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Proc Natl Acad Sci U S A. 2015 May 5;112(18):5714-9. doi: 10.1073/pnas.1503488112. Epub 2015 Apr 21.

Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel.

Author information

1
Department of Physiology and Biophysics, University of Miami, Miami, FL 33136; Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden; sara.liin@liu.se plarsson@med.miami.edu.
2
Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
3
Department of Physiology and Biophysics, University of Miami, Miami, FL 33136;
4
The Danish Arrhythmia Research Centre and Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; and.
5
Department of Physiology and Biophysics, University of Miami, Miami, FL 33136; Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
6
School of Pharmacy, University of Eastern Finland, FI-70211 Kuopio, Finland.
7
Department of Physiology and Biophysics, University of Miami, Miami, FL 33136; sara.liin@liu.se plarsson@med.miami.edu.

Abstract

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.

KEYWORDS:

IKs; KCNE1; KCNQ1; Kv7.1; antiarrhythmic

PMID:
25901329
PMCID:
PMC4426425
DOI:
10.1073/pnas.1503488112
[Indexed for MEDLINE]
Free PMC Article

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