observed with gamma-aminobutyric acid, and an uncompetitive inhibition with respect to pyridoxal 5'-phosphate and alpha-ketoglutarate. These results are explained in terms of a dual action of homocysteine on each of the enzymes: one involving a competition for substrate binding site and the other involving the formation of an inactive inhibitor-cofactor complex. The significance of the inhibition of these enzymes of gamma-aminobutyric acid metabolism is discussed in relation to the convulsant action of homocysteine.
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PMID:The mode of action of homocysteine on mouse brain glutamic decarboxylase and gamma-aminobutyrate aminotransferase. 90 1

The regional distribution of 9 amino acids, including glutamate and GABA and their metabolising enzymes, has been determined in 5 regions of the frog CNS. Glycine was relatively concentrated in the spinal cord whereas the highest concentration of each of the other amino acids was found in the midbrain. There was a good correlation between the activity of l-glutamate-1-carboxylase (GAD) and the level of GABA in all regions examined and both were concentrated in the midbrain. There was little regional variation in the distribution of 4-aminobutyrate-2-oxoglutarate transaminase (GABA-T).
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PMID:Glutamic acid, GABA and their metabolising enzymes in the frog central nervous system. 107 86

C57BL/10Bg sps/sps mice display behavioral arrest, similar to generalized absence seizures. Compared with the parent strain C57BL/10Bg SPS/SPS, the activities of glutamate decarboxylase (GAD, E. C. 2.6.1.15), GABA aminotransferase (GABA-T, E. C. 2.6.1.19), aspartate aminotransferase (ASP-T, E. C. 2.6.1.1), and glutamate dehydrogenase (GDH, E. C. 1.4.1.3) in whole brain crude supernatant were significantly reduced in the sps/sps mice. Alanine aminotransferase activity (ALA-T, E. C. 2.6.1.2), was not altered in any of the strains, and normalization of GAD, GABA-T and GDH activities by that of ALA-T, further revealed significant differences between the normal strain (SPS/SPS), the heterozygotes (SPS/sps), and behavioral arrest (sps/sps) mice. These results suggest the possible involvement of GABAergic and glutamatergic neurotransmission in the absence-like behavior displayed by sps/sps mice. Open field behavior of C57BL/10Bg sps/sps mice is characterized by periods of marked inactivity which easily distinguish affected homozygotes, from their heterozygotes littermates.
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PMID:The C57BL/10Bg sps/sps mouse: a mutant with absence-like seizures; neurochemical and behavioral correlates. 239 34

The technique of estimating gamma-aminobutyric acid (GABA) turnover by inhibiting its major degrading enzyme GABA-T (4-aminobutyrate:2-oxoglutarate aminotransferase; EC 2.6.1.19) and measuring GABA accumulation has been used repeatedly, but, at least in rats, its usefulness has been limited by several difficulties, including marked differences in the degree of GABA-T inhibition in different brain regions after systemic injection of GABA-T inhibitors. In an attempt to improve this type of approach for measuring GABA turnover, the time course of GABA-T inhibition and accumulation of GABA in 12 regions of rat brain has been studied after systemic administration of aminooxyacetic acid (AOAA), injected at various doses and with different routes of administration. A total and rapidly occurring inhibition of GABA-T in all regions was obtained with intraperitoneal injection of 100 mg/kg AOAA, whereas after lower doses, marked regional differences in the degree of GABA-T inhibition were found, thus leading to underestimation of GABA synthesis rates, e.g., in substantia nigra. The activity of the GABA-synthesizing enzyme GAD (L-glutamate-1-decarboxylase; EC 4.1.1.15) was not reduced significantly at any time after intraperitoneal injection of AOAA, except for a small decrease in olfactory bulbs. Even the highest dose of AOAA tested (100 mg/kg) was not associated with toxicity in rats, but induced motor impairment, which was obviously related to the marked GABA accumulation found with this dose. The increase in GABA concentrations induced with intraperitoneal injection of 100 mg/kg AOAA was rapid in onset, allowing one to estimate GABA turnover rates from the initial rate of GABA accumulation, i.e., during the first 30 min after AOAA injection. GABA turnover rates thus determined were correlated in a highly significant fashion with the GAD activities determined in brain regions, with highest turnover rates measured in substantia nigra, hypothalamus, olfactory bulb, and tectum. Pretreatment of rats with diazepam, 5 mg/kg i.p., 5-30 min prior to AOAA, reduced the AOAA-induced GABA accumulation in all 12 regions examined, most probably as a result of potentiation of postsynaptic GABA function. The data indicate that AOAA is a valuable tool for regional GABA turnover studies in rats, provided the GABA-T inhibitor is administered in sufficiently high doses to obtain complete inhibition of GABA degradation.
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PMID:Use of inhibitors of gamma-aminobutyric acid (GABA) transaminase for the estimation of GABA turnover in various brain regions of rats: a reevaluation of aminooxyacetic acid. 280 89

Acute exposure of adult male albino rats (110-120 g) to higher environmental temperature (40 +/- 1 degrees C) increased body temperature (BT). This increase of BT was also dependent on the duration of exposure. Treatment with muscimol (1 mg/kg, i.p.), a GABA agonist, produced hypothermia at room temperature (28 +/- 1 degree C) and resistance to increase the body temperature when exposed to higher temperature (40 +/- 1 degree C). Administration of bicuculline (1 mg/kg, i.p.), a GABA antagonist, on the other hand, enhanced BT more than that observed in control (normal) rat exposed to higher temperature (40 +/- 1 degree C), although at room temperature bicuculline treatment did not show any effect on BT. Pretreatment with ethanolamine-O-sulfate (EOS) (2 g/kg, s.c.), a GABA transaminase inhibitor, to rats exposed to higher temperature increased BT as in control (normal) rat. Inhibition of central GAD activity with mercaptopropionic acid (MPA) (70 mg/kg, i.p.) produced resistance to increase BT during its period of action when rats were exposed to higher environmental temperature (28 +/- 1 degree C). These results thus suggest that central inhibitory neuron, GABA, plays a regulatory role in thermoregulation.
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PMID:Involvement of GABA in environmental temperature-induced change in body temperature. 323 43

Uptake, synthesis, storage, and release of gamma-aminobutyric acid (GABA) are some of the characteristic properties of GABA-ergic neurons. In the present study, we have used these properties as physiological probes to follow the emergence and maturation of GABA-ergic neurons during postnatal development of the rabbit retina. There is autoradiographic, immunocytochemical, and pharmacological evidence that some amacrine cells and certain neurons in the ganglion cell layer probably use GABA as the neurotransmitter. These neurons take up GABA, contain the GABA-synthesizing enzyme L-glutamic acid decarboxylase (GAD, EC 4.1.1.15), and release the accumulated GABA by a CA++-dependent mechanism when depolorized with high extracellular K+ concentration. In this study, we show that certain neurons in the newborn retina already possess a specific mechanism for GABA uptake. The positions and numbers of these cells in the developing retina suggest that they will become GABA-ergic neurons in the adult retina. These putative GABA-ergic neurons are, however, probably immature at birth because newborn retinas contain only low levels of GABA and GAD. Additionally, there is relatively little K+-stimulated, Ca++-dependent release of (3H)-GABA from the newborn retinas. GABA concentrations and GAD activities in developing retinas increase steadily postnatally, reaching about 80% of the adult levels by day 9. The activities of the GABA-degrading enzyme, GABA-glutamate transaminase (GABA-T, EC 2.6.1.19), follow a similar pattern of maturation during retinal development. K+ stimulated GABA release, however, remains low until about day 6, and then increases dramatically from 20% to 85% of the adult level over the next 3 days. Taken together, our results indicate that in the rabbit retina, the commitment by certain neurons to use GABA as the transmitter is made prenatally. These neurons are immature at birth but are biochemically, physiologically, and probably functionally mature by about 9 days after birth.
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PMID:Postnatal development of GABA-ergic neurons in the rabbit retina. 625 33

Alteration of metabolism of taurine in prolonged light- and dark-adapted frog retinae were studied in comparison with that of gamma-aminobutyric acid (GABA) and the following results were obtained. (1) Statistically significant alterations in retinal taurine, an increase in dark-adapted, and a decrease in light-adapted states, respectively, occurred when frogs were adapted continuously to light or dark for more than 3 weeks. Under the same experimental conditions, no alteration in retinal GABA was noted. (2) At 3 weeks and thereafter, a significant increase of retinal cysteine sulfinic acid decarboxylase (CSD; EC 4.1.1.12) activity, an enzyme involved in the biosynthetic pathway of taurine, also occurred in the dark, whereas the activity in the light-adapted retina was reduced. On the other hand, the retinal activity of L-glutamate decarboxylase (GAD; EC 1.1.1.15), the rate-limiting enzyme of GABA biosynthesis, was not altered in dark- as well as light-adapted state. Similarly, retinal GABA-transaminase (GABA-T; EC 2.6.1.19)-succinic semialdehyde dehydrogenase (SSADH; EC 1.2.1.16) was unaltered. (3) These alterations in retinal taurine were, however, unaccompanied by any changes in factors related to transmitter actions such as evoked release, high affinity uptake, and specific binding to synaptic membranes. The above results suggest that, different from GABA as a potent candidate for inhibitory neurotransmitter, retinal taurine may act as neuromodulator and/or may play an important role as a basic factor for maintaining cellular integrity under certain pathophysiological conditions.
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PMID:Alteration of metabolism of retinal taurine following prolonged light and dark adaptation: a quantitative comparison with gamma-aminobutyric acid (GABA). 697 81

The accumulation of GABA in the cerebellum and medulla oblongata-pons of rats has been studied after inhibition of GABA-T (EC 2.6.1.19) by different doses of AOAA. It was found that intraperitoneal (i.p.) injections of AOAA were, at least during the first hour after injection, much less effective than intravenous (i.v.) injections probably due to poor absorption i.p. After i.v. injection, AOAA caused a maximal accumulation of GABA in the cerebellum at a dose of 50 mg/kg. This maximal effect was virtually unchanged up to a dose of 150 mg/kg (the highest dose tested i.v.). If GAD (EC 4.1.1.15) was inhibited by 3-mercaptopropionic acid 30 min after AOAA (90 mg/kg i.v.) the GABA level was stable for at least another 30 min. The rate of GABA accumulation in the cerebellum during the first 15 min after AOAA (50-150 mg/kg i.v.) was 0.086 mumol/g/min and thereafter 0.034 mumol/g/min. It is concluded that AOAA in vivo in a wide dose range inhibits GABA-T almost 100% without affecting GAD to any great extent, and that the onset of action is rapid after i.v. but not after i.p. injection.
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PMID:Effect of aminooxyacetic acid (AOAA) on GABA levels in some parts of the rat brain. 739 47

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is not solely located in the CNS, it and the enzymes responsible for its synthesis (glutamic acid decarboxylase, GAD, EC 4.1.1.15) and catabolism (GABA-transaminase, GABA-T, EC 2.6.1.19) are also present in non-neuronal organs. Following 2, 8 and 21 day oral administration of ethanolamine-O-sulphate (EOS) and gamma-vinyl GABA (GVG), two irreversible inhibitors of GABA-T, the GABA content and activities of GAD and GABA-T in rat brain, liver and kidney, and the GABA content of plasma were determined: GABA-T activity was significantly decreased (over 80%) in liver, brain and kidney, although there was 2-3 times the residual activity left in the brain compared with the peripheral organs. GABA content was subsequently significantly elevated in the liver (300-1500%), plasma (200-300%) and brain (200-300%), although, surprisingly, the kidney GABA content was reduced (by 60-70%) compared with control. GAD activity was decreased following 8 day treatment in liver and brain. Kidney GAD was reduced at all time points. These two compounds are anticonvulsant, GVG is used clinically for the treatment of epilepsy but it seems that these drugs have significant peripheral effects.
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PMID:Effects of chronic oral treatment with GABA-transaminase inhibitors on the GABA system in brain, liver, kidney, and plasma of the rat. 893 45


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