Functional modulation of cerebral gamma-aminobutyric acidA receptor/benzodiazepine receptor/chloride ion channel complex with ethyl beta-carboline-3-carboxylate: presence of independent binding site for ethyl beta-carboline-3-carboxylate.

Article date: 1990/5/1

PubMed ID: 2159999

Journal name: The Journal of pharmacology and experimental therapeutics (ISSN: 0022-3565)


Effect of ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of gamma-aminobutyric acid (GABA)A receptor/benzodiazepine receptor/chloride ion channel complex was studied. Beta-CCE noncompetitively and competitively inhibited [3H]flunitrazepam binding to benzodiazepine receptor, but not [3H]muscimol binding to GABAA receptor as well as t-[3H]butylbicycloorthobenzoate [( 3H] TBOB) binding to chloride ion channel, in particulate fraction of the mouse brain. Ro15-1788 also inhibited competitively [3H] flunitrazepam binding. On the other hand, the binding of beta-[3H]CCE was inhibited noncompetitively and competitively by clonazepam and competitively by Ro15-1788. In agreement with these results, benzodiazepines-stimulated [3H]muscimol binding was antagonized by beta-CCE and Ro15-1788. Gel column chromatography for the solubilized fraction from cerebral particulate fraction by 0.2% sodium deoxycholate (DOC-Na) in the presence of 1 M KCl indicated that beta-[3H]CCE binding site was eluted in the same fraction (molecular weight, 250,000) as the binding sites for [3H]flunitrazepam, [3H]muscimol and [3H]TBOB. GABA-stimulated 36Cl- influx into membrane vesicles prepared from the bovine cerebral cortex was stimulated and attenuated by flunitrazepam and beta-CCE, respectively. These effects of flunitrazepam and beta-CCE on the GABA-stimulated 36Cl- influx were antagonized by Ro15-1788. The present results suggest that the binding site for beta-CCE, which resides on GABAA receptor/benzodiazepine receptor/chloride ion channel complex, may be different from that for benzodiazepine. Possible roles of beta-CCE binding site in the allosteric inhibitions on benzodiazepine binding site as well as on the functional coupling between chloride ion channel and GABAA receptor are also suggested.

Author List: Taguchi J, Kuriyama K

Publication Types: Journal Article; Research Support, Non-U.S. Gov't

Substances mentioned in the article: Carbolines; Chloride Channels; Chlorides; Membrane Proteins; Receptors, GABA-A; Tritium; Muscimol; Flunitrazepam; beta-carboline-3-carboxylic acid ethyl ester; Baclofen;

Mesh terms: Animals; Baclofen/metabolism; Binding Sites; Brain/drug effects; Carbolines/metabolism; Cells, Cultured; Chloride Channels; Chlorides/metabolism; Drug Interactions; Flunitrazepam/metabolism; Male; Membrane Proteins/metabolism; Mice; Muscimol/metabolism; Receptors, GABA-A/drug effects; Tritium;

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