Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I Ks channel
| Autor: | Bo Hjorth Bentzen, Rene Barro-Soria, Teija Parkkari, Fredrik Elinder, Mark Alexander Skarsfeldt, Sara I. Liin, Johan E. Larsson, H. Peter Larsson, Malin Silverå Ejneby, Nicole Schmitt, Frida Starck Härlin |
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| Rok vydání: | 2015 |
| Předmět: |
KCNQ1 Potassium Channel
Guinea Pigs Static Electricity Kv7.1 KCNQ1 KCNE1 I-Ks antiarrhythmic Pharmacology Cardiac repolarization Rats sprague dawley Rats Sprague-Dawley Guinea pig Xenopus laevis Negative charge Animals Humans Myocytes Cardiac Neutral ph chemistry.chemical_classification Multidisciplinary Electric Conductivity Klinisk medicin food and beverages Arrhythmias Cardiac Heart Biological Sciences eye diseases Protein Structure Tertiary Rats Perfusion chemistry Biochemistry Mutation cardiovascular system Fatty Acids Unsaturated Microscopy Electron Scanning Oocytes Female lipids (amino acids peptides and proteins) sense organs Clinical Medicine Anti-Arrhythmia Agents human activities Polyunsaturated fatty acid |
| Zdroj: | Proceedings of the National Academy of Sciences. 112:5714-5719 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. 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 Finland |
| Databáze: | OpenAIRE |
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