Project Summary Long-‐‑chain polyunsaturated omega-‐‑3 fatty acids, such as docosahexaenoic acid (DHA) with a 22-‐‑carbon chain, are found abundantly in oily fish including anchovy, herring, mackerel, and salmon. These omega-‐‑3 fatty acids are widely thought to have multiple health-‐‑promoting effects. Evidence suggests that DHA decreases blood pressure, especially in hypertensive patients. We hypothesize that the hypotensive action of DHA is mediated by its stimulatory effect on large-‐‑conductance calcium and voltage-‐‑gated potassium (Slo1 BK) channels important in blood pressure regulation. The research program proposed here will provide molecular and atomic basis of the hypotensive action of DHA involving Slo1 BK channels using biophysical, biochemical, and whole-‐‑animal methods. We postulate that a hydrogen bond between a tyrosine residue in the S6 segment of the channel and the carboxylate group is critical in destabilizing the closed conformation of the ion conduction gate and this interaction underlies the whole-‐‑animal hypertensive action. Using the physicochemical principles elucidated, we will rationally design, synthesize and test fatty-‐‑acid activators of Slo1 BK channels. The anticipated outcome of the research program has potential to explain blood pressure regulation of whole animals based on the hydrogen bonds formed between specific tyrosine residues of the Slo1 BK channel and DHA and provide a solid mechanistic foundation for discovery and development of pharmaceuticals and nutraceuticals for blood pressure management.