Neurosteroids positively and negatively modulate γ-aminobutyric acid (GABA)A receptors and glutamate receptors, which underlie most fast inhibition and excitation in the central nervous system. We report the identification of a neuroactive steroid, (3α,5β)-20-oxo-pregnane-3-carboxylic acid (3α5βPC), with unique cellular actions. 3α5βPC positively modulates GABAA receptor function and negatively modulates N-methyl-D-aspartate (NMDA) receptor function, a combination that may be of particular clinical benefit. 3α5βPC promotes net GABAA potentiation at low steroid concentrations (<10 μM) and at negative membrane potentials. At higher concentrations, the steroid also blocks GABA receptors. Because this block would presumably counteract the NMDA receptor blocking actions of 3α5βPC, we characterize the GABA receptor block in some detail. Agonist concentration, depolarization, and high extracellular pH increase the block. The apparent pK for both potentiation and block was 6.4 to 6.9, substantially higher than expected from carboxylated steroid in an aqueous environment. Block is not dependent on the stereochemistry of the carboxylic acid at carbon 3 and is relatively insensitive to placement of the carboxylic acid at the opposite end of the steroid (carbon 24). Potentiation is critically dependent on the stereochemistry of the carboxylic acid group at carbon 3. Consistent with the pH dependence of potentiation, effects of the amide derivative (3α,5β)-20-oxo-pregnane-3-carboxamide, suggest that the unionized form of 3α5βPC is important for potentiation, whereas the ionized form is probably responsible for block. Further refinement of the neuroactive steroid to promote GABA potentiation and NMDA receptor block and diminish GABA receptor block may lead to a clinically useful neuroactive steroid.

Original languageEnglish
Pages (from-to)732-741
Number of pages10
JournalMolecular pharmacology
Issue number4
StatePublished - 2001


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