Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues

  1. Briana M Bohannon
  2. Jessica J Jowais
  3. Leif Nyberg
  4. Vanessa Olivier-Meo
  5. Valentina Corradi
  6. D Peter Tieleman
  7. Sara I Liin
  8. H Peter Larsson  Is a corresponding author
  1. University of Miami, United States
  2. Linköping University, Sweden
  3. University of Calgary, Canada

Abstract

Voltage-gated potassium (KV) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. KV channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore KV channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of KV channel activators with potential applications in the treatment of arrhythmogenic disorders such as Long QT Syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac IKs­­ channel - a tetrameric potassium channel complex formed by KV7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac IKs channel and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the IKs channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the IKs channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-6.

Article and author information

Author details

  1. Briana M Bohannon

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  2. Jessica J Jowais

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  3. Leif Nyberg

    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
    Competing interests
    No competing interests declared.
  4. Vanessa Olivier-Meo

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  5. Valentina Corradi

    Department of Biological Sciences, University of Calgary, Calgary, Canada
    Competing interests
    No competing interests declared.
  6. D Peter Tieleman

    Department of Biological Sciences, University of Calgary, Calgary, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5507-0688
  7. Sara I Liin

    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
    Competing interests
    Sara I Liin, A patent application (#62/032,739) including a description of the interaction of charged lipophilic compounds with the KCNQ1 channel has been submitted by the University of Miami with HPL and SIL identified as inventors..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8493-0114
  8. H Peter Larsson

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    For correspondence
    plarsson@med.miami.edu
    Competing interests
    H Peter Larsson, A patent application (#62/032,739) including a description of the interaction of charged lipophilic compounds with the KCNQ1 channel has been submitted by the University of Miamiwith HPL and SIL identified as inventors.Dr Hans Peter Larsson is the equity owner of VentricPharm, a company that operates in the same field of research as the study..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1688-2525

Funding

HORIZON EUROPE European Research Council (850622)

  • Sara I Liin

Swedish Research Council (2021-01885)

  • Sara I Liin

National Institutes of Health (R01HL131461)

  • H Peter Larsson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Bohannon 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. Briana M Bohannon
  2. Jessica J Jowais
  3. Leif Nyberg
  4. Vanessa Olivier-Meo
  5. Valentina Corradi
  6. D Peter Tieleman
  7. Sara I Liin
  8. H Peter Larsson
(2023)
Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues
eLife 12:e85773.
https://doi.org/10.7554/eLife.85773

Share this article

https://doi.org/10.7554/eLife.85773

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