Neurosteroid Modulation of GABAA Receptor Function by Independent Action at Multiple Specific Binding Sites

Neurosteroids are endogenous modulators of GABA(A) receptors that mediate anxiety, pain, mood and arousal. The 3-hydroxyl epimers, allopregnanolone (3 alpha-OH) and epi-allopregnanolone (3 beta-OH) are both prevalent in the mammalian brain and produce opposite effects on GABA(A) receptor function, acting as positive and negative allosteric modulators, respectively. This Perspective provides a model to explain the actions of 3 alpha-OH and 3 beta-OH neurosteroids. The model is based on evidence that the neurosteroid epimers bind to an overlapping subset of specific sites on GABA(A) receptors, with their net functional effect on channel gating being the sum of their independent effects at each site.