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

Ludovic Sauguet, Rebecca J. Howard, Laurie Malherbe, Ui S. Lee, Pierre-Jean Corringer, R. Adron Harris () and Marc Delarue ()
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Ludovic Sauguet: Unité de Dynamique Structurale des Macromolécules, Institut Pasteur
Rebecca J. Howard: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin
Laurie Malherbe: Unité de Dynamique Structurale des Macromolécules, Institut Pasteur
Ui S. Lee: Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin
Pierre-Jean Corringer: Groupe Récepteurs-Canaux, Institut Pasteur
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

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2682

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