Polyunsaturated fatty acid analogues differentially affect cardiac Nav, Cav, and Kv channels through unique mechanisms

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Abstract

The cardiac ventricular action potential depends on several voltage-gated ion channels, including Na_v, Ca_v, and K_v channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (Na_v, Ca_v, and K_V). In addition, a PUFA analogue selective for the cardiac I_Ks channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.

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Source data used in this manuscript is openly available and is listed as a source data file for accessibility.

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Briana M Bohannon

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

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3720-1477
Alicia de la Cruz

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

Competing interests
No competing interests declared.
Xiaoan Wu

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

Competing interests
No competing interests declared.
Jessica J Jowais

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

Competing interests
No competing interests declared.
Marta E Perez

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

Competing interests
No competing interests declared.
Sara I Liin

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

Competing interests
Sara I Liin, A patent application (62/032,739) has been submitted by the University of Miami with SIL and HPL as inventors. The authors declare no other competing interests.

"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) has been submitted by the University of Miami with SIL and HPL as inventors. The authors declare no other competing interests.

"This ORCID iD identifies the author of this article:" 0000-0002-1688-2525

Funding

National Institutes of Health (R01-HL131461)

H Peter Larsson

Swedish Research Council (2017-02040)

Sara I Liin

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

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.