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

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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-01721610
Contributor : Ana Cova Rodrigues <>
Submitted on : Friday, March 2, 2018 - 12:21:16 PM
Last modification on : Monday, January 13, 2020 - 5:08:18 PM

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Ludovic Sauguet, Rebecca Howard, Laurie Malherbe, Ui Lee, Pierre-Jean Corringer, et al.. Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel. Nature Communications, Nature Publishing Group, 2013, 4, pp.1697. ⟨10.1038/ncomms2682⟩. ⟨pasteur-01721610⟩

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