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

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Abstract

Voltage-gated potassium (K_V) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K_V 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 K_V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K_V 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 I_Kschannel - a tetrameric potassium channel complex formed by K_V7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I_Ks 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 I_Ks 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 I_Ks channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.

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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.

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Briana M Bohannon

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

Competing interests
No competing interests declared.
Jessica J Jowais

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

Competing interests
No competing interests declared.
Leif Nyberg

Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden

Competing interests
No competing interests declared.
Vanessa Olivier-Meo

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

Competing interests
No competing interests declared.
Valentina Corradi

Department of Biological Sciences, University of Calgary, Calgary, Canada

Competing interests
No competing interests declared.
D Peter Tieleman

Department of Biological Sciences, University of Calgary, Calgary, Canada

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5507-0688
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..

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

"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.

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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.