Characterization of steroid interactions with γ-aminobutyric acid receptor-gated chloride ion channels: Evidence for multiple steroid recognition sites

A. L. Morrow, J. R. Pace, R. H. Purdy, S. M. Paul

Research output: Contribution to journalArticlepeer-review

340 Scopus citations

Abstract

The potentiation of γ-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several of these steroids, including 3α-hydroxy-5α-pregnan-20-one(3α-OH-DHP) and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC), increase the potency of muscimol to stimulate 36Cl- uptake in a concentration-dependent and stereospecific manner. Concentration-response curves for 3α-OH-DHP, THDOC, 3α-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 GABA(A) 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 μM.

Original languageEnglish
Pages (from-to)263-270
Number of pages8
JournalMolecular pharmacology
Volume37
Issue number2
StatePublished - Mar 28 1990

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