Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the β-subunit KCNE1 form the cardiac I<inf>Ks</inf> channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as I<inf>Ks</inf> 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 pK<inf>a</inf> value, to preserve their negative charge at neutral pH, restore the sensitivity to open I<inf>Ks</inf> channels. PUFA analogs with a positively charged head group inhibit I<inf>Ks</inf> 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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - May 5 2015|
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