| First Author | Amlong CA | Year | 2016 |
| Journal | Anesth Analg | Volume | 123 |
| Issue | 5 | Pages | 1241-1246 |
| PubMed ID | 27331778 | Mgi Jnum | J:340435 |
| Mgi Id | MGI:7529330 | Doi | 10.1213/ANE.0000000000001358 |
| Citation | Amlong CA, et al. (2016) 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. Anesth Analg 123(5):1241-1246 |
| abstractText | BACKGROUND: Previous studies have shown that etomidate modulates gamma-aminobutyric acid type A receptors by binding at the beta-alpha subunit interface within the transmembrane domain of receptors that incorporate beta2 or beta3 subunits. Introducing an asparagine-to-methionine (N265M) mutation at position 265 of the beta3 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 gamma-aminobutyric acid type A receptors primarily by binding to a homologous site at the gamma-beta interface. Given this difference in drug-binding sites established by the in vitro experiments, we hypothesized that the beta3-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. METHODS: We 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 beta3-N265M mutation. RESULTS: Etomidate-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. CONCLUSIONS: The 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 beta3-containing receptors. We also extended previous findings by showing that etomidate-impaired balance and coordinated movement are not mediated by beta3-containing receptors, thus implicating beta2-containing receptors in this end point. |
