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Query: UNIPROT:P06889 (Mol)
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The pharmacological properties and modulation by lithium of the kainate (KA) receptor system coupled to the evoked release of [3H]-gamma-aminobutyric acid [( 3H]GABA) from purified populations of striatal neurons in primary culture were examined. KA evoked a dose-dependent (EC50, 100 microM) and saturable increase in [3H]GABA release from striatal neurons that was unaffected by the removal of extracellular calcium and resistant to the actions of tetrodotoxin. The release of [3H]GABA evoked by 100 microM KA was attenuated in a dose-dependent manner by the following excitatory amino acid antagonists (IC50):6-cyano-2, 3-dihydroxy-7-nitroquinoxaline (2 microM),2,3-dihydroxy-6,7-dinitroquinoxaline (2 microM), kynurenate (0.3 mM), and gamma-D-glutamylglycine (2 mM). The antagonist properties of 6-cyano-2,3-dihydroxy-7-nitroquinoxaline, kynurenate, and gamma-D-glutamylglycine were competitive in nature, inducing parallel rightward shifts of the KA dose-response curves. At concentrations at which it did not significantly increase basal levels of [3H]GABA release, quisqualate attenuated in a dose-dependent manner (IC50, 10 microM) the release due to 100 microM KA. The quisqualate receptor agonist alpha-amino-3-hydroxyisoxazolepropionic acid (AMPA), however, exerted a biphasic effect on 100 microM KA-evoked release of [3H]GABA. At lower concentrations of AMPA (0.1-10 microM), the release due to 100 microM KA was potentiated 25-50%; at higher concentrations (greater than 10 microM) AMPA induced a dose-dependent (IC50, 100 microM) attenuation of KA-evoked release. The release of [3H]GABA due to 100 microM KA was significantly potentiated by the replacement of sodium with lithium in the extracellular medium. A significant potentiation (20-30%) was detected with as little as 5-10 mM lithium, and maximal effects (100-110% increase) were obtained with 50-75 mM lithium. Replacement of sodium with choline or N-methyl-D-glucamine could not mimic the actions of lithium. Lithium (25 mM) also induced a 4-fold increase in the levels of endogenous GABA release due to 100 microM KA. Whole-cell voltage-clamp recordings of these striatal neurons indicated that the 100 microM KA-induced inward current was not significantly altered in the presence of 25 mM lithium. Lithium attenuated vasoactive intestinal polypeptide-stimulated cyclic AMP formation by 50%, with a dose dependence similar to that of its actions on KA-evoked release. The results of this study demonstrate a distinct pharmacological profile for the KA receptor system coupled to the evoked release of [3H]GABA from striatal neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1990 Aug
PMID:Kainate receptors coupled to the evoked release of [3H]-gamma-aminobutyric acid from striatal neurons in primary culture: potentiation by lithium ions. 216 3

GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by opening a chloride channel integral to the GABAA receptor. This action is potentiated by both benzodiazepine and barbiturate drugs. Since the isolation of cDNAs encoding GABAA receptor alpha 1 and beta 1 subunits, a further eight subunits have been identified. These subunits show GABAA receptor heterogeneity, unpredicted from classical pharmacological studies. I now report the isolation of a mouse cDNA clone encoding a novel GABAA receptor alpha subunit. The striking feature of this subunit is its regional distribution in the mouse brain. Northern hybridization and in situ hybridization experiments demonstrate that the subunit mRNA is expressed only in cerebellar granule cells. This is the first demonstration of the exclusive presence of a neuroreceptor subtype in a single neuronal cell type.
J Mol Biol 1990 Aug 05
PMID:Novel GABAA receptor alpha subunit is expressed only in cerebellar granule cells. 216 78

In order to assess changes in enkephalin release and biosynthesis, the levels of the tripeptide Tyr-Gly-Gly (YGG), a characteristic extracellular metabolite of enkephalins, and of the proenkephalin mRNA in mouse striatum were evaluated after a single administration of GABAergic agents. Significant and long-lasting decreases in steady state YGG levels were elicited by muscimol, a gamma-aminobutyric acid-A (GABAA) receptor agonist, diazepam, a benzodiazepine receptor agonist, or aminooxyacetic acid, a GABA-transaminase inhibitor. In addition, muscimol offset the elevation of striatal YGG elicited by bestatin, an aminopeptidase inhibitor, which entirely drives the released enkephalins into the metabolic pathway operated by enkephalinase (EC 3.4.24.11). Diazepam potentiated the effect of muscimol so that the YGG decrease induced by the combination of these two drugs was maximal after 30 min (-60%) and still significant (-40%) after 6 h, this potentiation being antagonized by pre-treatment with Ro 15-1788, a specific benzodiazepine receptor antagonist. By contrast [Met5]enkephalin steady-state levels were marginally affected by GABAergic agents, being only slightly reduced 6 h after the combination of muscimol and diazepam. After 3 h the same treatment also reduced by about 30% the level of proenkephalin mRNA, this change being maximal after 6 h (-45%) and still present after 24 h. These compared changes in various indexes of enkephalin neuron activity suggest that stimulation of GABAA receptors depresses enkephalin release immediately and for several hours, whereas preproenkephalin gene expression is decreased in a somewhat delayed and longer lasting manner. These patterns of temporal changes in biosynthesis and release of the neuropeptide presumably account for the limited changes in its steady state levels.
Brain Res Mol Brain Res 1990 Aug
PMID:Enkephalin biosynthesis and release in mouse striatum are inhibited by GABA receptor stimulation: compared changes in preproenkephalin mRNA and Tyr-Gly-Gly levels. 217 Aug

Desensitization of the gamma-aminobutyric acidA (GABAA) receptor was studied in cultured mammalian spinal cord neurons, using a GABA-induced 36Cl-influx assay. GABAA receptor agonists such as GABA and muscimol produced desensitization of GABAA receptor-gated Cl- channels. The ability of GABA to induce desensitization was time and concentration dependent and reversible. Involvement of protein kinase A in the desensitization phenomenon was studied by using activators of adenylate cyclase (forskolin analogs) and membrane-permeant analogs of cyclic AMP (8-bromo-cAMP and dibutyryl-cAMP). Both active forskolin and the inactive forskolin analog 1,9-dideoxyforskolin decreased GABA-induced 36Cl- influx alone, as well as when preincubated in conjunction with GABA. The effect of forskolin analogs appears to be nonspecific and unrelated to generation of cyclic AMP. GABA-induced 36Cl- influx was also inhibited directly by 8-bromo-cAMP, dibutyryl-cAMP, and cAMP. Furthermore, the protein kinase A inhibitor H-8 did not reverse the effect of cAMP analogs on the inhibition of GABA-induced 36Cl- influx. Taken together, these results suggest that cAMP analogs inhibit GABA-induced 36Cl- influx by acting via an extracellular site. The inability of the active phorbol ester to modify GABA-induced desensitization rules out the involvement of protein kinase C in the GABA receptor desensitization. These results suggest that protein kinases A and C are not involved in GABAA receptor desensitization in mouse spinal cord cultured neurons.
Mol Pharmacol 1990 Nov
PMID:gamma-Aminobutyric acidA receptor desensitization in mice spinal cord cultured neurons: lack of involvement of protein kinases A and C. 217 78

gamma-Hydroxybutyric acid (GHB) is a natural compound of mammalian brain synthesized from GABA. The characteristics of its synthesis, transport, release, distribution and turnover, in addition to the presence of a high affinity binding site for this substance in brain are in favor of a modulator role for GHB. The effects of hydrolytic enzymes on the specific binding capacity of GHB have been studied in the present work. Phospholipases A2 and C, neuraminidase and Pronase markedly decrease GHB binding to crude synaptosomal membranes from rat brain. This effect is time and enzyme concentration dependent. Trypsin, under the conditions employed, is less active. The inhibitory effects of phospholipases is correlated with phospholipid hydrolysis. Lysophospholipids, in the absence of bovine fatty acid free serum albumin partially inhibit GHB binding. The action of neuraminidase has been followed by sialic acid release and modifications of the ganglioside profile. The effects of phospholipase C and of neuraminidase are completely different to those on GABA binding sites. These results represent further data concerning the molecular existence of specific GHB binding sites on rat brain membranes.
Mol Cell Biochem 1990 Mar 05
PMID:Effects of phospholipases, proteases and neuraminidase on gamma-hydroxybutyrate binding sites. 218 47

The enzymatic activities of aspartate aminotransferase, GABA-transaminase and acetylcholinesterase were studied by means of histochemical methods in the mesencephalic trigeminal nucleus (MTN) neural complex of the turtle Mauremys caspica. Light microscope observations have demonstrated that MTN neurons have a positive reaction for these enzymes.
Cell Mol Biol 1990
PMID:Light microscope study of the enzymatic activities of aspartate aminotransferase, GABA transaminase and acetylcholinesterase in the mesencephalic trigeminal nucleus neural complex of Mauremys caspica. 237 32

gamma-Aminobutyric acid transaminase from pig liver, an alpha 2 dimeric enzyme of Mr 110,100, has been crystallized by the vapour diffusion method with polyethylene glycol as precipitant. The crystals are monoclinic, space group P2(1), unit cell dimensions a = 82.1 A, b = 230.0 A, c = 70.3 A, beta = 123.9 degrees and diffract to 2.5 A resolution. There are two dimers per asymmetric unit.
J Mol Biol 1990 Aug 20
PMID:Crystallization and preliminary X-ray analysis of gamma-aminobutyric acid transaminase. 238 71

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.
Cell Mol Neurobiol 1989 Jun
PMID:Release and effect of gamma-aminobutyric acid (GABA) on rat pineal melatonin production in vitro. 247 90

The meta- and para-isothiocyanato derivatives of t-butylbicycloorthobenzoate (TBOB) were synthesized by catalytic reduction of the corresponding nitro compounds, followed by treatment with thiophosgene. p-NCS-TBOB (2) inhibited the binding of both [3H]TBOB and [35S]t-butylbicyclophosphorothionate (TBPS) with potencies (IC50 of 61 and 23 nM, respectively) similar to the parent compound. In contrast, the meta derivative (m-NCS-TBOB, 1) was more than 1 order of magnitude less potent (IC50 of 1588 and 149 nM, respectively). The IC50 values for both 1 and 2 were strongly dependent on the tissue concentration, in a manner characteristic of irreversible inhibitors. Moreover, preincubation of tissue with these compounds, followed by extensive washing, resulted in a concentration-dependent reduction in the number of [35S]TBPS binding sites and in the apparent affinity of this radioligand. Similar effects were not observed in tissues treated in identical fashion with either TBOB or picrotoxin. Preincubation with p-NCS-TBOB at concentrations that significantly inhibit [35S]TBPS or [3H]TBOB binding did not affect radioligand binding to either benzodiazepine or gamma-aminobutyric acid receptors. These findings suggest that m- and p-NCS-TBOB bind irreversibly to sites labeled by cage convulsants such as TBOB and TBPS, which are on or near GABA-gated chloride channels. p-NCS-TBOB should prove useful in determining the molecular characteristics of the benzodiazepine receptor-coupled GABA-gated chloride ionophore.
Mol Pharmacol 1989 Feb
PMID:meta- and para-isothiocyanato-t-butylbicycloorthobenzoate: irreversible ligands of the gamma-aminobutyric acid-regulated chloride ionophore. 253 56

Chronic benzodiazepine administration has been reported to decrease gamma-aminobutyric acidA (GABAA) receptor function in animals and may alter benzodiazepine binding in neuronal cultures. To assess GABAA receptor function in neuronal cultures exposed to chronic clonazepam, we measured muscimol-stimulated chloride uptake in chick cerebral cortical cultures treated acutely and for 2, 4, and 10 days. Acute clonazepam administration (1 microM) led to an increase in GABA-related chloride uptake at lower doses of muscimol. After chronic clonazepam (1 microM), maximal uptake was markedly decreased at day 10, but maximal uptake was unchanged after 2- and 4-day treatments. Benzodiazepine receptor binding was decreased by approximately 60% after 10 days due to a decrease in receptor number. Decreases in chloride uptake were also observed after 10 days of treatment with 0.1 and 10 microM clonazepam. Concomitant treatment with 0.1 microM Ro15-1788 abrogated the effect of 0.1 microM clonazepam on chloride uptake. Chronic clonazepam treatment (1 microM) did not alter total cellular protein, cellular protein synthesis or degradation or percentage of neuronal cells, as determined morphologically and by [3H]ouabain binding.
Mol Pharmacol 1989 Nov
PMID:Chronic clonazepam administration decreases gamma-aminobutyric acidA receptor function in cultured cortical neurons. 255 77


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