Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel
2015 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 18, 5714-5719 p.Article in journal (Refereed) Published
Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the beta-subunit KCNE1 form the cardiac I-Ks channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as I-Ks 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(a) value, to preserve their negative charge at neutral pH, restore the sensitivity to open I-Ks channels. PUFA analogs with a positively charged head group inhibit I-Ks 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.
Place, publisher, year, edition, pages
National Academy of Sciences , 2015. Vol. 112, no 18, 5714-5719 p.
Kv7.1; KCNQ1; KCNE1; I-Ks; antiarrhythmic
IdentifiersURN: urn:nbn:se:liu:diva-118981DOI: 10.1073/pnas.1503488112ISI: 000353953800056PubMedID: 25901329OAI: oai:DiVA.org:liu-118981DiVA: diva2:818177
Funding Agencies|National Institutes of Health [R01GM109762]; American Heart Association [14GRNT20380041]; Swedish Research Council; Swedish Heart-Lung Foundation; County Council of Ostergotland; Queen Silvias Anniversary Foundation; Academy of Finland2015-06-082015-06-052016-04-25