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Steroid modulation of the GABA/benzodiazepine receptor-linked chloride lonophore

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Abstract

Recent findings suggest that steroids with sedative-hypnotic properties interact specifically with the γ-aminobutyric acidA/benzodiazepine receptor-chloride ionophore complex (GBRC). They show positive heterotropic cooperativity by allosterically enhancing the binding of GABA agonists and the clinically useful benzodiazepines (BZs) to their respective recognition sites. These steroids have stringent structural requirements for activity at the GBRC, with the essential requirements for high potency being a 3α-hydroxyl group and a 5α-reduced A-ring. Some of these steroids are naturally occurring metabolites of progesterone and deoxycorticosterone and have nanomolar potencies as potentiators of chloride channel conductance. These 3α-hydroxylated, 5α-reduced steroids do not act through any known sites on the GBRC. Thus, the exact site and mechanism of action remain to be determined. Together with the observation that physiological levels of these metabolites are sufficient to influence the function of the GBRC, the evidence clearly suggests a role for these steroids in the normal regulation of brain excitability by potentiating the postsynaptic effects of γ-aminobutyric acid (GABA). Pharmacological studies of the GBRC-active steroids show that they possess anxiolytic and anticonvylsan activities. The potential therapeutic application of these steriods in the treatment of mood disorders and catamenial exacerbation of seizures associated with the menstrual cycle is discussed. Collectively, the evidence from the studies of these steriods imply that another mechanism by which the endocrine system influences brain function has been identified. Its characterization will provide important insight into how steroids modulate brain excitability under normal and pathophysiological states.

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    Kelvin W. Gee

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Gee, K.W. Steroid modulation of the GABA/benzodiazepine receptor-linked chloride lonophore. Mol Neurobiol 2, 291–317 (1988). https://doi.org/10.1007/BF02935636

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