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Structural Models of Ligand-Gated Ion Channels: Sites of Action for Anesthetics and Ethanol

Authors

  • Richard W. Olsen,

    Corresponding author
    1. Department of Molecular & Medical Pharmacology , David Geffen School of Medicine at UCLA, Los Angeles, California
    2. Department of Anesthesiology , David Geffen School of Medicine at UCLA, Los Angeles, California
    • Reprint requests: Richard W. Olsen, PhD, Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Room CHS 23-120, 650 Young Drive South, Los Angeles, CA 90095-1735; Tel.: 310-825-5093; Fax: 310-267-2003; E-mail: rolsen@mednet.ucla.edu

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  • Guo-Dong Li,

    1. Department of Molecular & Medical Pharmacology , David Geffen School of Medicine at UCLA, Los Angeles, California
    2. Department of Anesthesiology , David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Martin Wallner,

    1. Department of Molecular & Medical Pharmacology , David Geffen School of Medicine at UCLA, Los Angeles, California
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  • James R. Trudell,

    1. Department of Anesthesia , Stanford University School of Medicine, Stanford, California
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  • Edward J. Bertaccini,

    1. Department of Anesthesia , Stanford University School of Medicine, Stanford, California
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  • Erik Lindahl,

    1. KTH Royal Institute of Technology , Stockholm, Sweden
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  • Keith W. Miller,

    1. Department of Anesthesia and Critical Care , Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Ronald L. Alkana,

    1. School of Pharmacy , University of Southern California, Los Angeles, California
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  • Daryl L. Davies

    1. School of Pharmacy , University of Southern California, Los Angeles, California
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  • The subject of this mini-review has been presented in a symposium held at the Research Society on Alcoholism (RSA), June 23 to June 27, 2012 (San Francisco, California). Organizers and Chairs of the symposium were Richard W. Olsen and Daryl L. Davies. Introducer was Richard W. Olsen. Speakers were James R. Trudell, Keith W. Miller, Richard W. Olsen, and Daryl Davies. Discussant was Daryl L. Davies.

Abstract

The molecular mechanism(s) of action of anesthetic, and especially, intoxicating doses of alcohol (ethanol [EtOH]) have been of interest even before the advent of the Research Society on Alcoholism. Recent physiological, genetic, and biochemical studies have pin-pointed molecular targets for anesthetics and EtOH in the brain as ligand-gated ion channel (LGIC) membrane proteins, especially the pentameric (5 subunit) Cys-loop superfamily of neurotransmitter receptors including nicotinic acetylcholine (nAChRs), GABAA (GABAARs), and glycine receptors (GlyRs). The ability to demonstrate molecular and structural elements of these proteins critical for the behavioral effects of these drugs on animals and humans provides convincing evidence for their role in the drugs' actions. Amino acid residues necessary for pharmacologically relevant allosteric modulation of LGIC function by anesthetics and EtOH have been identified in these channel proteins. Site-directed mutagenesis revealed potential allosteric modulatory sites in both the trans-membrane domain (TMD) and extracellular domain (ECD). Potential sites of action and binding have been deduced from homology modeling of other LGICs with structures known from crystallography and cryo-electron microscopy studies. Direct information about ligand binding in the TMD has been obtained by photoaffinity labeling, especially in GABAARs. Recent structural information from crystallized procaryotic (ELIC and GLIC) and eukaryotic (GluCl) LGICs allows refinement of the structural models including evaluation of possible sites of EtOH action.

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