title: Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel.
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.
authors.affiliation: 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.
authors.forename: Sara I
authors.initials: SI
authors.lastname: Liin
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
authors.forename: Malin
authors.initials: M
authors.lastname: Silverå Ejneby
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miami, FL 33136;
authors.forename: Rene
authors.initials: R
authors.lastname: Barro-Soria
authors.affiliation: The Danish Arrhythmia Research Centre and Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; and.
authors.forename: Mark Alexander
authors.initials: MA
authors.lastname: Skarsfeldt
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miami, FL 33136; Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
authors.forename: Johan E
authors.initials: JE
authors.lastname: Larsson
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miami, FL 33136; Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
authors.forename: Frida
authors.initials: F
authors.lastname: Starck Härlin
authors.affiliation: School of Pharmacy, University of Eastern Finland, FI-70211 Kuopio, Finland.
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
authors.affiliation: The Danish Arrhythmia Research Centre and Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; and.
authors.forename: Bo Hjorth
authors.initials: BH
authors.lastname: Bentzen
authors.affiliation: The Danish Arrhythmia Research Centre and Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.affiliation: Department of Physiology and Biophysics, University of Miami, Miami, FL 33136; sara.liin@liu.se plarsson@med.miami.edu.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Larsson
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
authors.forename: Fredrik
authors.initials: F
authors.lastname: Elinder
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D004553:Electric Conductivity; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000737:chemistry* / Q000235:genetics; D008855:Microscopy, Electron, Scanning; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D010477:Perfusion; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D055672:Static Electricity; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; D005231:Fatty Acids, Unsaturated; D051657:KCNQ1 Potassium Channel
keywords: IKs; KCNE1; KCNQ1; Kv7.1; antiarrhythmic