KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site

  1. Johan E Larsson
  2. H Peter Larsson
  3. Sara I Liin  Is a corresponding author
  1. Linköping University, Sweden
  2. University of Miami, United States

Abstract

The voltage-gated potassium channel KV7.1 and the auxiliary subunit KCNE1 together form the cardiac IKs channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate KV7.1 via an electrostatic mechanism. The activating effect was abolished when KV7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation. Here, we found that neutralization of negatively charged residues in the S5-P-helix loop of KV7.1 restored PUFA effects on KV7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of KV7.1 towards the PUFA binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on KV7.1. This mechanistic understanding of how KCNE1 alters KV7.1 pharmacology is essential for development of drugs targeting the IKs channel.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files (Supplementary File 1).

Article and author information

Author details

  1. Johan E Larsson

    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
    Competing interests
    No competing interests declared.
  2. H Peter Larsson

    Department of Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    H Peter Larsson, Inventor of a patent application (#62/032,739) based on these results, which has been submitted by the University of Miami.
  3. Sara I Liin

    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
    For correspondence
    sara.liin@liu.se
    Competing interests
    Sara I Liin, Inventor of a patent application (#62/032,739) based on these results, which has been submitted by the University of Miami.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8493-0114

Funding

National Institutes of Health (R01GM109762)

  • H Peter Larsson

Svenska Sällskapet för Medicinsk Forskning

  • Sara I Liin

Vetenskapsrådet

  • Sara I Liin

Linköpings Universitet

  • Sara I Liin

The County Council of Östergötland

  • Sara I Liin

The Lions Foundation

  • 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.

Ethics

Animal experimentation: Animal experiments were performed in strict accordance with the recommendation of The Linköping Animal Ethics Committee at Linköping University (protocol #53-13 ).

Reviewing Editor

  1. László Csanády, Semmelweis University, Hungary

Publication history

  1. Received: April 4, 2018
  2. Accepted: July 15, 2018
  3. Accepted Manuscript published: July 17, 2018 (version 1)
  4. Version of Record published: August 7, 2018 (version 2)

Copyright

© 2018, Larsson 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. Johan E Larsson
  2. H Peter Larsson
  3. Sara I Liin
(2018)
KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site
eLife 7:e37257.
https://doi.org/10.7554/eLife.37257
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