Fatty acid analogue N-Arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

Abstract
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Abstract

About 300 loss-of-function mutations in the I_Ks 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 I_Ks channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated I_Ks channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in I_Ks 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 I_Ks channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future I_Ks channel activators to treat Long QT syndrome caused by diverse I_Ks channel mutations.

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Author details

Sara I Liin

Department of Physiology and Biophysics, University of Miami, Miami, United States

For correspondence
sara.liin@liu.se

Competing interests
Sara I Liin, A patent application (62/032,739) based on these results has been submitted by the University of Miami with S.I.L. and H.P.L. identified as inventors.

"This ORCID iD identifies the author of this article:" 0000-0001-8493-0114
Johan E Larsson

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

Competing interests
No competing interests declared.
Rene Barro-Soria

Department of Physiology and Biophysics, University of Miami, Miami, United States

Competing interests
No competing interests declared.
Bo Hjorth Bentzen

The Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark

Competing interests
No competing interests declared.
H Peter Larson

Department of Physiology and Biophysics, University of Miami, Miami, United States

For correspondence
PLarsson@med.miami.edu

Competing interests
H Peter Larson, A patent application (62/032,739) based on these results has been submitted by the University of Miami with S.I.L. and H.P.L. identified as inventors.

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

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.