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Structural basis for alcohol modulation of a pentameric ligand-gated ion channel
University of Texas.
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
University of Texas.
Institut Pasteur.
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2011 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 29, 12149-54 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 108, no 29, 12149-54 p.
National Category
Biophysics Bioinformatics and Systems Biology Theoretical Chemistry
Research subject
SRA - E-Science (SeRC)
Identifiers
URN: urn:nbn:se:kth:diva-82584DOI: 10.1073/pnas.1104480108ISI: 000292876900084PubMedID: 21730162Scopus ID: 2-s2.0-79961074761OAI: oai:DiVA.org:kth-82584DiVA: diva2:498397
Funder
Swedish Research CouncilSwedish e‐Science Research Center
Note
Conference Neuroscience 2011. QC 20120217Available from: 2012-02-12 Created: 2012-02-12 Last updated: 2017-12-07Bibliographically approved

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Lindahl, Erik

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