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1.
GABA-transaminase has been characterized in cultured astrocytes. It is identical to the synaptosomal and perikaryal enzyme in terms of charge, molecular weight, and stability, but it differs in its affinity for GABA, which is much higher in the glial compartment. GABA-transaminase has been shown to be inducible by high GABA concentrations, which suggests that astrocytes have the possibility not only to transport GABA but also to metabolize the amino acid which is taken up.  相似文献   

2.
Gamma-aminobutyric acid (GABA), glutamate decarboxylase and GABA-transaminase were identified in the nematode Caenorhabditis elegans. The concentration of GABA in C. elegans (0.14 micrograms/mg protein) is approximately 10-fold lower than the concentration of GABA in rat brain. Glutamate decarboxylase and GABA-transaminase, the GABA anabolic and catabolic enzymes, are also present in C. elegans. Crude membrane fractions were prepared from C. elegans and used to study specific [3H] GABA binding sites. GABA binds to C. elegans membranes with high affinity (37 nM) and low capacity (Bmax = 2.25 pmol/mg protein). Muscimol is a competitive inhibitor of specific GABA binding with a KI value of 120 nM. None of the other GABA agonists or antagonists inhibited greater than 40% of the specific GABA binding at concentrations up to 10(-4)M. Thirteen spider venoms were examined as possible GABA agonists or antagonists, the venom from Calilena agelenidae inhibits specific GABA binding with a KI value of 6 nl/ml. These results suggest that GABA has a physiological role as a neurotransmitter in C. elegans.  相似文献   

3.
Clinical relevance of measuring GABA concentrations in cerebrospinal fluid   总被引:1,自引:1,他引:0  
Determination of GABA concentrations in human cerebrospinal fluid can be used to assess GABA-ergic activity in the central nervous system. As CSF free GABA concentrations may vary with age, sex, CSF fraction, and collection and storage conditions, careful attention to these factors are necessary to allow interpretation of results. Longitudinal studies to investigate the influence of pharmacological agents on CSF GABA have proven especially useful to define clinical biochemical activity and have been utilized to attribute the anti-epileptic action of vigabatrin, a selective inhibitor of GABA-transaminase, to its effects on brain GABA metabolism.Special issue dedicated to Dr. Sidney Udenfriend.  相似文献   

4.
Gamma-aminobutyric acid (GABA) plays a pivotal role in suppressing the origin and spread of seizure activity. Low occipital lobe GABA was associated with poor seizure control in patients with complex partial seizures. Vigabatrin irreversibly inhibits GABA-transaminase, raising brain and cerebrospinal fluid (CSF) GABA concentrations. The effect of vigabatrin on occipital lobe GABA concentrations was measured by in vivo nuclear magnetic-resonance spectroscopy. Using a single oral dose of vigabatrin, the rate of GABA synthesis in human brain was estimated at 17% of the Krebs cycle rate. As the daily dose of vigabatrin was increased to up to 3 g, the fractional elevation of brain GABA was similar to CSF increase. Doubling the daily dose from 3 to 6g failed to increase brain GABA further. Increased GABA concentrations appear to reduce GABA synthesis in humans as it does in animals. With traditional antiepileptic drugs, remission of the seizure disorder was associated with normal GABA levels. With vigabatrin, elevated CSF and brain GABA was associated with improved seizure control. Vigabatrin enhances the vesicular and nonvesicular release of GABA. The release of GABA during seizures may be mediated in part by transporter reversal that may serve as an important protective mechanism. During a seizure, this mechanism may be critical in stopping the seizure or preventing its spread.  相似文献   

5.
GABA release and uptake were examined in Genetic Absence Epilepsy Rats from Strasbourg and in non-epileptic control animals, using crude synaptosomes prepared from the cerebral cortex and thalamus. Uptake of [3H]GABA over time was reduced in thalamic synaptosomes from epileptic rats, compared to controls. The affinity of the uptake process in thalamic synaptosomes was lower in epileptic animals. NNC-711, a ligand for the GAT-1 uptake protein, reduced synaptosomal uptake by more than 95%; beta-alanine, an inhibitor selective for the uptake proteins GAT-2 and -3, did not significantly reduce synaptosomal uptake. Autoradiography studies using [3H]tiagabine, a ligand selective for GAT-1, revealed no differences between the strains in either affinity or levels of binding. Ethanolamine O-sulphate (100 microM), a selective inhibitor of GABA-transaminase, did not affect uptake levels. Aminooxyacetic acid (10-100 microM), an inhibitor of GABA-transaminase and, to a lesser extent, glutamate decarboxylase, caused an increase in measured uptake in both thalamic and cortical synaptosomes, in both strains. We found no difference in in vitro basal or KCl-stimulated endogenous GABA release between epileptic and control rats. These results indicate that GABA uptake in the thalamus of Genetic Absence Epilepsy Rats from Strasbourg was reduced, compared to control animals. The lower uptake affinity in the epileptic animals probably contributed to the reduction in uptake over time. Uptake appeared to be mediated primarily by the 'neuronal' transporter GAT-1. Autoradiography studies revealed no differences in the number or affinity of this uptake protein. It is therefore possible that altered functional modulation of GAT-1 caused the decrease in uptake shown in the epileptic animals. Inhibition of GABA-transaminase activity had no effect on measured GABA uptake, whereas a reduction in glutamate decarboxylase activity may have affected measured uptake levels.  相似文献   

6.
S Nagaki  N Kato  Y Minatogawa  T Higuchi 《Life sciences》1990,46(22):1587-1595
Immunoreactive somatostatin (IR-SRIF) and gamma-aminobutyric acid (GABA) contents in the rat brain were investigated to study chronic effects of the treatment with anticonvulsants, carbamazepine (CBZ), valproic acid (VPA) and phenytoin (PHT). Decreased IR-SRIF levels were found in several brain regions after chronic treatment with VPA and CBZ. GABA concentrations were found to be increased significantly in chronic CBZ and VPA treatment in the rat brain, especially in limbic structures. PHT had no effect on both IR-SRIF and GABA contents in the rat brain. Effects of several GABA-mimetic drugs also were studied on IR-SRIF contents in the rat brain. Aminooxyacetic acid an inhibitor of GABA transaminase, induced a decrease in IR-SRIF concentration in the pyriform and entorhinal cortex, whereas ethanolamine-o-sulfate, another GABA-transaminase inhibitor and muscimol, a GABA receptor agonist had no effect on brain IR-SRIF after acute administration. The present results suggest that endogenous somatostatin has an important role for anticonvulsant properties of CBZ and VPA, but not of PHT. The relationship between the changes in IR-SRIF and the GABA transmitter system in the anticonvulsant action of CBZ and VPA remains to be clarified.  相似文献   

7.
In order to obtain an index of the rate of GABA synthesis in different rat brain regions, we examined the rate of accumulation of GABA after irreversible inhibition of GABA-transaminase. Gamma-vinyl-GABA (GVG), a catalytic inhibitor of GABA-transaminase, was microinjected directly into each of four brain areas: superior colliculus (SC), substantia nigra (SN), frontal cortex (CTX) and caudate-putamen (CP). The subsequent rate of GABA accumulation was linear for at least 90 min in all regions, and was found to be 2–3 times higher in the SC and SN than in the CTX and CP. The nerve terminal contribution to the initial rate of GABA accumulation after GVG was determined by comparing values obtained in the intact SN with those obtained in the SN in which the GABAergic afferent terminals had been destroyed. The initial rate of GABA accumulation in the denervated SN was less than one-half of that measured in the intact SN, indicating that, under normal conditions, both nerve-terminal and non-nerve-terminal (perikarya, glia) compartments contribute to the rate of GABA accumulation after GABA-transaminase inhibition. Our results indicate that the intracerebral injection of GVG is a sensitive and reliable method for studying invivo GABA synthesis in brain. Although the rate of GABA accumulation after GVG is sensitive to changes in the nerve terminal compartment, other GABA compartments may also influence these measurements.  相似文献   

8.
The conversion of succinic semialdehyde into gamma-aminobutyric acid (GABA) by GABA-transaminase was measured in rat brain homogenate in the presence of different concentrations of the cosubstrate glutamate. The calculated kinetic parameters of succinic semialdehyde for GABA-transaminase were a limiting Km value of 168 microM and a limiting Vmax value of 38 mumol g-1 h-1. Combination with previously obtained data for the conversion of GABA into succinic semialdehyde revealed a kEq value of 0.04, indicating that equilibrium of GABA-transaminase is biased toward the formation of GABA. The increased formation of GABA in the presence of succinic semialdehyde was not due to an increased conversion of glutamate into GABA by glutamic acid decarboxylase. Therefore these results indicate that succinic semialdehyde can act as a precursor for GABA synthesis.  相似文献   

9.
Summary The biochemical elements of GABA-ergic synapses in the central nervous tissue were examined by a comparative neurochemical approach. The high concentration of GABA as well as the activities of glutamate decarboxylase and GABA-transaminase suppose a high content of GABAergic elements in the nervous system of the locust.Nerve endings isolated from the ganglia of locusts accumulated exogenous GABA in a carriermediated, sodium dependent process into compartments from where it could partially be released under depolarizing conditions. The transport was stimulated by extracellular chloride, was modulated by specific ionophores (enhanced by valinomycin, inhibited by CCCP) and could effectively be blocked by GABAergic ligands (DABA, muscimol). Binding studies revealed the existence of multiple binding sites for GABA which differ in number, affinity, pharmacology and ion dependency. The putative receptors for GABA (Na+-independent binding sites) in locust nervous tissue exceeded the concentrations found in vertebrate brain tissue and showed different binding pharmacology.Abbreviations GABA -amino butyric acid - GAD glutamate decarboxylase - GABA-T GABA-transaminase - DABA diamino butyric acid  相似文献   

10.
M Kihara  Y Misu  T Kubo 《Life sciences》1988,42(19):1817-1824
Slices of the rat medulla oblongata were superfused and electrically stimulated. The amount of endogenous GABA, beta-alanine and glutamate release from the slices was determined by high performance liquid chromatography with fluorometric detection. Inhibitors of GABA-transaminase (GABA-T), aminooxyacetic acid (10(-5) M), gamma-acetylenic GABA (10(-4) and 10(-3) M) and gabaculine (10(-5) M), enhanced the stimulus-evoked release of GABA and reduced that of beta-alanine, while no change was observed in the release of glutamate. These changes in amino acid release from the slices were accompanied by an increase in the content of GABA and a decrease in that of beta-alanine. The stimulus-evoked release of these amino acids was abolished by Ca2+-deprivation, in either the presence or absence of GABA-T inhibitors. These results suggest a modulatory role of GABA-T for synaptically releasable GABA and involvement of this enzyme in the synthesis of releasable beta-alanine.  相似文献   

11.
The occurrence and the localization of 4-aminobutyrate:2-oxoglutarate transaminase (GABA-transaminase) in the non-pregnant and pregnant rat oviduct were examined using biochemical and enzyme histochemical techniques. Specific GABA-transaminase activity was detected in the ampullary and isthmic portions of the oviduct as well as in the utero-tubal junction. The enzymic activity was lower in the ampullary than in the isthmic or intramural segments of the oviduct. Pregnancy induced a significant increase of GABA-transaminase activity in each portion of the oviduct. Enzyme histochemistry showed the highest GABA-transaminase reactivity at the level of the epithelial cells of the oviduct irrespective of the portion of the tube examined. A faint specific activity was demonstrated in the smooth muscle of the oviduct while the serosa did not show specific staining. Our findings indicate that: the observed increase of GABA-transaminase activity in the oviduct of the pregnant rat may be responsible for the reduced GABA levels in the oviduct during gestation; and the extraneuronal localization of GABA-transaminase activity does not seem to support the suggestion of a possible GABAergic innervation of the oviduct.  相似文献   

12.
Single exposure of adult male rats to low environmental temperature (LET, 12 ± 0.5°C) for 2 h significantly increased the hypothalamic and striatal GABA levels without affecting those in other regions of brain. The activity of glutamate decarboxylase (GAD) was elevated in hypothalamus (H) and corpus striatum (CS) under these conditions. GABA accumulation rate (measured with ethanolamine-O-sulfate, an inhibitor of GABA-transaminase) was also increased in both H and CS of rats exposed to LET for 2 h. Unlike after a single exposure, the repeated exposure (2 h/day) for 7, 15, and 30 onsecutive days did not change the hypothalamic GABA metabolism. No change in GABA metabolism was observed in CS when rats were repeatedly exposed to LET for 7 consecutive days. Prolongation of repeated exposure to LET (2 h/day) for 15 and 30 consecutive days decreased the striatal GABA level and increased the activity of GABA-transaminase, although GAD activity was not altered under these conditions. These results suggest that single exposure to LET accelerates GABA synthesis and may reduce the GABAergic activity in both H and CS; whereas repeated exposure to LET for 15 or 30 consecutive days enhances GABAergic activity with the stimulation of GABA utilization only in CS without affecting its synthesizing process. Thus, it may be suggested that the hypothalamic and striatal GABA system may play a characteristic role in response to short-and long-term exposure to LET.  相似文献   

13.
Summary The formation of GABA from L-glutamate was investigated in homogenates of rat brain, liver, and kidney, using highly purified [14C]-L-glutamic acid as substrate and a thin-layer chromatographic separation of products. In agreement with other workers, liberation of [14C]-CO2 was found to be stoichiometric with GABA formation in brain homogenates, but not in liver or kidney extracts. Subcellular fractionation and dialysis experiments suggested that most of the GABA synthesis in these peripheral tissues, unlike brain, does not occur via a direct decarboxylation of glutamate and requires one or more cofactors other than pyridoxal phosphate. NAD stimulated GABA formation in dialyzed extracts, and inhibition of GABA-transaminase, bothin vitro andin vivo, caused marked inhibition of GABA formation from glutamate in peripheral extracts. Although a very low GAD activity in liver and kidney cannot be excluded, these experiments suggest a major pathway from glutamate to GABA in these homogenates which includes (1) conversion of glutamate to -ketoglutarate by glutamate dehydrogenase or transaminases, (2) conversion of -ketoglutarate to succinic semialdehyde, and (3) formation of GABA from succinic semialdehyde and glutamate by GABA-transaminase.  相似文献   

14.
S P Sivam  I K Ho 《Life sciences》1985,37(3):199-208
Drugs affecting various steps of GABA transmission exhibit analgesia in a variety of experimental models in animals; this analgesic response generally requires high doses of the drugs and does not appear to be opiate-like since the GABAergic analgesia is naloxone-insensitive and lacks dependence liability. The outcome of the analgesia response is variable when opiate and GABAergic drugs are administered together; however, directly acting GABA receptor stimulants and GABA-transaminase inhibitors generally enhance the analgesic effect of opiates. The development of newer GABAergic drugs with greater potency and specificity may offer an alternative to opiate analgesics. The results obtained over the years, on the possible involvement of the GABA system in morphine tolerance and dependence are equivocal. Studies on region-specific changes in opiate-GABA interaction as well as opiate-GABA-benzodiazepine interaction are needed to further elucidate the role of GABA on opiate system.  相似文献   

15.
Shifts in the system of GABA transformation in ischemia and specific inhibition of GABA-transaminase under conditions of quantitative measurement of the blood circulation by means of hydrogen clearance permitted to establish a definite association between the increased GABA level in the brain and the tissues of the wall of its arteries, and the development of compensation of disturbed cerebral circulation. Consequently, one of the principal manifestations of an increased amount of endogenous GABA in deficiency of the brain blood supply was GABA capacity to improve the cerebral circulation.  相似文献   

16.
The effects of pentobarbitone on the binding of gamma-aminobutyric acid (GABA) to crude synaptosomal rat brain membranes were studied. In extensively washed P2 membranes, pentobarbitone had a biphasic action: at concentrations ranging between 12.5 and 500 microM, pentobarbitone enhanced GABA binding in a concentration-dependent manner; at concentrations greater than 500 microM, this enhancement was progressively reversed towards control levels of GABA binding. The effect of pentobarbitone seen at higher concentrations may reflect a GABA-mimetic action, since similar concentrations enhanced diazepam binding to washed P2 membranes, an effect antagonized by bicuculline methochloride and picrotoxinin. When washed P2 membranes were incubated in 0.5% Triton X-100 (30 min at 37 degrees C), the enhancement of GABA binding by low concentrations of pentobarbitone was abolished, while at higher concentrations GABA binding was progressively inhibited, suggesting that the GABA-mimetic action is retained. When washed P2 membranes were subjected to high-frequency homogenization, the biphasic dose-response relationship for pentobarbitone was markedly shifted to the right. The choice of membrane preparation appears to be a critical factor in examining drug-receptor interactions in vitro, at least for those involving GABA and the barbiturates.  相似文献   

17.
Intracisternal injections of ethanolamine-O-sulfate (EOS), an irreversible selective inhibitor of GABA-transaminase (GABA-T), resulted in relatively long lasting dose dependent decreases in food consumption and body weight of rats. The anorexic effects of EOS generally corresponded in both time course and magnitude to the elevation of GABA levels and associated decreases in GABA-T activity. Chronic treatment with very high intraperitoneal doses of EOS which were able to cross the blood-brain barrier elevated GABA levels and resulted in weight loss. Muscimol, a GABA receptor agonist also produced anorexia. These findings are consistent with the view that GABA may be involved in mediation of satiety in the rat.  相似文献   

18.
The activity of glutamate decarboxylase (L-glutamate carboxy-1-lyase; EC 4.1.1.15), GABA-transaminase (GABA-alpha-ketoglutarate aminotransferase, EC 2.6.1.19), content of gamma-aminobutyric, glutamic and aspartic acids were studied in different parts and subcellular particles of the cat and rat brain. It is shown that regional and subcellular distribution of the GABA metabolic components in the cat and rat brain are mainly similar, but quantitative indices are different.  相似文献   

19.
Abstract: Measurements of the activities of the two key enzymes in cerebral GABA metabolism—glutamate decarboxylase (GAD) and GABA-transaminase (GABA-T)—were performed in normal rabbits and in rabbits with hepatic encephalopathy due to galactosamine-induced liver failure. Furthermore the uptake of GABA by synaptosomes was studied. Hepatic encephalopathy was associated with a marked decrease in the activity of GAB A-T. This decrease in activity was already apparent in galactosamine-treated rabbits before the onset of hepatic encephalopathy. Sera and serum ultrafiltrates of rabbits with hepatic encephalopathy but not of normal rabbits or of rabbits with uremic encephalopathy were shown to inhibit GABA-T activity in vitro . Cerebral GAD activity and synaptosomal GABA uptake in rabbits with hepatic encephalopathy and in untreated animals were not different. These later findings indicate that hepatic encephalopathy is not associated with alterations of presynaptic GABA nerve terminals in the central nervous system. The demonstration of a decrease in cortical GABA-T activity provides indirect evidence for decreased GABA turnover in the brains of rabbits with hepatic encephalopathy and thus is compatible with augmented GABA-ergic inhibitory neurotransmission contributing to the neural inhibition of hepatic encephalopathy.  相似文献   

20.
We have previously shown that short-lasting reduction of cerebral blood flow by bilateral clamping of carotid arteries (BCCA) results in long-lasting increase in regional GABA concentration and decrease in seizure susceptibility in rats. In the present experiments, the effect of BCCA on GABA turnover and the enzymes involved in GABA synthesis and degradation were studied in rats. Regional GABA turnover was measured by means of GABA accumulation induced by the GABA-transaminase (GABA-T) inhibitor aminooxyacetic acid (AOAA). Fourteen days after BCCA, GABA turnover was significantly increased in hippocampus, substantia nigra and cortex, but not different from sham-operated controls in several other brain regions, including striatum, hypothalamus and cerebellum. The activity of glutamate decarboxylase (GAD) measured ex vivo did not show any changes in investigated structures, while the activity of GABA-T was slightly increased in hippocampus. The increased GABA turnover in some brain regions may explain our previous findings of increased GABA content in these brain regions and decreased sensitivity of BCCA treated animals to the GABAA-receptor antagonist bicuculline.  相似文献   

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