Potentiation of GABAA receptors by neurosteroids: Mechanisms and sites

Neurosteroids increase the strength of neuronal inhibition by enhancing the activity of GABA-A receptors. The response to lower concentrations of GABA is increased in the presence of these drugs. One question is the nature of the basis for the potentiation - is there a change in the affinity of the receptor for GABA or an increase in the efficacy of activation? The answer for these drugs is that the major change occurs in the efficacy of activation, with no change in channel opening but a decrease in rates for entering states with a closed channel. There are at least 2 sites of action, which can be distinguished by the activity of steroid analogues with different structures. There are at least 3 mechanisms of action. Mutations of GABAA receptor subunits indicate that at least one site for steroid action is likely to be at the extreme carboxyl end of the γ2 subunit. Analysis of data obtained at a low concentration of GABA suggests that the ability of steroids to potentiate the GABAA receptor may be affected by the extent of ligation with GABA.