1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites

  1. Noah M Dietzen
  2. Mark J Arcario
  3. Lawrence J Chen
  4. John T Petroff II
  5. K Trent Moreland
  6. Kathiresan Krishnan
  7. Grace Brannigan
  8. Douglas F Covey
  9. Wayland WL Cheng  Is a corresponding author
  1. Washington University in St. Louis, United States
  2. Rutgers University, United States
Research Article
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Cite this article as: eLife 2022;11:e74306 doi: 10.7554/eLife.74306

Abstract

Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) but the mechanism of inhibition is not well understood. The PUFA, docosahexaenoic acid (DHA), inhibits agonist responses of the pLGIC, ELIC, more effectively than palmitic acid, similar to the effects observed in the GABAA receptor and nicotinic acetylcholine receptor. Using photo-affinity labeling and coarse-grained molecular dynamics simulations, we identified two fatty acid binding sites in the outer transmembrane domain (TMD) of ELIC. Fatty acid binding to the photolabeled sites is selective for DHA over palmitic acid, and specific for an agonist-bound state. Hexadecyl-methanethiosulfonate modification of one of the two fatty acid binding sites in the outer TMD recapitulates the inhibitory effect of PUFAs in ELIC. The results demonstrate that DHA selectively binds to multiple sites in the outer TMD of ELIC, but that state-dependent binding to a single intrasubunit site mediates DHA inhibition of ELIC.

Data availability

Figure 4- source data 1 contains the numerical data used to generate Figure 4A and 4B. Figure 4- source data 2 contains the numerical data used to generate Figure 4C and Figure 4- figure supplement 5. Figure 4- source data 3 contains the statistical analysis (linear mixed effects model) for Figure 4- figure supplement 5.

Article and author information

Author details

  1. Noah M Dietzen

    Department of Anesthesiology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mark J Arcario

    Department of Anesthesiology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5017-1519
  3. Lawrence J Chen

    Department of Anesthesiology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. John T Petroff II

    Department of Anesthesiology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1323-0273
  5. K Trent Moreland

    Department of Anesthesiology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kathiresan Krishnan

    Department of Developmental Biology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Grace Brannigan

    Center for the Computational and Integrative Biology, Rutgers University, Camden, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Douglas F Covey

    Department of Developmental Biology, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Wayland WL Cheng

    Department of Anesthesiology, Washington University in St. Louis, St Louis, United States
    For correspondence
    wayland.cheng@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9529-9820

Funding

National Institutes of Health (R35GM137957)

  • Wayland WL Cheng

National Institutes of Health (F32GM139351)

  • John T Petroff II

National Institutes of Health (R01HL067773)

  • Douglas F Covey

National Institutes of Health (R01GM108799)

  • Douglas F Covey

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Marcel P Goldschen-Ohm, University of Texas at Austin, United States

Publication history

  1. Received: September 29, 2021
  2. Accepted: December 31, 2021
  3. Accepted Manuscript published: January 4, 2022 (version 1)
  4. Accepted Manuscript updated: January 7, 2022 (version 2)

Copyright

© 2022, Dietzen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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