Neurosteroid binding sites on GABA(A) receptors. 
Controlling neuronal excitability is vitally important for maintaining a healthy central nervous system (CNS) and this relies on the activity of type A gamma-aminobutyric acid (GABA(A)) neurotransmitter receptors.  Given this role, it is therefore important to understand how these receptors are regulated by endogenous modulators in the brain and determine where they bind to the receptor.  One of the most potent groups of modulators is the neurosteroids which regulate the activity of synaptic and extrasynaptic GABA(A) receptors.  This level of regulation is thought to be physiologically important and its dysfunction may be relevant to numerous neurological conditions.  The aim of this review is to summarise those studies that over the last 20 years have focussed upon finding the binding sites for neurosteroids on GABA(A) receptors.  We consider the nature of steroid binding sites in other proteins where this has been determined at atomic resolution and how their generic features were mapped onto GABA(A) receptors to help locate 2 putative steroid binding sites.  Altogether, the findings strongly suggest that neurosteroids do bind to discrete sites on the GABA(A) receptor and that these are located within the transmembrane domains of alpha and beta receptor subunits.  The implications for neurosteroid binding to other inhibitory receptors such as glycine and GABA(C) receptors are also considered.  Identifying neurosteroid binding sites may enable the precise pathophysiological role(s) of neurosteroids in the CNS to be established for the first time, as well as providing opportunities for the design of novel drug entities.