Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons

  1. Pratibha Narayanan
  2. Meike Hütte
  3. Galina Kudryasheva
  4. Francisco J Taberner
  5. Stefan G Lechner
  6. Florian Rehfeldt
  7. David Gomez-Varela
  8. Manuela Schmidt  Is a corresponding author
  1. Max Planck Institute for Experimental Medicine, Germany
  2. University of Göttingen, Germany
  3. Heidelberg University, Germany

Abstract

Piezo2 ion channels are critical determinants of the sense of light touch in vertebrates. Yet, their regulation is only incompletely understood. We recently identified myotubularin related protein-2 (Mtmr2), a phosphoinositide (PI) phosphatase, in the native Piezo2 interactome of murine dorsal root ganglia (DRG). Here, we demonstrate that Mtmr2 attenuates Piezo2-mediated rapidly adapting mechanically activated (RA-MA) currents. Interestingly, heterologous Piezo1 and other known MA current subtypes in DRG appeared largely unaffected by Mtmr2. Experiments with catalytically inactive Mtmr2, pharmacological blockers of PI(3,5)P2 synthesis, and osmotic stress suggest that Mtmr2-dependent Piezo2 inhibition involves depletion of PI(3,5)P2. Further, we identified a PI(3,5)P2 binding region in Piezo2, but not Piezo1, that confers sensitivity to Mtmr2 as indicated by functional analysis of a domain-swapped Piezo2 mutant. Altogether, our results propose local PI(3,5)P2 modulation via Mtmr2 in the vicinity of Piezo2 as a novel mechanism to dynamically control Piezo2-dependent mechanotransduction in peripheral sensory neurons.

Data availability

The following previously published data sets were used

Article and author information

Author details

  1. Pratibha Narayanan

    Emmy Noether-Group Somatosensory Signaling and Systems Biology, Max Planck Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Meike Hütte

    Emmy Noether-Group Somatosensory Signaling and Systems Biology, Max Planck Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Galina Kudryasheva

    3rd Institute of Physics - Biophysics, University of Göttingen, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Francisco J Taberner

    Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Stefan G Lechner

    Institute of Pharmacology, Heidelberg University, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Florian Rehfeldt

    3rd Institute of Physics - Biophysics, University of Göttingen, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. David Gomez-Varela

    Emmy Noether-Group Somatosensory Signaling and Systems Biology, Max Planck Institute for Experimental Medicine, Göttingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Manuela Schmidt

    Emmy Noether-Group Somatosensory Signaling and Systems Biology, Max Planck Institute for Experimental Medicine, Göttingen, Germany
    For correspondence
    mschmidt@em.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1972-3519

Funding

Deutsche Forschungsgemeinschaft (SCHM 2533/2-1)

  • Manuela Schmidt

Max-Planck-Gesellschaft (Open-access funding)

  • Meike Hütte
  • David Gomez-Varela
  • Manuela Schmidt

Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften (PhD fellowship)

  • Pratibha Narayanan
  • Meike Hütte

Deutsche Forschungsgemeinschaft (CRC889 Project A9)

  • Manuela Schmidt

Deutsche Forschungsgemeinschaft (GO 2481/2-1)

  • David Gomez-Varela

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 experiments involving primary tissue isolated from mice were carried out in strict accordance with the recommendations of the institutional animal care and use committee (IACUC) of the Max Planck Institute of Experimental Medicine, Goettingen.

Reviewing Editor

  1. Patricia Bassereau, Institut Curie, France

Publication history

  1. Received: September 28, 2017
  2. Accepted: March 8, 2018
  3. Accepted Manuscript published: March 9, 2018 (version 1)
  4. Version of Record published: April 13, 2018 (version 2)

Copyright

© 2018, Narayanan 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. Pratibha Narayanan
  2. Meike Hütte
  3. Galina Kudryasheva
  4. Francisco J Taberner
  5. Stefan G Lechner
  6. Florian Rehfeldt
  7. David Gomez-Varela
  8. Manuela Schmidt
(2018)
Myotubularin related protein-2 and its phospholipid substrate PIP2 control Piezo2-mediated mechanotransduction in peripheral sensory neurons
eLife 7:e32346.
https://doi.org/10.7554/eLife.32346

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