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Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. University of Miami, FL 33136 USA.ORCID-id: 0000-0001-8493-0114
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.ORCID-id: 0000-0002-8151-5430
University of Miami, FL 33136 USA.
University of Copenhagen, Denmark; University of Copenhagen, Denmark.
Vise andre og tillknytning
2015 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 18, s. 5714-5719Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
National Academy of Sciences , 2015. Vol. 112, nr 18, s. 5714-5719
Emneord [en]
Kv7.1; KCNQ1; KCNE1; I-Ks; antiarrhythmic
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-118981DOI: 10.1073/pnas.1503488112ISI: 000353953800056PubMedID: 25901329OAI: oai:DiVA.org:liu-118981DiVA, id: diva2:818177
Merknad

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

Tilgjengelig fra: 2015-06-08 Laget: 2015-06-05 Sist oppdatert: 2024-01-10

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