Neurosteroid: Molecular Mechanisms of Action on the GABAA Receptor

Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals and the gonads and have potent and selective effects on the gamma-aminobutyric acid type A (GABAA receptor). 3α-Hydroxy A-ring-reduced metabolites of progesterone, deoxycorticosterone and testosterone enhance the the Cl– flux through GABAA receptor conductance at nanomolar concentrations in a non-genomic (rapid and direct) manner. Studies on the GABAA receptors have shown that allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α,17α- diol (Adiol) and (3 5 3, 21-dihydroxypregnan-20-one (3α5αTHDOC) enhance the GABA mediated Cl– currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate and picrotoxin binding sites. This modulation site (or sites) has a well-defined structure–activity relationship with a 3α-hydroxy and a 20-ketone configuration in the pregnane molecule required for agonist action. However, the neurosteroid pregnenolone sulfate (PS) is a non-competitive GABAA receptor antagonist and inhibits GABA-activated Cl– currents in an activationdependent manner. 3β-hydroxy A-ring reduced pregnane steroids are pregnenolone sulfate-like GABAA receptors antagonists and inhibit the GABAA receptor’s function and its potentiation induced by their 3α-diasteromers in a non-competitive manner. The specificity of neurosteroid action on the GABAA receptor results from a variety of molecular mechanisms, including receptor subunit composition, receptor activation–deactivation, and steroid concentration. Here, we will review the GABAmodulatory actions of the neurosteroids. The molecular mechanisms underpinning the non-genomic effect of agonist and antagonist neurosteroids will be discussed with particular emphasis being given to the role of GABAA receptor isoforms.