Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel

Significance More than 300 mutations in the genes encoding the cardiac IKs channel have been identified in patients with cardiac arrhythmia. These mutations cause either loss of function or gain of function of the IKs channel. This study describes how polyunsaturated fatty acids and their analogues activate or inhibit the IKs channel. These modulators can restore rhythmic firing in arrhythmic firing cardiac myocytes and restore prolonged QT interval in guinea pig hearts. The study also describes a mechanism by which an auxiliary β-subunit alters the pharmacological sensitivity of the IKs channel. Our findings may form the basis for future design of antiarrhythmic compounds that target IKs channels for treating different cardiac arrhythmias caused by mutations in the IKs channel. Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the β-subunit KCNE1 form the cardiac IKs channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as IKs channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pKa value, to preserve their negative charge at neutral pH, restore the sensitivity to open IKs channels. PUFA analogs with a positively charged head group inhibit IKs channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.