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Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity
Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..ORCID iD: 0000-0003-3224-4547
Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
Stockholm Univ, Dept Biochem & Biophys, S-11419 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 42, p. 10672-10677Article in journal (Refereed) Published
Abstract [en]

Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to similar to 30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2018. Vol. 115, no 42, p. 10672-10677
Keywords [en]
ion channels, molecular dynamics, oocyte, general anesthetic, allostery
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:kth:diva-238118DOI: 10.1073/pnas.1809650115ISI: 000447491300054PubMedID: 30275330Scopus ID: 2-s2.0-85054997177OAI: oai:DiVA.org:kth-238118DiVA, id: diva2:1264576
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20181120

Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2018-11-20Bibliographically approved

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Lindahl, Erik

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