1. Structural Biology and Molecular Biophysics

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

  1. Briana M Bohannon
  2. Alicia de la Cruz
  3. Xiaoan Wu
  4. Jessica J Jowais
  5. Marta E Perez
  6. Sara I Liin
  7. H Peter Larsson  Is a corresponding author
  1. University of Miami, United States
  2. Linköping University, Sweden
https://doi.org/10.7554/eLife.51453
Share this article
Cite this article
  1. Briana M Bohannon
  2. Alicia de la Cruz
  3. Xiaoan Wu
  4. Jessica J Jowais
  5. Marta E Perez
  6. Sara I Liin
  7. H Peter Larsson
(2020)
Polyunsaturated fatty acid analogues differentially affect cardiac Nav, Cav, and Kv channels through unique mechanisms
eLife 9:e51453.
https://doi.org/10.7554/eLife.51453
  2. Download BibTeX
  3. Download .RIS

Abstract

The cardiac ventricular action potential depends on several voltage-gated ion channels, including Nav, Cav, and Kv 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 (Nav, Cav, and KV). In addition, a PUFA analogue selective for the cardiac IKs 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.

Data availability

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

Article and author information

Author details

  1. Briana M Bohannon

    Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3720-1477

  2. Alicia de la Cruz

    Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  3. Xiaoan Wu

    Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  4. Jessica J Jowais

    Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  5. Marta E Perez

    Physiology and Biophysics, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.

  6. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8493-0114

  7. 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.
    ORCID icon "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

© 2020, 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.

Metrics

  • 2,040
    views
  • 378
    downloads
  • 14
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Briana M Bohannon
  2. Alicia de la Cruz
  3. Xiaoan Wu
  4. Jessica J Jowais
  5. Marta E Perez
  6. Sara I Liin
  7. H Peter Larsson
(2020)
Polyunsaturated fatty acid analogues differentially affect cardiac Nav, Cav, and Kv channels through unique mechanisms
eLife 9:e51453.
https://doi.org/10.7554/eLife.51453

Share this article

https://doi.org/10.7554/eLife.51453

Categories and tags

Further reading

    1. Structural Biology and Molecular Biophysics

    Water and chloride as allosteric inhibitors in WNK kinase osmosensing

    Liliana R Teixeira, Radha Akella ... Elizabeth J Goldsmith
    Research Article

    Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1 and CWN2). Here, we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride-binding site are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here, we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.

    1. Structural Biology and Molecular Biophysics

    Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ

    Jinsai Shang, Douglas J Kojetin
    Research Advance

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates gene expression programs in response to ligand binding. Endogenous and synthetic ligands, including covalent antagonist inhibitors GW9662 and T0070907, are thought to compete for the orthosteric pocket in the ligand-binding domain (LBD). However, we previously showed that synthetic PPARγ ligands can cooperatively cobind with and reposition a bound endogenous orthosteric ligand to an alternate site, synergistically regulating PPARγ structure and function (Shang et al., 2018). Here, we reveal the structural mechanism of cobinding between a synthetic covalent antagonist inhibitor with other synthetic ligands. Biochemical and NMR data show that covalent inhibitors weaken—but do not prevent—the binding of other ligands via an allosteric mechanism, rather than direct ligand clashing, by shifting the LBD ensemble toward a transcriptionally repressive conformation, which structurally clashes with orthosteric ligand binding. Crystal structures reveal different cobinding mechanisms including alternate site binding to unexpectedly adopting an orthosteric binding mode by altering the covalent inhibitor binding pose. Our findings highlight the significant flexibility of the PPARγ orthosteric pocket, its ability to accommodate multiple ligands, and demonstrate that GW9662 and T0070907 should not be used as chemical tools to inhibit ligand binding to PPARγ.