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

Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, gamma-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that "primary" or "genetic" epilepsy must be a disorder of GABA synapses and that GABA agonists would be universal anticonvulsants if permeability and drug metabolism were controlled. The GABA synthetic gene was a logical "candidate gene" for epilepsy. However, the GABA-deficiency theory of epilepsy is less convincing today. GABA agonists were found to intensify seizures in some rodent and human cases. Absence and other generalized seizures in humans often worsened when treated with GABA transaminase inhibitors such as gamma-vinyl-GABA. Surprisingly, the GABA transaminase inhibitors appear to be more useful in partial than in generalized epilepsies. Neuronal GABA uptake blockers are proconvulsant. GABA agonists aggravate seizures in several mutants, ranging from the photosensitive baboon to the genetically epilepsy-prone rat. How can this be understood? Muscimol injections into the pedunculopontine nucleus increase seizures due to systematically administered convulsants, while the receptor blocker bicuculline suppresses seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with GABA uptake blockers and the GABAB agonist baclofen are presented in which their combined administration provoked seizures in rats. Baclofen was shown also to increase the incidence of seizures evoked by pentylenetetrazole without increasing seizures due to local injections of excitatory amino acids. Baclofen antagonized the myoclonic effect of 5-hydroxytryptophan in rats with serotonin lesions. Baclofen augments some seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have convulsant or anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always anticonvulsant. GABAB receptor stimulation may facilitate absence seizures and related primary generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal epilepsy seen in childhood. It is likely that mutations of GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure epilepsy."
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PMID:GABA and epilepsy: their complex relationship and the evolution of our understanding. 131 57

1. 3H-gamma-Aminobutyric acid (GABA) release elicited by a depolarizing K+ stimulus or by noradrenergic transmitter was examined in rat pineals in vitro. 2. The release of 3H-GABA was detectable at a 20 mM K+ concentration in medium and increased steadily up to 80 mM K+. 3. In a Ca2+-free medium 3H-GABA release elicited by 30 mM K+, but not that elicited by 50 mM K+, became blunted. 4. Norepinephrine (NE; 10(-6)-10(-4) M) stimulated 3H-GABA release from rat pineal explants in a dose-dependent manner. 5. The activity of 10(-5) M NE on pineal GABA release was suppressed by equimolecular amounts of prazosin or phentolamine (alpha 1- and alpha 1/alpha 2-adrenoceptor blockers, respectively) and was unaffected by propranolol (beta-adrenoceptor blocker). 6. The alpha 1-adrenoceptor agonist phenylephrine (10(-7)-10(-5) M) and the beta-adrenoceptor agonist isoproterenol (10(-5) M) mimicked the GABA releasing activity of NE, while 10(-7) M isoproterenol failed to affect it; the alpha 2-adrenoceptor agonist clonidine (10(-7)-10(-5) M) did not modify 3H-GABA release. 7. The addition of 10(-4) M GABA or of the GABA transaminase inhibitor gamma-acetylenic GABA or aminooxyacetic acid inhibited the melatonin content and/or release to the medium in rat pineal organotypic cultures. 8. GABA at concentrations of 10(-5) M or greater partially inhibited the NE-induced increase in melatonin production by pineal explants. 9. The depressant effect of GABA on melatonin production was inhibited by the GABA type A receptor antagonist bicuculline; bicuculline alone increased the pineal melatonin content. Baclofen, a GABA type B receptor agonist, did not affect the pineal melatonin content or release. 10. The decrease in serotonin (5-HT) content of rat pineal explants brought about by NE was not modified by GABA; GABA by itself increased 5-HT levels. 11. These results indicate that (a) GABA is released from rat pineals by a depolarizing stimulus of K+ through a mechanism which is partially Ca2+ dependent; (b) NE releases rat pineal GABA via interaction with alpha 1-adrenoceptors; (c) GABA inhibits melatonin production in vitro via interaction with GABA type A receptor sites; and (d) GABA's effect on NE-induced melatonin release does not correlate with the lack of effect on the NE-induced decrease in pineal 5-HT content.
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PMID:Release and effect of gamma-aminobutyric acid (GABA) on rat pineal melatonin production in vitro. 247 90

The hypothetical modulation by GABAergic neurons of yawning behavior in the rat was explored with GABA-active drugs. Gamma-acetylenic-GABA, a specific inhibitor of GABA-T, increases yawning frequency when injected at a dose of 7 mg/kg. Baclofen, a GABAB agonist (3 mg/kg), inhibits yawning completely; GABA antagonists, bicuculline and picrotoxin, at subconvulsant doses, also decrease yawning. All drugs were injected intraperitoneally with the exception of apomorphine, which was injected subcutaneously. It is suggested that GABAB receptors play a role in yawning behavior by modulating ACh release, and that GABAA receptors may modify yawning frequency by modulating inhibitory influences on ACh neurons.
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PMID:GABAergic modulation of yawning behavior. 256 Feb 2

The involvement of gamma-aminobutyric acid (GABA) in regulation of pituitary gonadotropin-II (GTH-II) release was studied in the goldfish. Intraperitoneal injection of GABA (300 micrograms/g) stimulated an increase in serum GTH-II levels at 30 min postinjection. The GABAA receptor agonist muscimol (0.1-10 micrograms/g) stimulated GTH-II in a dose-dependent manner. Baclofen, a GABAB receptor agonist, had a small but significant stimulatory effect at 1 and 10 micrograms/g; the amount of GTH-II released in response to baclofen was significantly less (P < 0.05) than that released by muscimol. Pretreatment of goldfish with bicuculline, a GABAA receptor antagonist, but not saclofen, a GABAB receptor antagonist, blocked the stimulatory effect of GABA on serum GTH-II. Elevation of brain and pituitary GABA levels with the GABA transaminase inhibitor, gamma-vinyl-GABA (GVG), decreased hypothalamic and pituitary dopamine (DA) turnover rates, indicating that GABA may stimulate GTH-II release in the goldfish by decreasing dopaminergic inhibition of GTH-II release. The release of GTH-II stimulated by muscimol and GVG was potentiated by pharmacological agents that decrease inhibitory dopaminergic tone, indicating that DA may also inhibit GABA-stimulated GTH-II release. Based on the linear 24-h accumulation of GABA in brain and pituitary after GVG injection, implantation of testosterone, estradiol, or progesterone, previously shown to regulate the serum GTH-II release response to gonadotropin-releasing hormone and GABA, was also found to modulate GABA synthesis in the brain and pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:GABA stimulation of gonadotropin-II release in goldfish: involvement of GABAA receptors, dopamine, and sex steroids. 839 53

Drugs facilitating GABAergic neurotransmission have been reported to block some behavioral actions of dopaminergic stimulation but not others. The present experiments were performed with the purpose to extend the range of behaviors in which the interaction between GABA and dopamine have been studied. The ability of the GABAB agonist baclofen and the GABA transaminase inhibitor sodium valproate to block the enhanced distractibility produced by amphetamine was evaluated in a procedure especially designed for analyzing drugs' effects on distractibility. Briefly, rats were trained to traverse a straight runway with a sucrose solution as reinforcement. Once the response had been acquired, an additional runway ending in an empty box was connected. The time spent investigating this additional runway is the measure of distractibility. Male rats treated with amphetamine, 1 mg/kg, displayed an increase of the time spent in the additional runway. Baclofen, 2.5 and 5 mg/kg, and sodium valproate, 100 and 200 mg/kg, had no effect on distraction behavior when administered alone. However, when these drugs were administered together with amphetamine, 1 mg/kg, they completely inhibited the effects of the stimulant on distractibility. These data show that distractibility is similar to discrimination learning with regard to the capacity of GABAergic drugs to block the effects of dopaminergic stimulation. It is different from locomotor activity, however, where GABAergic drugs are ineffective in this respect.
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PMID:GABAergic drugs inhibit amphetamine-induced distractibility in the rat. 926 79

Some synthetic taurine analogues, namely ethanolamine-O-sulphate (EOS), N,N-dimethyltaurine (DMT), N,N,N-trimethyltaurine (TMT) and 2-aminoethylphosphonic acid (AEP) were shown to interact with rabbit brain GABA(A)- or GABA(B)-receptors, while (+/-)piperidine-3-sulfonic acid (PSA) inhibited the activity of rabbit brain 4-aminobutyrate transaminase. This suggests that they behave like direct/indirect GABA agonists or GABA antagonists and affect thermoregulation and gross motor behaviour (GMB) which are under GABA control. In the present study micromole (1.2-48) amounts of these compounds were i.c.v. injected in conscious, restrained rabbits while monitoring rectal temperature (RT), ear skin temperature (EST) and GMB. AEP, EOS, DMT and TMT induced a dose-related hyperthermia, ear vasoconstriction and excitation of GMB, while PSA induced a dose-related hypothermia, ear vasodilation and inhibition of GMB. EOS antagonized in a dose-related fashion hypothermia induced by 60 nmol THIP, a GABA(A) agonist, while AEP, DMT and TMT counteracted that induced by 8 nmol R(-)Baclofen, a GABA(B) agonist. In conclusion, EOS and AEP, DMT, TMT seem to act as GABA(A) and GABA(B) antagonists, respectively, while PSA behaves like an indirect GABA agonist, all affecting the central mechanisms which drive rabbit thermoregulation.
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PMID:GABA-mediated effects of some taurine derivatives injected i.c.v. on rabbit rectal temperature and gross motor behavior. 1658 17

GABA plays a pivotal role in reproduction by regulating luteinising hormone (LH) release from the anterior pituitary. Current evidence indicates that there is a prominent stimulatory effect of GABA on LH release in teleost fish which results from enhanced gonadotrophin-releasing hormone (GnRH) release and decreased dopamine turnover in the brain and pituitary. We hypothesised that there may be additional mechanisms underlying LH release in goldfish and investigated the relative mRNA levels of GABA synthesising enzymes (GAD65 and GAD67), degrading enzyme (GABA-T), activin betaa and betab, salmon GnRH (sGnRH), and tyrosine hydroxylase (TH) with the real-time reverse transcriptase-polymerase chain reaction after GABA agonist treatment. Sexually regressed female goldfish were i.p. injected with either the GABA(A) agonist muscimol (1 microg/g body weight) or the GABA(B) agonist baclofen (10 microg/g body weight). Both agonists significantly increased serum LH after 6 h. Muscimol decreased GAD65 (approximately ten-fold), GABA-T (approximately 15-fold) and TH (approximately three-fold) mRNA in the telencephalon. Baclofen significantly reduced GAD67 (approximately two-fold) and GABA-T (approximately two-fold) mRNA levels in the hypothalamus. Activin betaa, but not activin betab, steady-state mRNA was increased approximately three- to four-fold in both the hypothalamus and telencephalon after baclofen treatment. There was no change in sGnRH mRNA levels in either tissue after GABA agonist treatment. We show that the GABA(A) and GABA(B) receptor agonists have differing and rapid effects on gene transcription in the goldfish neuroendocrine brain and, by affecting specific targets, we identify putative genomic mechanisms underlying GABA-stimulated LH release in fish.
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PMID:The effects of GABA agonists on glutamic acid decarboxylase, GABA-transaminase, activin, salmon gonadotrophin-releasing hormone and tyrosine hydroxylase mRNA in the goldfish (Carassius auratus) neuroendocrine brain. 1742 14