1. Structural Biology and Molecular Biophysics
  2. Neuroscience
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Chemical activation of the mechanotransduction channel Piezo1

  1. Ruhma Syeda
  2. Jie Xu
  3. Adrienne E Dubin
  4. Bertrand Coste
  5. Jayanti Mathur
  6. Truc Huynh
  7. Jason Matzen
  8. Jianmin Lao
  9. David C Tully
  10. Ingo H Engels
  11. H Michael Petrassi
  12. Andrew M Schumacher
  13. Mauricio Montal
  14. Michael Bandell
  15. Ardem Patapoutian  Is a corresponding author
  1. Howard Hughes Medical Institute, The Scripps Research Institute, United States
  2. Genomics Institute of the Novartis Research Foundation, United States
  3. Centre national de la recherche scientifique, Aix Marseille Université, United States
  4. Novartis Institutes for Biomedical Research, United States
  5. Appalachian College of Pharmacy, United States
  6. University of California, San Diego, United States
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Cite this article as: eLife 2015;4:e07369 doi: 10.7554/eLife.07369

Abstract

Piezo ion channels are activated by various types of mechanical stimuli and function as biological pressure sensors in both vertebrates and invertebrates. To date mechanical stimuli are the only means to activate Piezo ion channels and whether other modes of activation exist is not known. Here, we screened ~3.25 million compounds using a cell-based fluorescence assay and identified a synthetic small molecule we termed Yoda1 that acts as an agonist for both human and mouse Piezo1. Functional studies in cells revealed that Yoda1 affects the sensitivity and the inactivation kinetics of mechanically induced responses. Characterization of Yoda1 in artificial droplet lipid bilayers showed that Yoda1 activates purified Piezo1 channels in the absence of other cellular components. Our studies demonstrate that Piezo1 is amenable to chemical activation, and raise the possibility that endogenous Piezo1 agonists might exist. Yoda1 will serve as a key tool compound to study Piezo1 regulation and function.

Article and author information

Author details

  1. Ruhma Syeda

    Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jie Xu

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Adrienne E Dubin

    Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bertrand Coste

    Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Centre national de la recherche scientifique, Aix Marseille Université, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jayanti Mathur

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Truc Huynh

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jason Matzen

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jianmin Lao

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. David C Tully

    Novartis Institutes for Biomedical Research, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Ingo H Engels

    Department of Pharmaceutical Sciences, Appalachian College of Pharmacy, Oakwood, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. H Michael Petrassi

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Andrew M Schumacher

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Mauricio Montal

    University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Michael Bandell

    Genomics Institute of the Novartis Research Foundation, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Ardem Patapoutian

    Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States
    For correspondence
    ardem@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Jeremy Nathans, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: March 7, 2015
  2. Accepted: May 8, 2015
  3. Accepted Manuscript published: May 22, 2015 (version 1)
  4. Version of Record published: June 5, 2015 (version 2)

Copyright

© 2015, Syeda 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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  1. Further reading

Further reading

    1. Cell Biology
    2. Neuroscience
    Stuart M Cahalan et al.
    Short Report Updated

    Red blood cells (RBCs) experience significant mechanical forces while recirculating, but the consequences of these forces are not fully understood. Recent work has shown that gain-of-function mutations in mechanically activated Piezo1 cation channels are associated with the dehydrating RBC disease xerocytosis, implicating a role of mechanotransduction in RBC volume regulation. However, the mechanisms by which these mutations result in RBC dehydration are unknown. In this study, we show that RBCs exhibit robust calcium entry in response to mechanical stretch and that this entry is dependent on Piezo1 expression. Furthermore, RBCs from blood-cell-specific Piezo1 conditional knockout mice are overhydrated and exhibit increased fragility both in vitro and in vivo. Finally, we show that Yoda1, a chemical activator of Piezo1, causes calcium influx and subsequent dehydration of RBCs via downstream activation of the KCa3.1 Gardos channel, directly implicating Piezo1 signaling in RBC volume control. Therefore, mechanically activated Piezo1 plays an essential role in RBC volume homeostasis.

  1. Edited by Kenton J Swartz et al.
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