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.