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omega-6 and omega-9 polyunsaturated fatty acids with double bonds near the carboxyl head have the highest affinity and largest effects on the cardiac I-Ks potassium channel
Univ Miami, FL 33136 USA.
Univ Miami, FL 33136 USA.
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-8493-0114
Univ Miami, FL 33136 USA.
2019 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 225, no 2, article id UNSP e13186Article in journal (Refereed) Published
Abstract [en]

Aim The I-Ks channel is important for termination of the cardiac action potential. Hundreds of loss-of-function mutations in the I-Ks channel reduce the K+ current and, thereby, delay the repolarization of the action potential, causing Long QT Syndrome. Long QT predisposes individuals to Torsades de Pointes which can lead to ventricular fibrillation and sudden death. Polyunsaturated fatty acids (PUFAs) are potential therapeutics for Long QT Syndrome, as they affect I-Ks channels. However, it is unclear which properties of PUFAs are essential for their effects on I-Ks channels. Methods To understand how PUFAs influence I-Ks channel activity, we measured effects on I-Ks current by two-electrode voltage clamp while changing different properties of the hydrocarbon tail. Results There was no, or weak, correlation between the tail length or number of double bonds in the tail and the effects on or apparent binding affinity for I-Ks channels. However, we found a strong correlation between the positions of the double bonds relative to the head group and effects on I-Ks channels. Conclusion Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I-Ks channels and increased I-Ks current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the I-Ks current. Interestingly, we found that omega-6 and omega-9 PUFAs, with the first double bond closer to the head group, left-shifted the voltage dependence of activation the most. These results allow for informed design of new therapeutics targeting I-Ks channels in Long QT Syndrome.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 225, no 2, article id UNSP e13186
Keywords [en]
I-Ks; KCNE1; KCNQ1; Kv7.1; Long QT Syndrome; polyunsaturated fatty acids
National Category
Physiology
Identifiers
URN: urn:nbn:se:liu:diva-154317DOI: 10.1111/apha.13186ISI: 000456161200001PubMedID: 30184322OAI: oai:DiVA.org:liu-154317DiVA, id: diva2:1285540
Note

Funding Agencies|NIH [R01-HL131461]; Swedish Society for Medical Research

Available from: 2019-02-04 Created: 2019-02-04 Last updated: 2019-03-07

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