Neurosteroid Modulation of GABA_A 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 (3α-OH) and epi-allopregnanolone (3β-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 3α-OH and 3β-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.