Fatty acid analogue N-Arachidonoyl taurine restores function of IKs channels with diverse long QT mutations
Abstract
About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.
Article and author information
Author details
Funding
National Institutes of Health (R01GM109762)
- H Peter Larson
American Heart Association (14GRNT20380041)
- H Peter Larson
Svenska Sällskapet för Medicinsk Forskning
- Sara I Liin
Vetenskapsrådet (524-2011-6806)
- Sara I Liin
Northwest Lions Foundation
- Sara I Liin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experiments were performed in strict accordance with the recommendations of The Linköping Animal Ethics Committee at Linköping University and The Animal Experiments Inspectorate under the Danish Ministry of Food, Agriculture and Fisheries. Protocols were approved by The Linköping Animal Ethics Committee at Linköping University (#53-13 ) and The Animal Experiments Inspectorate under the Danish Ministry of Food, Agriculture and Fisheries (University of Copenhagen; #2014-15-2934-01061).
Copyright
© 2016, Liin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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