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© Marie Prévost, Institut Pasteur
Image of a portion of a Xenopus oocyte expressing a channel receptor.
Publication : Proceedings of the National Academy of Sciences of the United States of America

Structural basis for alcohol modulation of a pentameric ligand-gated ion channel

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Proceedings of the National Academy of Sciences of the United States of America - 05 Jul 2011

Howard RJ, Murail S, Ondricek KE, Corringer PJ, Lindahl E, Trudell JR, Harris RA

Link to Pubmed [PMID] – 21730162

Proc. Natl. Acad. Sci. U.S.A. 2011 Jul;108(29):12149-54

Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the “linking tunnel.” These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member.

http://www.ncbi.nlm.nih.gov/pubmed/21730162