Atomic determinants of BK channel activation by polyunsaturated fatty acids

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