The Contrasting Effects of the Gamma-Aminobutyric Acid Type A Receptor Beta3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R–mTFD-MPAB

摘要

BackgroundPrior studies have shown that etomidate modulates γ-aminobutyric acid type A (GABAA) receptors by binding at the β⁺ – α⁻ subunit interface within the transmembrane domain of receptors that incorporate β2 or β3 subunits. Introducing an asparagine-to-methionine (N265M) mutation at position 265 of the β3 subunit, which sits within the etomidate binding site, attenuates the hypnotic effect of etomidate in vivo. It was reported recently that the photoactivatable barbiturate R–mTFD-MPAB also acts on GABAA receptors primarily by binding to a homologous site at the γ - β interface. Given this difference in drug binding sites established by in vitro experiments, we hypothesized that the β3-N265M mutant mice would not be resistant to the anesthetic effects of R–mTFD-MPAB in vivo, whereas the same mutant mice would be resistant to the anesthetic effects of R-etomidate.