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

Nat Commun. 2013;4:1697. doi: 10.1038/ncomms2682.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anesthetics / chemistry
  • Anesthetics / pharmacology*
  • Crystallography, X-Ray
  • Drug Synergism
  • Ethanol / chemistry
  • Ethanol / pharmacology*
  • Humans
  • Ion Channel Gating*
  • Ion Channels / chemistry
  • Ion Channels / drug effects*
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Sequence Homology, Amino Acid

Substances

  • Anesthetics
  • Ion Channels
  • Ligands
  • Ethanol

Associated data

  • PDB/4FHF
  • PDB/4HFB
  • PDB/4HFC
  • PDB/4HFD
  • PDB/4HFE