Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel

Sara I. Liin, Malin Silverå Ejneby, Rene Barro-Soria, Mark Alexander Skarsfeldt, Johan E. Larsson, Frida Starck Härlin, Teija Parkkari, Bo Hjorth Bentzen, Nicole Schmitt, H. Peter Larsson, Fredrik Elinder

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5714-5719
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number18
DOIs
StatePublished - May 5 2015

Keywords

  • Antiarrhythmic
  • I
  • KCNE1
  • KCNQ1
  • Kv7.1

ASJC Scopus subject areas

  • General

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  • Cite this

    Liin, S. I., Ejneby, M. S., Barro-Soria, R., Skarsfeldt, M. A., Larsson, J. E., Härlin, F. S., Parkkari, T., Bentzen, B. H., Schmitt, N., Larsson, H. P., & Elinder, F. (2015). Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel. Proceedings of the National Academy of Sciences of the United States of America, 112(18), 5714-5719. https://doi.org/10.1073/pnas.1503488112