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Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites

Noah M. Dietzen, View ORCID ProfileMark J. Arcario, Lawrence J. Chen, View ORCID ProfileJohn T. Petroff II, Kathiresan Krishnan, Grace Brannigan, Douglas F. Covey, View ORCID ProfileWayland W. L. Cheng
doi: https://doi.org/10.1101/2021.10.08.463634
Noah M. Dietzen
1Department of Anesthesiology, Washington University in St. Louis, MO, USA
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Mark J. Arcario
1Department of Anesthesiology, Washington University in St. Louis, MO, USA
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Lawrence J. Chen
1Department of Anesthesiology, Washington University in St. Louis, MO, USA
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John T. Petroff II
1Department of Anesthesiology, Washington University in St. Louis, MO, USA
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Kathiresan Krishnan
2Department of Developmental Biology, Washington University in St. Louis, MO, USA
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Grace Brannigan
5Center for the Computational and Integrative Biology, Rutgers University, Camden, NJ, USA
6Department of Physics, Rutgers University, Camden, NJ, USA
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Douglas F. Covey
1Department of Anesthesiology, Washington University in St. Louis, MO, USA
2Department of Developmental Biology, Washington University in St. Louis, MO, USA
3Department of Psychiatry, Washington University in St. Louis, MO, USA
4Department of Taylor Institute for Innovative Psychiatric Research, Washington University in St. Louis, MO, USA
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Wayland W. L. Cheng
1Department of Anesthesiology, Washington University in St. Louis, MO, USA
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  • ORCID record for Wayland W. L. Cheng
  • For correspondence: wayland.cheng@wustl.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 08, 2021.
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Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
Noah M. Dietzen, Mark J. Arcario, Lawrence J. Chen, John T. Petroff II, Kathiresan Krishnan, Grace Brannigan, Douglas F. Covey, Wayland W. L. Cheng
bioRxiv 2021.10.08.463634; doi: https://doi.org/10.1101/2021.10.08.463634
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Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
Noah M. Dietzen, Mark J. Arcario, Lawrence J. Chen, John T. Petroff II, Kathiresan Krishnan, Grace Brannigan, Douglas F. Covey, Wayland W. L. Cheng
bioRxiv 2021.10.08.463634; doi: https://doi.org/10.1101/2021.10.08.463634

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