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Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel

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  • Ludovic Sauguet

    (Unité de Dynamique Structurale des Macromolécules, Institut Pasteur
    UMR 3258, Centre National de la Recherche Scientifique
    Groupe Récepteurs-Canaux, Institut Pasteur
    Unité de Recherche Associée 2182, Centre National de la Recherche Scientifique)

  • Rebecca J. Howard

    (Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin
    Present address: Chemistry Department, Skidmore College, Saratoga Springs, NY 12866, USA)

  • Laurie Malherbe

    (Unité de Dynamique Structurale des Macromolécules, Institut Pasteur
    UMR 3258, Centre National de la Recherche Scientifique
    Groupe Récepteurs-Canaux, Institut Pasteur
    Unité de Recherche Associée 2182, Centre National de la Recherche Scientifique)

  • Ui S. Lee

    (Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin)

  • Pierre-Jean Corringer

    (Groupe Récepteurs-Canaux, Institut Pasteur
    Unité de Recherche Associée 2182, Centre National de la Recherche Scientifique)

  • R. Adron Harris

    (Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin)

  • Marc Delarue

    (Unité de Dynamique Structurale des Macromolécules, Institut Pasteur
    UMR 3258, Centre National de la Recherche Scientifique)

Abstract

Ethanol alters nerve signalling by interacting with proteins in the central nervous system, particularly pentameric ligand-gated ion channels. A recent series of mutagenesis experiments on Gloeobacter violaceus ligand-gated ion channel, a prokaryotic member of this family, identified a single-site variant that is potentiated by pharmacologically relevant concentrations of ethanol. Here we determine crystal structures of the ethanol-sensitized variant in the absence and presence of ethanol and related modulators, which bind in a transmembrane cavity between channel subunits and may stabilize the open form of the channel. Structural and mutagenesis studies defined overlapping mechanisms of potentiation by alcohols and anaesthetics via the inter-subunit cavity. Furthermore, homology modelling show this cavity to be conserved in human ethanol-sensitive glycine and GABA(A) receptors, and to involve residues previously shown to influence alcohol and anaesthetic action on these proteins. These results suggest a common structural basis for ethanol potentiation of an important class of targets for neurological actions of ethanol.

Suggested Citation

  • Ludovic Sauguet & Rebecca J. Howard & Laurie Malherbe & Ui S. Lee & Pierre-Jean Corringer & R. Adron Harris & Marc Delarue, 2013. "Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel," Nature Communications, Nature, vol. 4(1), pages 1-10, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2682
    DOI: 10.1038/ncomms2682
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    Cited by:

    1. Steven J Tobin & Eliedonna E Cacao & Daniel Wing Wo Hong & Lars Terenius & Vladana Vukojevic & Tijana Jovanovic-Talisman, 2014. "Nanoscale Effects of Ethanol and Naltrexone on Protein Organization in the Plasma Membrane Studied by Photoactivated Localization Microscopy (PALM)," PLOS ONE, Public Library of Science, vol. 9(2), pages 1-7, February.
    2. Nikhil Bharambe & Zhuowen Li & David Seiferth & Asha Manikkoth Balakrishna & Philip C. Biggin & Sandip Basak, 2024. "Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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