The sticky issue of neurosteroids and GABA_A receptors

Endogenous neurosteroids and their synthetic analogs (neuroactive steroids) are potent modulators of GABA_A receptors. Thus, they are of physiological and clinical relevance for their ability to modulate inhibitory function in the CNS. Despite their importance, fundamental issues of neurosteroid actions remain unresolved. Recent evidence suggests that glutamatergic principal neurons, rather than glia, are the major sources of neurosteroid synthesis. Other recent studies have identified putative neurosteroid binding sites on GABA_A receptors. In this Opinion, we argue that neurosteroids require a membranous route of access to transmembrane-domain binding sites within GABA_A receptors. This has implications for the design of future neuroactive steroids because the lipid solubility and related accessibility properties of the ligand are likely to be key determinants of receptor modulation.