RT Journal Article
SR Electronic
T1 Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.08.463634
DO 10.1101/2021.10.08.463634
A1 Noah M. Dietzen
A1 Mark J. Arcario
A1 Lawrence J. Chen
A1 John T. Petroff II
A1 Kathiresan Krishnan
A1 Grace Brannigan
A1 Douglas F. Covey
A1 Wayland W. L. Cheng
YR 2021
UL http://biorxiv.org/content/early/2021/10/08/2021.10.08.463634.abstract
AB 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 StatementThe authors have declared no competing interest.