Another, related, mutagenesis study utilizing homology models of the TMD region of GABAAR identified two potential binding pockets important for neurosteroid action: one intrasubunit site shared within αM1and αM4 mediating enhancement of GABA, and a second, intersubunit site αM1/βM3, involved in direct gating of channels, respectively (Hosie et al., 2006). The steroid and etomidate site models have the intersubunit pockets near each other but steroids do not inhibit etomidate binding (Li et al.,2006). It is possible that the residues needed for steroid action identified by mutagenesis are involved in conformational coupling and not binding. More information is needed to understand how these important residues participate in structure and function. Better models of GABAAR structure will not only be useful for future rational drug design but also for aiding our understanding of their functional mechanism of action. The generation of knock-in mice carrying a mutation of the respective residues will be invaluable in a more detailed clarification of the action of these drugs and help to identify the receptor subtypes involved in their effects.
