Subunit-specific modulation of glycine receptors by neurosteroids

The effects of pregnene and androstane steroids were studied on recombinant human glycine receptors GlyRs) by whole-cell voltage-clamp electrophysiology. The 3 beta -sulphates of pregnenolone (PREGS) and dehydroepiandrosterone (DHEAS) inhibited GlyR currents with K-i values of 2-20 muM for different (alpha (1), alpha (2), alpha (4) and beta) GlyR subunits. PREGS resulted in a parallel shift of the response curve of glycine for al GlyRs. The inhibitory potencies of DHEAS relative to PREGS were decreased in transition from embryonic alpha (2) towards adult alpha (1)beta GlyRs. A decreased potency of DHEAS for alpha (4) versus alpha (2) GlyRs represents the first pharmacological difference reported between these subunits. A negative charge at C3 is required for GlyR antagonism but androsterone sulphate epimers at C3 inhibited without stereo selectivity. Some point mutations of alpha (1) GlyRs with characteristic functional consequences did not significantly affect the inhibitory potency of PREGS. Progesterone selectively inhibited alpha (2) GlyRs, while PREG and its acetic ester potentiated alpha (1) GlyRs. Coexpression of the alpha subunits with the beta subunit eliminated the enhancing effects of PREG and attenuated the inhibitory potencies of the neurosteroids. Based on these data we propose that neurosteroids might modulate perinatal GlyR activity and thereby influence neuronal development, (C) 2001 Elsevier Science Ltd. All rights reserved.