The effects of pregnene and androstane steroids were studied on recombinant human glycine receptors (GlyRs) by whole-cell voltage-clamp electrophysiology. The 3β-sulphates of pregnenolone (PREGS) and dehydroepiandrosterone (DHEAS) inhibited GlyR currents with KI values of 2-20 μM for different (α1, α2, α4 and β) GlyR subunits. PREGS resulted in a parallel shift of the response curve of glycine for α1 GlyRs. The inhibitory potencies of DHEAS relative to PREGS were decreased in transition from embryonic α2 towards adult α1β GlyRs. A decreased potency of DHEAS for α4 versus α2 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 stereoselectivity. Some point mutations of α1 GlyRs with characteristic functional consequences did not significantly affect the inhibitory potency of PREGS. Progesterone selectively inhibited α2 GlyRs, while PREG and its acetic ester potentiated α1 GlyRs. Coexpression of the α subunits with the β 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.
- Androsterone sulphate
- Dehydroepiandrosterone sulphate
- Glycine receptors
- Neuronal steroids
- Structure-activity relationships of neurosteroids and glycine receptors
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience