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Query: UNIPROT:P06889 (Mol)
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gamma-Aminobutyric acid (GABA)-activated Cl- currents in neonatal rat cortical neurons and in cultured cells engineered for the expression of specific molecular forms of the GABAA receptor alpha, beta, and gamma subunits, were recorded with the patch-clamp technique in the whole-cell configuration. The effects of various allosteric modulators of GABAA receptors were determined. Diazepam and clonazepam showed greater efficacy as positive modulators of GABA-elicited currents in alpha 2 beta 1 gamma 2 or alpha 3 beta 1 gamma 2 receptors than in alpha 1 beta 1 gamma 2 or alpha 5 beta 1 gamma 2 receptors or in cortical neurons. Alpidem was more efficacious at alpha 1 beta 1 gamma 2 or alpha 2 beta 1 gamma 2 receptors than at alpha 1 beta 1 gamma 2 or alpha 5 beta 1 gamma 2 receptors or in cortical neurons. Conversely, zolpidem was equally efficacious for all these receptors except for alpha 5 beta 1 gamma 2. Both imidazopyridines (alpidem and zolpidem) were virtually ineffective at modulating the GABA response of alpha 5 beta 1 gamma 2 receptors and in almost all the receptors assembled from alpha 1, alpha 2, alpha 3 or alpha 5 subunits together with beta 1 and gamma 1 subunits. The beta-carboline derivatives methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and methyl-beta-carboline-3-carboxylate (beta-CCM) elicited a positive allosteric modulation of alpha 1 beta 1 gamma 1 or alpha 2 beta 1 gamma 1 receptors, whereas they acted as negative allosteric modulators at nearly all other receptors tested, as they do in cortical neurons. Although the positive allosteric modulation by beta-carbolines never exceeded a doubling of the GABA response, DMCM was more efficacious at alpha 1 beta 1 gamma 1 receptors and beta-CCM was more efficacious at alpha 2 beta 1 gamma 1 receptors. DMCM was inactive at alpha 3 beta 1 gamma 1 receptors, whereas beta-CCM was virtually inactive at alpha 5 beta 1 gamma 1 receptors. The benzodiazepine 4'-chlorodiazepam, which is a negative modulator resistent to flumazenil inhibition, acted at all the various GABAA receptors that contained a gamma subunit.
Mol Pharmacol 1991 Jun
PMID:Influence of recombinant gamma-aminobutyric acid-A receptor subunit composition on the action of allosteric modulators of gamma-aminobutyric acid-gated Cl- currents. 164 44

3-Acyloxy-, 3-methoxy-, and 3-alkyl-substituted derivatives of the benzodiazepine (BZ) agonist desmethyl-diazepam (DMD) were resolved, and the stereochemical properties of binding to central BZ receptors were investigated in synaptosomal membrane preparations of rat brain. Decreasing potency and stereoselectivity of 3-methyl, 3-ethyl, and 3-isopropyl derivatives in displacement of [3H]diazepam binding can be attributed to differential susceptibilities for steric hindrance of 3-axial versus 3-equatorial substituents of the binding conformation M. Chirality in the alpha-methyl-beta-phenyl-propionic acyl moiety of oxazepam, the 3-OH-derivative of DMD, was noncritical in binding, whereas the beta-phenyl substituent selectively increased the binding of the 3S-stereoisomer. Changing the pH from 7.4 to 5.6 significantly increased the IC50 of (3R)-oxazepam acetate but not those of (3R)-methyl-DMD and diazepam. Binding data led to a steric model of the BZ binding site with the postulation of an additional hydrogen-bond-donating moiety, probably histidine in the "ceiling" of the receptor cavity, that binds the 3-carbonyloxy groups and hinders the 3-alkyl ones. In vitro efficacies of 3-substituted BZs were estimated by allosteric binding interactions within the gamma-aminobutyric acidA (GABAA) receptor-ionophore complex. Non-equilibrium enhancement of t-butyl-bicyclophosphoro[35S]thionate binding by the BZ agonist oxazepam was stereoselectively antagonized by (3S)-oxazepam-(S)-alpha-methyl-beta-phenyl-propionate, suggesting a mixed agonist-antagonist character. GABA enhanced the [3H]diazepam-displacing potencies of the 3S-enantiomers of the acetate, hemisuccinate, and (S)-alpha-methyl-beta-phenyl-propionate esters of oxazepam by a factor of about 1.5-1.6, whereas the GABA shifts for 3R-esters were about 1.2. UV affinity labeling with flunitrazepam resulted in a significantly smaller decrease in the displacing potency of (3R)-oxazepam acetate than in that of the 3S-enantiomer. GABA shifts of successively 3-methylated DMD derivatives were also compared. The GABA shifts of DMD and its (3S)-methyl and 3,3-dimethyl derivatives were all characteristic of full agonists (2.4-2.7), whereas that of (3R)-methyl-DMD was 1.5. The 3-methoxy enantiomers of DMD displayed stereoselectivity and GABA shift values intermediate between those of 3-methyl and 3-acetoxy derivatives. These allosteric interactions suggest that 3-carbonyloxy derivatives in general, as well as (3R)-BZ enantiomers bound with axial 3-alkyl and 3-alkyloxy groups, decrease the agonist efficacies of 1,4-BZs to modulate the GABAA receptor complex.
Mol Pharmacol 1991 Jun
PMID:Central benzodiazepine receptors: in vitro efficacies and potencies of 3-substituted 1,4-benzodiazepine stereoisomers. 164 47

Peptides derived from prodynorphin and preproenkephalin are located in GABAergic striatal projection neurons. We have used nucleic acid hybridization techniques to investigate the role of GABA in the regulation of striatal opioid peptide gene expression. Rats were treated with the GABA-transaminase inhibitors aminooxy acetic acid, ethanolamine O-sulphate and gamma-vinyl-GABA for one week. The GABA levels in the striatum were significantly elevated after each treatment. The GABA-transaminase-inhibitors decreased the striatal levels of the opioid peptides met-enkephalin and dynorphin(1-8) and concomitantly decreased the concentrations of the mRNAs coding for proenkephalin and prodynorphin. These findings indicate that GABA exerts an inhibitory influence on prodynorphin and proenkephalin gene expression in the striatum. The mechanisms underlying these inhibitions are discussed.
Brain Res Mol Brain Res 1991 Apr
PMID:GABAergic regulation of striatal opioid gene expression. 164 82

1. In this commentary we discuss results obtained by a micromethod for the study of Cl- permeability across single nerve membranes from rabbit Deiters' neurons. 2. These results showed the presence of GABAA receptors on the nerve cell membrane cytoplasmic side. 3. We could show that these receptor complexes have a higher affinity for GABA than their extracellularly facing counterparts. Moreover, they present a phenomenon of desensitization. Another distinct property is that upon activation by GABA, they expose positive charges at their cytoplasmic mouths. 4. We propose that these receptor complexes could function in situ as a device for extruding Cl- anions from the nerve cell interior. This phenomenon would create an electrochemical gradient for Cl- penetration into the cell upon the action of extracellular GABA, after its presynaptic release.
Cell Mol Neurobiol 1991 Jun
PMID:Can Cl- ions be extruded from a gamma-aminobutyric (GABA)-acceptive nerve cell via GABAA receptors on the plasma membrane cytoplasmic side? 165 Nov 63

We have characterized the gamma-aminobutyric acid-A (GABAA) and benzodiazepine (BZ) receptors in in vitro living slices of adult rat neocortex using [3H]SR95531, a GABAA antagonist, and [3H]flunitrazepam (FNZ), a BZ ligand. [3H]SR95531 labelled a single population of GABAA receptors with a Bmax of 1030.7 fmol/mg protein and a Kd of 43.5 nM. [3H]FNZ also labelled a single binding site with a Bmax of 4239 fmol/mg protein and a Kd of 22 nM. The GABAA receptor labelled using [3H]SR95531 could be down-regulated by 2 h preincubations in GABA and the GABAA agonist muscimol (8% and 11%, respectively). Increases in cellular electrical activity induced by a combination of veratridine and glutamate led to an average increase in GABAA receptor number of 58%. The BZ binding site labelled with [3H]FNZ was down-regulated by clonazepam (-55%), increased by GABA (+17%), but not altered by changes in electrical activity. The present results demonstrate the rapid differential regulation of a ligand-gated receptor by agonist stimulation or increases in bioelectric activity. Such regulation may provide clues to the nature of the modifications which occur following changes in cellular activity in the cortex.
Brain Res Mol Brain Res 1991 Oct
PMID:Characterization and differential regulation of GABAA and benzodiazepine receptors in rat neocortex. 168 29

Glial cells of the central nervous system express receptors for the main inhibitory and excitatory neurotransmitters, GABA and glutamate. The glial GABA and glutamate receptors share many properties with the neuronal GABAA and kainate/quisqualate receptors, but are molecularly and, in some aspects, pharmacologically distinct from their neuronal counterparts. The functional role of these receptors is as yet speculative: They have been proposed to control proliferation of astrocytes, serve to balance ion changes at GABAergic synapses, or they could enable the glial cell to detect neuronal synaptic activity.
Mol Neurobiol 1991
PMID:Glutamate and GABA receptors in vertebrate glial cells. 168 51

In previous reports, we have described the use of primary neuronal cultures derived from chick brain to study the regulation of the gamma-aminobutyric acidA (GABAA) receptor complex. Chronic exposure of cultures to GABA, benzodiazepines, or methylxanthines results in decreased enhancement of [3H]flunitrazepam binding by GABA, consistent with an allosteric uncoupling of GABA and benzodiazepine recognition sites of the GABAA receptor. In the present communication, we extend our studies of the pharmacology of benzodiazepine- and methylxanthine-induced uncoupling of GABA/benzodiazepine recognition site interactions and present evidence to show that certain barbiturates (barbital and pentobarbital) also induce uncoupling. Chronic exposure to flurazepam (a high efficacy benzodiazepine) elicits no change in the number of benzodiazepine binding sites or the affinity of benzodiazepine binding in the absence of GABA. Whereas flurazepam and theophylline decrease coupling, Ro15-1788 (a low efficacy benzodiazepine) inhibits flurazepam-induced but not theophylline-induced uncoupling, suggesting that theophylline and flurazepam act through separate receptors. Flurazepam-induced uncoupling is not prevented by SR-95531 or picrotoxin (specific inhibitors of GABA action) and, therefore, is not an indirect effect mediated by endogenous GABA. The onset of flurazepam-induced uncoupling (EC50 approximately 1 microM) exhibits a t 1/2 of about 18 hr, in general agreement with the half-time for receptor turnover. Uncoupling is reversible following washout and recovery at 37 degrees. These results are discussed in terms of mechanisms of GABAA receptor regulation in response to chronic exposure to functionally homologous or heterologous ligands.
Mol Pharmacol 1990 May
PMID:gamma-Aminobutyric acidA receptor regulation in culture: altered allosteric interactions following prolonged exposure to benzodiazepines, barbiturates, and methylxanthines. 169 7

1. Retina-cell aggregate cultures expressed glutamate decarboxylase activity (L-glutamate 1-carboxylase; EC 4.1.1.15) as a function of culture differentiation. 2. Glutamic acid decarboxylase (GAD) activity was low in the initial phases of culture and increased eight-fold until culture day 7, remaining high up to day 13 (last stage studied). 3. The addition of GABA to the culture medium 24 h after cell seeding almost totally prevented the expression of GAD activity. 4. In association with decreased enzyme activity, aggregates exposed to GABA did not display immunoreactivity for GAD, suggesting that GAD molecules were either lost from GABAergic neurons or significantly altered with GABA treatment. 5. Control, untreated aggregates showed intense GAD immunoreactivity in neurons. Positive cell bodies were characterized by a thin rim of labeled cytoplasm with thickest labeling at the emergence of the main neurite. 6. Heavily labeled patches were also observed throughout the aggregates, possibly reflecting regions enriched in neurites. 7. The GABA-mediated reduction of GAD immunoreactivity was a reversible phenomenon and could be prevented by picrotoxin.
Cell Mol Neurobiol 1991 Oct
PMID:Glutamic acid decarboxylase of embryonic avian retina cells in culture: regulation by gamma-aminobutyric acid (GABA). 174 70

Pregnenolone (P) and dehydroepiandrosterone (D) accumulate in the brain as unconjugated steroids and their sulfate (S) and fatty acid (L) esters. The microsomal acyl-transferase activity is highest in immature (1-3 weeks old) male rats. The immunocytochemical and biochemical evidence for P biosynthesis by differentiated oligodendrocytes is reviewed. The importance of P synthesis for its brain accumulation is assessed by the intracysternal injection of the inhibitor aminoglutethimide. Primary glial cell cultures convert P to 20-OH-P, PL, progesterone, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnane-20-one (Polone). Astroglial cell cultures also produce these metabolites, whereas neurons from 17-day mouse embryos only form 20-OH-P. P and D are converted to the corresponding 7 alpha-hydroxylated metabolites by a very active P-450 enzyme from rat brain microsomes. Several functions of neurosteroids are documented. P decreases in olfactory bulb of intact male rats exposed to the scent of estrous females. D inhibits the aggressive behavior of castrated male mice towards lactating female intruders. The D analog 3 beta-methyl-androst-5-en-17-one, which cannot be metabolized into sex steroids and is not demonstrably androgenic or estrogenic is at least as efficient as D. Both compounds elicit a marked decrease of PS in rat brain. The Cl- conductance of gamma-aminobutyric (GABAA) receptor is stimulated by GABA agonists, an effect which is enhanced by Polone and antagonized by PS. Thus, P metabolites in brain as well as steroids of extraencephalic sources may be involved physiologically in GABAA receptor function. The neurosteroids accumulated in brain may be precursors of sex steroid hormones and progesterone receptors have been localized in glial cells. P and D do not bind to any known intracellular receptor. A heat stable P binding protein has been found in brain cytosol with distinct ligand specificity. A binding component specific for steroids sulfates, including Polone S, DS and PS, in the order of decreasing affinity is localized in adult rat brain synaptosomal membranes. Its relationship to the GABAA receptor is under current investigation.
J Steroid Biochem Mol Biol 1991
PMID:Neurosteroids: biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain. 183 45

Interleukin-1 (IL-1), a cytokine involved in the acute phase reaction to injury and infection, has multiple effects in the central nervous system, including induction of fever and sleep and the release of several neuropeptides. We evaluated effects of IL-1 beta on inhibitory postsynaptic function at the gamma-aminobutyric acidA (GABAA) receptor. IL-1 (100 pg/ml to 10 ng/ml) augmented GABAA receptor function in cortical synaptic preparations. This effect of IL-1 was largely prevented by incubation with a specific IL-1 receptor antagonist. The related cytokines interleukin-6 and tumor necrosis factor did not augment GABA-dependent chloride transport. Similar enhancement of GABAA receptor function was observed in tissue prepared from mice previously injected intraperitoneally with IL-1 (1 microgram). Electrophysiological studies in cultured primary cortical neurons demonstrated that IL-1 enhanced the GABA-mediated increase in chloride permeability, whereas IL-1 alone produced no alterations in resting conductance. Behavioral studies indicated that IL-1 is similarly active in vivo; mice treated with IL-1 showed a decrease in open-field activity and an increase in the threshold for pentylenetetrazol-induced seizures. The interaction of IL-1 with GABAA receptors might account for the somnogenic and motor-depressant effects of this cytokine.
Mol Pharmacol 1991 Feb
PMID:Interleukin-1 augments gamma-aminobutyric acidA receptor function in brain. 184 88


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