1. Structural Biology and Molecular Biophysics
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Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure

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Cite this article as: eLife 2020;9:e56655 doi: 10.7554/eLife.56655

Abstract

PKD2 (polycystin-2, TRPP1), a TRP polycystin channel, is expressed in endothelial cells (ECs), but its physiological functions in this cell type are unclear. Here, we generated inducible, EC-specific Pkd2 knockout mice to examine vascular functions of PKD2. Data show that a broad range of intravascular flow rates stimulate EC PKD2 channels, producing vasodilation. Flow-mediated PKD2 channel activation leads to calcium influx that activates SK/IK channels and eNOS serine 1176 phosphorylation in ECs. These signaling mechanisms produce arterial hyperpolarization and vasodilation. In contrast, EC PKD2 channels do not contribute to acetylcholine-induced vasodilation, suggesting stimulus-specific function. EC-specific PKD2 knockout elevated blood pressure in mice without altering cardiac function or kidney anatomy. These data demonstrate that flow stimulates PKD2 channels in ECs, leading to SK/IK channel and eNOS activation, hyperpolarization, vasodilation and a reduction in systemic blood pressure. Thus, PKD2 channels are a major component of functional flow sensing in the vasculature.

Article and author information

Author details

  1. Charles E MacKay

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. M Dennis Leo

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Carlos Fernández-Peña

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0726-3204
  4. Raquibul Hasan

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Wen Yin

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alejandro Mata-Daboin

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Simon Bulley

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5985-0489
  8. Jesse Gammons

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Salvatore Mancarella

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jonathan H Jaggar

    Department of Physiology, University of Tennessee Health Science Center, Memphis, United States
    For correspondence
    jjaggar@uthsc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1505-3335

Funding

National Institutes of Health (HL133256)

  • Jonathan H Jaggar

National Institutes of Health (HL137745)

  • Jonathan H Jaggar

American Heart Association (16SDG27460007)

  • Simon Bulley

American Heart Association (15SDG22680019)

  • M Dennis Leo

American Heart Association (20POST35210200)

  • Charles E MacKay

American Heart Association (16POST30960010)

  • Raquibul Hasan

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

Ethics

Animal experimentation: All procedures were approved by the Animal Care and Use Committee of the University of Tennessee (protocol 17-068.0).

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Publication history

  1. Received: March 5, 2020
  2. Accepted: May 4, 2020
  3. Accepted Manuscript published: May 4, 2020 (version 1)
  4. Version of Record published: May 15, 2020 (version 2)
  5. Version of Record updated: June 30, 2020 (version 3)

Copyright

© 2020, MacKay 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.

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Further reading

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    Transcription-coupled repair (TCR) is a sub-pathway of nucleotide excision repair (NER) that preferentially removes lesions from the template-strand (t-strand) that stall RNA polymerase (RNAP) elongation complexes (EC). Mfd mediates TCR in bacteria by removing the stalled RNAP concealing the lesion and recruiting Uvr(A)BC. We used cryo-electron microscopy to visualize Mfd engaging with a stalled EC and attempting to dislodge the RNAP. We visualized seven distinct Mfd-EC complexes in both ATP and ADP-bound states. The structures explain how Mfd is remodeled from its repressed conformation, how the UvrA-interacting surface of Mfd is hidden during most of the remodeling process to prevent premature engagement with the NER pathway, how Mfd alters the RNAP conformation to facilitate disassembly, and how Mfd forms a processive translocation complex after dislodging the RNAP. Our results reveal an elaborate mechanism for how Mfd kinetically discriminates paused from stalled ECs and disassembles stalled ECs to initiate TCR.