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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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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. |
format | Online Article Text |
id | pubmed-8786314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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