Atomic determinants of BK channel activation by polyunsaturated fatty acids.

ABSTRACT: Docosahexaenoic acid (DHA), a polyunsaturated ?-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca²⁺- and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery.

SUBMITTER: Tian Y 

PROVIDER: S-EPMC5137720 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature