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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effects of external sodium on GABA-induced chloride currents were examined with whole-cell voltage-clamp recordings obtained from enzymatically dissociated solitary Muller cells in culture. Our goal was to determine whether a sodium-dependent GABA uptake mechanism influences the GABAa-mediated responses of skate Muller cells. 2. At low concentrations of GABA (0.01 to 0.5 microM), removal of sodium from the external solution resulted in a marked increase in the ligand-gated currents mediated by activation of GABAa receptors. The enhancement by lowered sodium was greatest at hyperpolarizing potentials and decreased progressively as the cell was depolarized. 3. The reversal potential for the GABA-induced response was not significantly altered by the removal of sodium, suggesting that sodium ions did not directly contribute to the GABAa-mediated current. 4. Lowering external sodium had no effect on the currents induced by the GABAa-agonist muscimol, consistent with its much lower affinity for the GABA transport carrier. 5. Application of the GABA uptake blocker nipecotic acid also abolished the effects of lowered sodium. 6. These findings suggest that the effects of lowered external sodium resulted from a decrease in the uptake of GABA into the Muller cells, thus raising the effective concentration of GABA acting upon the GABAa receptors.
Cell Mol Neurobiol 1993 Apr
PMID:The effects of lowered extracellular sodium on gamma-aminobutyric acid (GABA)-induced currents of Muller (glial) cells of the skate retina. 839 15

Transport of 4-aminobutyric acid (GABA) in Saccharomyces cerevisiae is mediated by three transport systems: the general amino acid permease (GAP1 gene), the proline permease (PUT4 gene), and a specific GABA permease (UGA4 gene) which is induced in the presence of GABA. The UGA4 gene encoding the inducible GABA-specific transporter was cloned and sequenced and its expression analyzed. The predicted amino acid sequence shows that UGA4 encodes a 62 kDa protein having 9-12 putative membrane-spanning regions. The predicted UGA4 protein shares significant sequence similarity with the yeast choline transporter (CTR gene), exhibiting but limited similarity to the previously reported GABA transporters, i.e. the yeast GAP1 and PUT4 permeases and the rat brain GAT-1 transporter. Induction of UGA4 in the presence of GABA is exerted at the level of UGA4 mRNA accumulation, most probably at the level of transcription itself. This induction is conferred by the 5' flanking region and requires the integrity of two positive regulatory proteins, the inducer-specific factor UGA3 and the pleiotropic factor UGA35/DURL/DAL81. In the absence of the pleiotropic UGA43/DAL80 repressor, UGA4 is constitutively expressed at high level.
Mol Gen Genet 1993 Feb
PMID:Cloning and expression of the UGA4 gene coding for the inducible GABA-specific transport protein of Saccharomyces cerevisiae. 845 53

The existence of a large number of GABA receptors in the cerebellar molecular layer, and the observation of numerous punctate immunoreactive deposits of GABA synthesizing enzyme (GAD) throughout this layer, could indicate the existence of numerous axon terminals that may be involved in neurotransmission modulated by GABA. These axon terminals may be different from those considered classically as cerebellar GABAergic axon terminals. Therefore, we have reinvestigated the localization of GABA- and GAD-immunoreactivities in the cerebellar cortex of the rat with the PAP method, using different antisera obtained from rabbits immunized with GABA, baclofen and GAD. The results observed in our investigation have demonstrated GABA- and GAD-immunoreactivities in the axon terminals considered classically as GABAergic, as well as in others which, until now, have not been considered GABAergic. This fact leads us to think that the distribution of GABA or molecules structurally similar to GABA is far more extended than previously thought in the cerebellum. We have also observed both GABA- and GAD-immunoreactivities within dendrites and glial cells. These facts suggest us a possible extrasynaptic release of GABA.
Cell Mol Biol (Noisy-le-grand) 1993 Feb
PMID:Synaptic and non-synaptic immunolocalization of GABA and glutamate acid decarboxylase (GAD) in cerebellar cortex of rat. 846 37

The aim of this work was to characterize the 4-aminobutyric acid (GABA) transport in the Saccharomyces cerevisiae D27 strain, followed by the study of the relationship between 5-aminolevulinic acid (ALA) and GABA transport systems. It was found that the general amino acid permease (GAP) is not active in D27 strain, suggesting that GABA incorporation should be mediated by PUT4 and UGA4 permeases. However, after kinetic studies only one system was detected. It was also shown that GABA uptake is competitively inhibited by ALA. GABA incorporation is regulated by the carbon source but not by the nitrogen source. When cells were grown in the presence of GABA, its entrance was very low.
Cell Mol Biol (Noisy-le-grand) 1995 Sep
PMID:GABA uptake in a Saccharomyces cerevisiae strain. 853 78

The effects of intracerebroventricular and intrahypothalamic injections of picrotoxin, a GABA antagonist, on gastric acid secretion were studied in perfused stomachs of rats under anesthesia. Injection of picrotoxin into the lateral cerebroventricle inhibited the 2-deoxy-D-glucose-stimulated acid secretion. In experiments of intrahypothalamic injections, picrotoxin produced a significant depression of 2-deoxy-D-glucose-stimulated acid secretion when administered to the ventromedial hypothalamus but not to the lateral hypothalamus. In contrast, picrotoxin produced a definite stimulatory effect on basal acid secretion when injected to the lateral hypothalamus or ventromedial hypothalamus; the stimulatory effect of the injection to the lateral hypothalamus was greater than that of the injection to the ventromedial hypothalamus. These findings indicate that picrotoxin acts centrally, probably hypothalamus, to depress the 2-deoxy-D-glucose-stimulated acid secretion. On the other hand, blockade of GABA activity in the lateral hypothalamus or ventromedial hypothalamus may elicit gastric acid secretion. These results, indicate that central GABAergic mechanism is important in regulating gastric acid secretion in the rat.
Res Commun Mol Pathol Pharmacol 1995 Aug
PMID:Effect of intracerebroventricular and intrahypothalamic administrations of picrotoxin on basal and stimulated gastric acid secretion. 855 69

In this study we have shown, by in situ hybridization and RNase protection assay, a significant trkC mRNA increase confined to the dentate gyrus of hippocampus, both after seizures induced by intracerebroventricular injection of kainic acid and bicuculline. Moreover, after bicuculline treatment we observed an earlier increase of trkC mRNA level, which peaked after 3 h and returned back to normal levels by 12 h. In contrast, the kainic acid treatment produced a delayed increase of trkC mRNA, which initiated after 6 h, peaked at 12 h, and returned to normal levels at 24 h. This increase, which involves also trkC mRNA receptor with tyrosine kinase activity, was mediated by non-NMDA receptors and counteracted by GABA potentiating agent diazepam. Using embryonic neuronal cultures from cerebral hemispheres, including hippocampus, we found that glutamate receptor agonists, including glutamate, kainate, NMDA, and t-ACPD, increase trkC mRNA levels with the following rank order of efficacy: NMDA > t-ACPD > kainic acid > glutamate. In conclusion, our data show that trkC mRNA expression in granule cells of the hippocampus dentate gyrus is increased during seizure activity and that it is mediated by non-NMDA receptors.
J Mol Neurosci 1995
PMID:Seizures increase trkC mRNA expression in the dentate gyrus of rat hippocampus. Role of glutamate receptor activation. 856 16

Phosphoethanolamine is a phosphomonoester that is reduced in Alzheimer disease brain. Despite its close structural similarity to GABA and the GABAB partial agonist 3-aminopropylphosphonic acid, phosphoethanolamine binds very poorly to GABAB receptors (IC50 = 7.5 +/- 0.8 mM). In this study, we examined whether the marked decrease in binding affinity associated with the presence of an ester oxygen in place of the alpha-CH2 group of GABAergic compounds also occurred in sulfonates and used high resolution solution NMR and molecular mechanics calculations to determine the structural basis of this decrease in activity. The sulfonate analog of GABA, 3-amino-propylsulfonic acid, became > 2500-fold less potent when the alpha-CH2 was replaced by an ester oxygen. Structural studies showed that the active alpha-CH2 compounds (GABA, 3-aminopropylphosphonic acid, and 3-aminopropylsulfonic acid) prefer a fully extended conformation. The inactive compounds, phosphoethanolamine and ethanolamine-O-sulfate, exist in a gauche conformation around the C beta-C gamma bond. This study, which suggests conformational differences, may explain how PE can be so efficiently excluded from GABAB receptors, despite being present in millimolar concentrations in brain. Exclusion of phosphoethanolamine from GABAB receptors may be an important physiologic control mechanism in the regulation of inhibitory neurotransmission.
Mol Chem Neuropathol 1995 Sep
PMID:Structural determinants of activity at the GABAB receptor. A comparison of phosphoethanolamine and related GABA analogs. 858 21

Progesterone and its metabolites have a variety of diverse effects in the brain, uterus, smooth muscle, sperm and the oocyte. The effects include changes in electrophysiological excitability, induction of anesthesia, regulation of gonadotropin secretion, regulation of estrogen receptors, modulation of uterine contractility and induction of acrosome reaction and oocyte maturation. The latency of the effects vary from several seconds to several hours. Thus, it is not surprising that multiple mechanisms of action are involved. The classical mechanism of steroid hormone action of intracellular receptor binding has been supplemented by the possibility of the steroid acting as a transcription factor after the binding of the receptor protein to DNA. Other mechanisms include influence of the steroids on membrane fluidity and acting through other cell signalling systems, membrane receptors and GABA(A) receptors. Of particular interest are multiple mechanisms for the same types of action. For example the effect of progesterone on gonadotropin release is largely exerted via the classical intracellular receptor as well as membrane receptors, whereas 3(alpha),5(alpha)-tetrahydroprogesterone-induced LH release occurs via the GABA(A) receptor system. The inhibition of uterine contractility by progesterone is regulated by progesterone receptors while the action of 3(alpha),5(alpha)-tetrahydroprogesterone on uterine contractility is regulated by GABA(A) receptors. The regulation of the differences in the pattern of progesterone effects on estrogen receptor dynamics in the anterior pituitary and the uterus in the same animal are also of considerable interest.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Diverse modes of action of progesterone and its metabolites. 860 42

Neuroactive steroids bind to a unique site on the gamma-aminobutyric acidA (GABAA) receptor complex and allosterically modulate the binding of convulsant ([35S]t-butylbicyclophosphorothionate, [35S]TBPS), GABA ([3H]muscimol), and benzodiazepine ([3H]flunitrazepam) site ligands. In rat cortical membranes, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-P) is a full agonist at the steroid site, inhibiting 96% of specific [35S]TBPS binding and enhancing [3H]flunitrazepam and [3H]muscimol binding 95% and 69% above control levels, respectively. In contrast, the synthetic steroid 3 alpha-hydroxy-3 beta-trifluoromethyl-5 alpha-pregnan-20-one (Co 2-1970) has limited efficacy for modulating the binding of [35S]TBPS (44% inhibition), [3H]flunitrazepam (41% enhancement), and [3H]muscimol (< 10% enhancement). In competition experiments, Co 2-1970 (10 microM) reduced the apparent potency of 3 alpha, 5 alpha-P by 7-17-fold for modulating the binding of these radioligands in rat cortical membranes, suggesting that it has partial agonist properties. Because cortical membranes contain a heterogeneous population of receptors, Co 2-1970 was examined in recombinant GABAA receptors stably expressed in human embryonic kidney 293 cells. Co 2-1970 inhibited [35S]TBPS binding with limited efficacy (39-65% inhibition) in the five receptor combinations examined and, at 10 microM, reduced the apparent potency of 3 alpha, 5 alpha-P 57-fold for inhibiting [35S]TBPS binding to alpha 1 beta 1 gamma 2L receptors. To verify these findings functionally, the effects of 3 alpha, 5 alpha-P and Co 2-1970 were examined electrophysiologically in Xenopus oo-cytes expressing alpha 1 beta 1 gamma 2L receptors. Co 2-1970 showed limited efficacy potentiation of GABA-evoked chloride currents relative to 3 alpha, 5 alpha-P (28% and 86% of the GABA maximum current, respectively). Moreover, Co 2-1970 produced a concentration-dependent antagonism of the 3 alpha, 5 alpha-P-induced potentiation that was associated with a reduction in the apparent affinity of 3 alpha, 5 alpha-P (11-fold at 10 microM Co 2-1970). Taken together, these data indicate that Co 2-1970 is a partial agonist at the neuroactive steroid site associated with GABAA receptors.
Mol Pharmacol 1996 May
PMID:3 alpha-Hydroxy-3 beta-trifluoromethyl-5 alpha-pregnan-20-one (Co 2-1970): a partial agonist at the neuroactive steroid site of the gamma-aminobutyric acidA receptor. 862 40

A cDNA encoding the human gamma-aminobutyric acidA (GABAA) receptor alpha 6 subunit has been cloned and sequenced. The deduced amino acid sequence of this cDNA shows 91.4% identity with the published rat alpha 6 subunit. In situ hybridization histochemistry reveals the alpha 6 mRNA to be located within the granule cell layer of the human cerebellar cortex. Recombinant human alpha 6 beta gamma 2S GABAA receptors have been expressed in both stably transfected cells and Xenopus oocytes, and the pharmacology of the benzodiazepine binding site has been determined. The recombinant receptor has a diazepam-insensitive pharmacology, with negligible affinity for a number of classic benzodiazepines. A number of compounds that bind to the benzodiazepine site potentiated the GABA response of alpha 6 beta 2 gamma 2 receptors. Most importantly, the classic benzodiazepine antagonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788) and the partial inverse agonist ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (Ro 15-4513) both acted as agonists at the alpha 6 containing receptor. This observation demonstrates definitively that efficacy of benzodiazepine compounds cannot be generalized across receptor subtypes and may also help explain some of the behavioral effects that have been reported for these compounds.
Mol Pharmacol 1996 Feb
PMID:Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors. 863 57


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