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Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors

Abstract

Volatile anaesthetics have historically been considered to act in a nonspecific manner on the central nervous system1,2. More recent studies, however, have revealed that the receptors for inhibitory neurotransmitters such as γ-aminobutyric acid (GABA) and glycine are sensitive to clinically relevant concentrations of inhaled anaesthetics3. The function of GABAA and glycine receptors is enhanced by a number of anaesthetics4,5,6,7,8,9 and alcohols10,11,12, whereas activity of the related13 GABA ρ1 receptor is reduced14. We have used this difference in pharmacology to investigate the molecular basis for modulation of these receptors by anaesthetics and alcohols. By using chimaeric receptor constructs, we have identified a region of 45 amino-acid residues that is both necessary and sufficient for the enhancement of receptor function. Within this region, two specific amino-acid residues in transmembrane domains 2 and 3 are critical for allosteric modulation of both GABAA and glycine receptors by alcohols and two volatile anaesthetics. These observations support the idea that anaesthetics exert a specific effect on these ion-channel proteins, and allow for the future testing of specific hypotheses of the action of anaesthetics.

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Figure 1: Effects of ethanol and enflurane on wild-type glycine α1, GABA ρ1 and chimaeric receptors.
Figure 2: Sequence alignment of the TM2 and TM3 domains that are important for the action of ethanol and enflurane.
Figure 3: Identification of amino-acid residues in glycine and GABAA receptors critical for the actions of ethanol.
Figure 4: Amino-acid residues in glycine and GABAA receptors critical for the action of the volatile anaesthetic enflurane.

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Acknowledgements

We thank P. Schofield, G. Cutting, P. Whiting and the late D. Pritchett for cDNA; J. L. Kugler and W.-J. Tang for discussions on mutagenesis techniques, T. Dunwiddie, J. Weiner, C. Rick, H. Fozzard and D. McGehee for carefully reading our manuscript; and E. Eger and the UCSF Anesthesia Research Foundation for support of our collaborative project. This research was supported by NIH grants to N.L.H. and R.A.H., a young investigator award from the Foundation for Anesthesia Education and Research (E.P.G.), and an institutional postdoctoral training grant at the University of Chicago (V.V.K.).

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Correspondence to Neil L. Harrison.

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Mihic, S., Ye, Q., Wick, M. et al. Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature 389, 385–389 (1997). https://doi.org/10.1038/38738

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