title: 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.
authors.affiliation: Unité de Dynamique Structurale des Macromolécules, Institut Pasteur, F-75015 Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Sauguet
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Howard
authors.forename: Laurie
authors.initials: L
authors.lastname: Malherbe
authors.forename: Ui S
authors.initials: US
authors.lastname: Lee
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Corringer
authors.forename: R Adron
authors.initials: RA
authors.lastname: Harris
authors.forename: Marc
authors.initials: M
authors.lastname: Delarue
mesh_terms: D000595:Amino Acid Sequence; D000777:Anesthetics / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004357:Drug Synergism; D000431:Ethanol / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry / Q000187:drug effects*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid
chemical_list: D000777:Anesthetics; D007473:Ion Channels; D008024:Ligands; D000431:Ethanol