Article date: 1990/2/1
PubMed ID: 1689453
Journal name: Molecular pharmacology (ISSN: 0026-895X)
The potentiation of gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several of these steroids, including 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC), increase the potency of muscimol to stimulate 36Cl- uptake in a concentration-dependent and stereospecific manner. Concentration-response curves for 3 alpha-OH-DHP, THDOC, 3 alpha-hydroxy-pregn-4-en-20-one, and pentobarbital enhancement of muscimol-stimulated 36Cl- uptake are biphasic, with Hill coefficients significantly less than 1.0. Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s). In contrast, the concentration-response curve for THDOC 21-mesylate is monophasic, with a smaller maximal response, and yields a Hill coefficients of 1.0. In addition to modulating GABA receptor-mediated 36Cl- uptake, THDOC enhanced the ability of the benzodiazepine clonazepam to potentiate muscimol-stimulated 36Cl- uptake. The central benzodiazepine antagonist Ro15-1788 failed to inhibit THDOC-induced potentiation of muscimol-stimulated 36Cl- uptake, although it has been previously reported to inhibit some of the behavioral actions of THDOC. In contrast to the A ring-reduced metabolites and analogues of progesterone and deoxycorticosterone, glucocorticoids had no effect on muscimol-stimulated 36Cl- uptake in cerebral cortical synaptoneurosomes at concentrations between 20 nM and 5 microM.
Author List: Morrow A L, Pace J R, Purdy R H, Paul S M
Publication Types: Journal Article
Substances mentioned in the article: Chloride Channels; Chlorides; Ion Channels; Membrane Proteins; Receptors, GABA-A; Steroids; 20-alpha-Dihydroprogesterone; 3-hydroxypregn-4-en-20-one; Desoxycorticosterone; tetrahydrodeoxycorticosterone; Pregnanolone;
Mesh terms: 20-alpha-Dihydroprogesterone/analogs & derivatives; Animals; Cerebral Cortex/drug effects; Chloride Channels; Chlorides/metabolism; Desoxycorticosterone/analogs & derivatives; In Vitro Techniques; Ion Channel Gating/drug effects; Ion Channels/drug effects; Membrane Proteins/metabolism; Pregnanolone/pharmacology; Rats; Receptors, GABA-A/drug effects; Steroids/metabolism; Structure-Activity Relationship; Synaptosomes/drug effects;