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Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels
Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France.;UPMC Univ Paris 6, Sorbonne Univ, F-75005 Paris, France..
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2018 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 23, no 4, p. 993-1004Article in journal (Refereed) Published
Abstract [en]

Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

Place, publisher, year, edition, pages
Cell Press , 2018. Vol. 23, no 4, p. 993-1004
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:kth:diva-229036DOI: 10.1016/j.celrep.2018.03.108ISI: 000432453100009PubMedID: 29694907Scopus ID: 2-s2.0-85045563225OAI: oai:DiVA.org:kth-229036DiVA, id: diva2:1211525
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilSwedish eā€Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20180531

Available from: 2018-05-31 Created: 2018-05-31 Last updated: 2018-05-31Bibliographically approved

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Lindahl, Erik

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