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

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Abstract

The voltage-gated potassium channel K_V7.1 and the auxiliary subunit KCNE1 together form the cardiac I_Ks channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate K_V7.1 via an electrostatic mechanism. The activating effect was abolished when K_V7.1 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 K_V7.1 restored PUFA effects on K_V7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of K_V7.1 towards the PUFA binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on K_V7.1. This mechanistic understanding of how KCNE1 alters K_V7.1 pharmacology is essential for development of drugs targeting the I_Ks channel.

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

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Johan E Larsson

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

Competing interests
No competing interests declared.
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.
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.

"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 ).

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.