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Proc Natl Acad Sci U S A 2015 May 05;11218:5714-9. doi: 10.1073/pnas.1503488112.
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Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel.

Liin SI , Silverå Ejneby M , Barro-Soria R , Skarsfeldt MA , Larsson JE , Starck Härlin F , Parkkari T , Bentzen BH , Schmitt N , Larsson HP , Elinder F .

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.

PubMed ID: 25901329
PMC ID: PMC4426425
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: kcne1

Article Images: [+] show captions
References [+] :
Aiba, Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil. 2005, Pubmed