• Corey A Amlong, Mark G Perkins, Timothy T Houle, Keith W Miller, and Robert A Pearce.
• From the *Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; and †Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.
• Anesth. Analg. 2016 Nov 1; 123 (5): 124112461241-1246.

BackgroundPrevious studies have shown that etomidate modulates γ-aminobutyric acid type A 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 γ-aminobutyric acid type A receptors primarily by binding to a homologous site at the γ-β interface. Given this difference in drug-binding sites established by the 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.MethodsWe measured the effects of IV injection of etomidate and R-mTFD-MPAB on loss and recovery of righting reflex in wild-type mice and in mice carrying the β3-N265M mutation.ResultsEtomidate-induced hypnosis, as measured by the duration of loss of righting reflex, was attenuated in the N265M knock-in mice, confirming prior results. By contrast, recovery of balance and coordinated movement, as measured by the ability to maintain all 4 paws on the ground, was unaffected by the mutation. Neither hypnosis nor impairment of coordinated movement produced by the barbiturate R-mTFD-MPAB was affected by the mutation.ConclusionsThe findings confirmed our hypothesis that mutating the etomidate-binding site would not alter the response to the barbiturate R-mTFD-MPAB. Furthermore, we confirmed previous studies indicating that etomidate-induced hypnosis is mediated in part by β3-containing receptors. We also extended previous findings by showing that etomidate-impaired balance and coordinated movement are not mediated by β3-containing receptors, thus implicating β2-containing receptors in this end point.

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