Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I_Ks channel

TY - JOUR

T1 - Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel

AU - Liin, Sara I.

AU - Silverå Ejneby, Malin

AU - Barro-Soria, Rene

AU - Skarsfeldt, Mark Alexander

AU - Larsson, Johan E.

AU - Starck Härlin, Frida

AU - Parkkari, Teija

AU - Bentzen, Bo Hjorth

AU - Schmitt, Nicole

AU - Larsson, H. Peter

AU - Elinder, Fredrik

PY - 2015/5/5

Y1 - 2015/5/5

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1503488112

DO - 10.1073/pnas.1503488112

M3 - Journal article

C2 - 25901329

SN - 0027-8424

VL - 112

SP - 5714

EP - 5719

JO - Proceedings of the National Academy of Science of the United States of America

JF - Proceedings of the National Academy of Science of the United States of America

IS - 18

ER -