1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor

  1. Anastasiia Stratiievska
  2. Sara Nelson
  3. Eric N Senning
  4. Jonathan D Lautz
  5. Stephen EP Smith
  6. Sharona E Gordon  Is a corresponding author
  1. University of Washington, United States
  2. Seattle Children's Research Institute, United States
Research Article
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Cite this article as: eLife 2018;7:e38869 doi: 10.7554/eLife.38869

Abstract

Although it has been known for over a decade that the inflammatory mediator NGF sensitizes pain-receptor neurons through increased trafficking of TRPV1 channels to the plasma membrane, the mechanism by which this occurs remains mysterious. NGF activates phosphoinositide 3-kinase (PI3K), the enzyme that generates PI(3,4)P2 and PIP3, and PI3K activity is required for sensitization. One tantalizing hint came from the finding that the N-terminal region of TRPV1 interacts directly with PI3K. Using 2-color total internal reflection fluorescence microscopy, we show that TRPV1 potentiates NGF-induced PI3K activity. A soluble TRPV1 fragment corresponding to the N-terminal Ankyrin repeats domain (ARD) was sufficient to produce this potentiation, indicating that allosteric regulation was involved. Further, other TRPV channels with conserved ARDs also potentiated NGF-induced PI3K activity. Our data demonstrate a novel reciprocal regulation of PI3K signaling by the ARD of TRPV channels.

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. Anastasiia Stratiievska

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sara Nelson

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Eric N Senning

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jonathan D Lautz

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephen EP Smith

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sharona E Gordon

    Department of Physiology and Biophysics, University of Washington, Seattle, United States
    For correspondence
    seg@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0914-3361

Funding

National Eye Institute (R01EY017564)

  • Sharona E Gordon

National Institute of General Medical Sciences (R01GM100718)

  • Sharona E Gordon

National Institute of General Medical Sciences (R01GM125351)

  • Sharona E Gordon

University of Washington (Royalty Research Fund)

  • Sharona E Gordon

National Institute of Mental Health (R01MH113545)

  • Stephen EP Smith

National Institute of Biomedical Imaging and Bioengineering (T32EB001650)

  • Anastasiia Stratiievska

National Institutes of Health (S10RR025429)

  • Sharona E Gordon

National Institutes of Health (P30DK017047)

  • Sharona E Gordon

National Institutes of Health (P30EY001730)

  • Sharona E Gordon

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

Publication history

  1. Received: June 2, 2018
  2. Accepted: December 6, 2018
  3. Accepted Manuscript published: December 18, 2018 (version 1)
  4. Version of Record published: December 31, 2018 (version 2)

Copyright

© 2018, Stratiievska 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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