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Contrasting Effects of the γ-Aminobutyric Acid Type A Receptor β3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R–mTFD-MPAB

Amlong, Corey A. MD, MS; Perkins, Mark G. BS; Houle, Timothy T. PhD; Miller, Keith W. DPhil; Pearce, Robert A. MD, PhD

Erratum

In the article, “Contrasting Effects of the γ-Aminobutyric Acid Type A Receptor β3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R–mTFD-MPAB,” that printed in the November 2016 issue on page 1241, contained an error. In the Methods section of the article, the first sentence of the second paragraph should read: “Etomidate (Tocris Bioscience, Bristol, UK) was dissolved in DMSO (Sigma, St. Louis, MO) to 5mg/ml stock solution.” The authors regret this error.

Anesthesia & Analgesia. 124(1):374, January 2017.

doi: 10.1213/ANE.0000000000001358
Neuroscience and Neuroanesthesiology: Original Laboratory Research Report

BACKGROUND: Previous studies have shown that etomidate modulates γ-aminobutyric acid type A receptors by binding at the β+ 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.

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 β3-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 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.

Published ahead of print June 30, 2016.

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.

Published ahead of print June 30, 2016.

Accepted for publication March 17, 2016.

Funding: National Institutes of Health grants: GM 58448 (KWM) and GM 101497 (RAP). Additional support came from the Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, as well as the Department of Anesthesiology, University of Wisconsin, Madison.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Robert A. Pearce, MD, PhD, Department of Anesthesiology, University of Wisconsin, School of Medicine and Public Health, 600 Highland Ave, B6/319 CSC, Madison, WI 53792. Address e-mail to rapearce@wisc.edu.

© 2016 International Anesthesia Research Society
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