title: Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca²⁺-dependent K⁺ channels.
abstract: Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA), found abundantly in oily fish, may have diverse health-promoting effects, potentially protecting the immune, nervous, and cardiovascular systems. However, the mechanisms underlying the purported health-promoting effects of DHA remain largely unclear, in part because molecular signaling pathways and effectors of DHA are only beginning to be revealed. In vascular smooth muscle cells, large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels provide a critical vasodilatory influence. We report here that DHA with an EC50 of ∼500 nM rapidly and reversibly activates BK channels composed of the pore-forming Slo1 subunit and the auxiliary subunit β1, increasing currents by up to ∼20-fold. The DHA action is observed in cell-free patches and does not require voltage-sensor activation or Ca(2+) binding but involves destabilization of the closed conformation of the ion conduction gate. DHA lowers blood pressure in anesthetized wild-type but not in Slo1 knockout mice. DHA ethyl ester, contained in dietary supplements, fails to activate BK channels and antagonizes the stimulatory effect of DHA. Slo1 BK channels are thus receptors for long-chain omega-3 fatty acids, and these fatty acids--unlike their ethyl ester derivatives--activate the channels and lower blood pressure. This finding has practical implications for the use of omega-3 fatty acids as nutraceuticals for the general public and also for the critically ill receiving omega-3-enriched formulas.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA. hoshi@hoshi.org
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
authors.forename: Bianka
authors.initials: B
authors.lastname: Wissuwa
authors.forename: Yutao
authors.initials: Y
authors.lastname: Tian
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Tajima
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.forename: Shangwei
authors.initials: S
authors.lastname: Hou
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D004281:Docosahexaenoic Acids; C067518:4,7,10,13,16,19-docosahexaenoic acid ethyl ester; D002118:Calcium