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

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...

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Autores principales: Dietzen, Noah M, Arcario, Mark J, Chen, Lawrence J, Petroff, John T, Moreland, K Trent, Krishnan, Kathiresan, Brannigan, Grace, Covey, Douglas F, Cheng, Wayland WL
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786314/
https://www.ncbi.nlm.nih.gov/pubmed/34982031
http://dx.doi.org/10.7554/eLife.74306
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author Dietzen, Noah M
Arcario, Mark J
Chen, Lawrence J
Petroff, John T
Moreland, K Trent
Krishnan, Kathiresan
Brannigan, Grace
Covey, Douglas F
Cheng, Wayland WL
author_facet Dietzen, Noah M
Arcario, Mark J
Chen, Lawrence J
Petroff, John T
Moreland, K Trent
Krishnan, Kathiresan
Brannigan, Grace
Covey, Douglas F
Cheng, Wayland WL
author_sort Dietzen, Noah M
collection PubMed
description 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 GABA(A) 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.
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spelling pubmed-87863142022-01-26 Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites Dietzen, Noah M Arcario, Mark J Chen, Lawrence J Petroff, John T Moreland, K Trent Krishnan, Kathiresan Brannigan, Grace Covey, Douglas F Cheng, Wayland WL eLife Biochemistry and Chemical Biology 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 GABA(A) 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. eLife Sciences Publications, Ltd 2022-01-04 /pmc/articles/PMC8786314/ /pubmed/34982031 http://dx.doi.org/10.7554/eLife.74306 Text en © 2022, Dietzen et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Dietzen, Noah M
Arcario, Mark J
Chen, Lawrence J
Petroff, John T
Moreland, K Trent
Krishnan, Kathiresan
Brannigan, Grace
Covey, Douglas F
Cheng, Wayland WL
Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
title Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
title_full Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
title_fullStr Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
title_full_unstemmed Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
title_short Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
title_sort polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786314/
https://www.ncbi.nlm.nih.gov/pubmed/34982031
http://dx.doi.org/10.7554/eLife.74306
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