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

Autor: Dietzen NM; Department of Anesthesiology, Washington University in St. Louis, St Louis, United States., Arcario MJ; Department of Anesthesiology, Washington University in St. Louis, St Louis, United States., Chen LJ; Department of Anesthesiology, Washington University in St. Louis, St Louis, United States., Petroff JT 2nd; Department of Anesthesiology, Washington University in St. Louis, St Louis, United States., Moreland KT; Department of Anesthesiology, Washington University in St. Louis, St Louis, United States., Krishnan K; Department of Developmental Biology, Washington University in St. Louis, St Louis, United States., Brannigan G; Center for the Computational and Integrative Biology, Rutgers University, Camden, United States.; Department of Physics, Rutgers University, Camden, United States., Covey DF; Department 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 States., Cheng WW; Department of Anesthesiology, Washington University in St. Louis, St Louis, United States.
Jazyk: angličtina
Zdroj: ELife [Elife] 2022 Jan 04; Vol. 11. Date of Electronic Publication: 2022 Jan 04.
DOI: 10.7554/eLife.74306
Abstrakt: 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.
Competing Interests: ND, MA, LC, JP, KM, KK, GB, DC, WC No competing interests declared
(© 2022, Dietzen et al.)
Databáze: MEDLINE
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