1. Structural Biology and Molecular Biophysics

Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure

  1. Charles E MacKay
  2. M Dennis Leo
  3. Carlos Fernández-Peña
  4. Raquibul Hasan
  5. Wen Yin
  6. Alejandro Mata-Daboin
  7. Simon Bulley
  8. Jesse Gammons
  9. Salvatore Mancarella
  10. Jonathan H Jaggar  Is a corresponding author
  1. University of Tennessee Health Science Center, United States
https://doi.org/10.7554/eLife.56655
Share this article
Cite this article
  1. Charles E MacKay
  2. M Dennis Leo
  3. Carlos Fernández-Peña
  4. Raquibul Hasan
  5. Wen Yin
  6. Alejandro Mata-Daboin
  7. Simon Bulley
  8. Jesse Gammons
  9. Salvatore Mancarella
  10. Jonathan H Jaggar
(2020)
Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure
eLife 9:e56655.
https://doi.org/10.7554/eLife.56655
  2. Download BibTeX
  3. Download .RIS

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

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.

Reviewing Editor

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

Ethics

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

Version 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.

Metrics

  • 1,935
    views
  • 341
    downloads
  • 25
    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. Charles E MacKay
  2. M Dennis Leo
  3. Carlos Fernández-Peña
  4. Raquibul Hasan
  5. Wen Yin
  6. Alejandro Mata-Daboin
  7. Simon Bulley
  8. Jesse Gammons
  9. Salvatore Mancarella
  10. Jonathan H Jaggar
(2020)
Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure
eLife 9:e56655.
https://doi.org/10.7554/eLife.56655

Share this article

https://doi.org/10.7554/eLife.56655

Categories and tags

Research organism

Further reading

    1. Structural Biology and Molecular Biophysics

    Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics

    Nicholas James Ose, Paul Campitelli ... Sefika Banu Ozkan
    Research Article

    We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) of the SARS-CoV-2 S protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of the S protein compared to the closed form. In particular, the CAP sites control the dynamics of binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly additive mutations. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.

    1. Structural Biology and Molecular Biophysics

    The substrate-binding domains of the osmoregulatory ABC importer OpuA transiently interact

    Marco van den Noort, Panagiotis Drougkas ... Bert Poolman
    Research Article

    Bacteria utilize various strategies to prevent internal dehydration during hypertonic stress. A common approach to countering the effects of the stress is to import compatible solutes such as glycine betaine, leading to simultaneous passive water fluxes following the osmotic gradient. OpuA from Lactococcus lactis is a type I ABC-importer that uses two substrate-binding domains (SBDs) to capture extracellular glycine betaine and deliver the substrate to the transmembrane domains for subsequent transport. OpuA senses osmotic stress via changes in the internal ionic strength and is furthermore regulated by the 2nd messenger cyclic-di-AMP. We now show, by means of solution-based single-molecule FRET and analysis with multi-parameter photon-by-photon hidden Markov modeling, that the SBDs transiently interact in an ionic strength-dependent manner. The smFRET data are in accordance with the apparent cooperativity in transport and supported by new cryo-EM data of OpuA. We propose that the physical interactions between SBDs and cooperativity in substrate delivery are part of the transport mechanism.