Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel

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  • Ailing Tong
    Department of Anesthesiology, Washington University, Saint Louis, United States
  • John T Petroff
    Department of Anesthesiology, Washington University, Saint Louis, United States
  • Fong-Fu Hsu
    Department of Internal Medicine, Mass Spectrometry Resource, Division of Endocrinology, Diabetes, Metabolism, and Lipid Research, Washington University, Saint Louis, United States
  • Philipp AM Schmidpeter
    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
  • Crina M Nimigean
    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
  • Liam Sharp
    Center for Computational and Integrative Biology, Rutgers University, Camden, United States
  • Grace Brannigan
    Center for Computational and Integrative Biology, Rutgers University, Camden, United States
  • Wayland WL Cheng
    Department of Anesthesiology, Washington University, Saint Louis, United States

Abstract

<jats:p>Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.</jats:p>

Journal

  • eLife

    eLife 8 2019-11-14

    eLife Sciences Publications, Ltd

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