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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/74306 |
| _version_ | 1811199430469091328 |
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| author | Noah M Dietzen Mark J Arcario Lawrence J Chen John T Petroff II K Trent Moreland Kathiresan Krishnan Grace Brannigan Douglas F Covey Wayland WL Cheng |
| author_facet | Noah M Dietzen Mark J Arcario Lawrence J Chen John T Petroff II K Trent Moreland Kathiresan Krishnan Grace Brannigan Douglas F Covey Wayland WL Cheng |
| author_sort | Noah M Dietzen |
| collection | DOAJ |
| 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 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. |
| first_indexed | 2024-04-12T01:47:58Z |
| format | Article |
| id | doaj.art-28bf0dd55ae64ba8b05cd03aeee35398 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:47:58Z |
| publishDate | 2022-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-28bf0dd55ae64ba8b05cd03aeee353982022-12-22T03:53:00ZengeLife Sciences Publications LtdeLife2050-084X2022-01-011110.7554/eLife.74306Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sitesNoah M Dietzen0Mark J Arcario1https://orcid.org/0000-0001-5017-1519Lawrence J Chen2John T Petroff II3https://orcid.org/0000-0002-1323-0273K Trent Moreland4Kathiresan Krishnan5Grace Brannigan6Douglas F Covey7Wayland WL Cheng8https://orcid.org/0000-0002-9529-9820Department of Anesthesiology, Washington University in St. Louis, St Louis, United StatesDepartment of Anesthesiology, Washington University in St. Louis, St Louis, United StatesDepartment of Anesthesiology, Washington University in St. Louis, St Louis, United StatesDepartment of Anesthesiology, Washington University in St. Louis, St Louis, United StatesDepartment of Anesthesiology, Washington University in St. Louis, St Louis, United StatesDepartment of Developmental Biology, Washington University in St. Louis, St Louis, United StatesCenter for the Computational and Integrative Biology, Rutgers University, Camden, United States; Department of Physics, Rutgers University, Camden, United StatesDepartment of Anesthesiology, Washington University in St. Louis, St Louis, United States; Department of Developmental Biology, Washington University in St. Louis, St Louis, United States; Department of Psychiatry, Washington University in St. Louis, St. Louis, United States; Taylor Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, United StatesDepartment of Anesthesiology, Washington University in St. Louis, St Louis, United StatesPolyunsaturated 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.https://elifesciences.org/articles/74306ligand-gated ion channeldocosahexaenoic acidpolyunsaturated fatty acidphotoaffinity labelingmass spectrometrycoarse-grained molecular dynamics simulations |
| spellingShingle | Noah M Dietzen Mark J Arcario Lawrence J Chen John T Petroff II K Trent Moreland Kathiresan Krishnan Grace Brannigan Douglas F Covey Wayland WL Cheng Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites eLife ligand-gated ion channel docosahexaenoic acid polyunsaturated fatty acid photoaffinity labeling mass spectrometry coarse-grained molecular dynamics simulations |
| 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 | ligand-gated ion channel docosahexaenoic acid polyunsaturated fatty acid photoaffinity labeling mass spectrometry coarse-grained molecular dynamics simulations |
| url | https://elifesciences.org/articles/74306 |
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