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 electrophysiolo gy. The 3 beta -sulphates of pregnenolone (PREGS) and dehydroepiandrosteron e (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 i n a parallel shift of the response curve of glycine for al GlyRs. The inhib itory potencies of DHEAS relative to PREGS were decreased in transition fro m embryonic alpha (2) towards adult alpha (1)beta GlyRs. A decreased potenc y of DHEAS for alpha (4) versus alpha (2) GlyRs represents the first pharma cological 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) Gly Rs 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. Coe xpression of the alpha subunits with the beta subunit eliminated the enhanc ing effects of PREG and attenuated the inhibitory potencies of the neuroste roids. Based on these data we propose that neurosteroids might modulate per inatal GlyR activity and thereby influence neuronal development, (C) 2001 E lsevier Science Ltd. All rights reserved.