Mutations in the GABAA receptor that mimic the allosteric ligand etomidate.

Etomidate is a hydrophobic molecule, a potent general anesthetic, and the best understood drug in this group. Etomidate's target molecules are GABA(A) receptors, its site of action has been identified with photolabeling, and a quantitative allosteric coagonist model has emerged for etomidate effects on GABA(A) receptors. We have shown that when methionine residues that are thought to be adjacent to the etomidate site are mutated to tryptophan, that the bulky hydrophobic side-chains alter mutant GABA(A) receptor function in ways that mimic the effects of etomidate binding to wild-type receptors. Furthermore, these mutations reduce receptor modulation by etomidate. Both of these observations support the hypothesis that these methionine residues form part of the etomidate binding pocket.