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.

Reviewing Editor

  1. Baron Chanda, University of Wisconsin-Madison, United States

Version history

  1. Received: August 29, 2019
  2. Accepted: March 24, 2020
  3. Accepted Manuscript published: March 24, 2020 (version 1)
  4. Version of Record published: April 15, 2020 (version 2)
  5. Version of Record updated: June 18, 2020 (version 3)

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

  • 1,878
    Page views
  • 351
    Downloads
  • 10
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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

Categories and tags

Further reading

    1. Microbiology and Infectious Disease
    2. Structural Biology and Molecular Biophysics

    A pH-sensitive switch activates virulence in Salmonella

    Dasvit Shetty, Linda J Kenney
    Research Article Updated

    The transcriptional regulator SsrB acts as a switch between virulent and biofilm lifestyles of non-typhoidal Salmonella enterica serovar Typhimurium. During infection, phosphorylated SsrB activates genes on Salmonella Pathogenicity Island-2 (SPI-2) essential for survival and replication within the macrophage. Low pH inside the vacuole is a key inducer of expression and SsrB activation. Previous studies demonstrated an increase in SsrB protein levels and DNA-binding affinity at low pH; the molecular basis was unknown (Liew et al., 2019). This study elucidates its underlying mechanism and in vivo significance. Employing single-molecule and transcriptional assays, we report that the SsrB DNA-binding domain alone (SsrBc) is insufficient to induce acid pH-sensitivity. Instead, His12, a conserved residue in the receiver domain confers pH sensitivity to SsrB allosterically. Acid-dependent DNA binding was highly cooperative, suggesting a new configuration of SsrB oligomers at SPI-2-dependent promoters. His12 also plays a role in SsrB phosphorylation; substituting His12 reduced phosphorylation at neutral pH and abolished pH-dependent differences. Failure to flip the switch in SsrB renders Salmonella avirulent and represents a potential means of controlling virulence.

    1. Plant Biology
    2. Structural Biology and Molecular Biophysics

    Carotenoid assembly regulates quinone diffusion and the Roseiflexus castenholzii reaction center-light harvesting complex architecture

    Jiyu Xin, Yang Shi ... Xiaoling Xu
    Research Article

    Carotenoid (Car) pigments perform central roles in photosynthesis-related light harvesting (LH), photoprotection, and assembly of functional pigment-protein complexes. However, the relationships between Car depletion in the LH, assembly of the prokaryotic reaction center (RC)-LH complex, and quinone exchange are not fully understood. Here, we analyzed native RC-LH (nRC-LH) and Car-depleted RC-LH (dRC-LH) complexes in Roseiflexus castenholzii, a chlorosome-less filamentous anoxygenic phototroph that forms the deepest branch of photosynthetic bacteria. Newly identified exterior Cars functioned with the bacteriochlorophyll B800 to block the proposed quinone channel between LHαβ subunits in the nRC-LH, forming a sealed LH ring that was disrupted by transmembrane helices from cytochrome c and subunit X to allow quinone shuttling. dRC-LH lacked subunit X, leading to an exposed LH ring with a larger opening, which together accelerated the quinone exchange rate. We also assigned amino acid sequences of subunit X and two hypothetical proteins Y and Z that functioned in forming the quinone channel and stabilizing the RC-LH interactions. This study reveals the structural basis by which Cars assembly regulates the architecture and quinone exchange of bacterial RC-LH complexes. These findings mark an important step forward in understanding the evolution and diversity of prokaryotic photosynthetic apparatus.