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

  1. Sara I Liin  Is a corresponding author
  2. Johan E Larsson
  3. Rene Barro-Soria
  4. Bo Hjorth Bentzen
  5. H Peter Larson  Is a corresponding author
  1. University of Miami, United States
  2. Linköping University, Sweden
  3. University of Copenhagen, Denmark

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

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8493-0114
  2. Johan E Larsson

    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
    Competing interests
    No competing interests declared.
  3. Rene Barro-Soria

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  4. Bo Hjorth Bentzen

    The Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  5. 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).

Reviewing Editor

  1. Kenton J Swartz, National Institutes of Health, United States

Version history

  1. Received: August 19, 2016
  2. Accepted: September 28, 2016
  3. Accepted Manuscript published: September 30, 2016 (version 1)
  4. Version of Record published: October 26, 2016 (version 2)
  5. Version of Record updated: November 1, 2016 (version 3)

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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  1. Sara I Liin
  2. Johan E Larsson
  3. Rene Barro-Soria
  4. Bo Hjorth Bentzen
  5. H Peter Larson
(2016)
Fatty acid analogue N-Arachidonoyl taurine restores function of IKs channels with diverse long QT mutations
eLife 5:e20272.
https://doi.org/10.7554/eLife.20272

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