Molecular mechanism of TRPV2 channel modulation by cannabidiol

  1. Ruth A Pumroy
  2. Amrita Samanta
  3. Yuhang Liu
  4. Taylor ET Hughes
  5. Siyuan Zhao
  6. Yevgen Yudin
  7. Tibor Rohacs
  8. Seungil Han  Is a corresponding author
  9. Vera Y Moiseenkova-Bell  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Pfizer Research and Development, United States
  3. New Jersey Medical School, Rutgers, the State University of New Jersey, United States

Abstract

Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV2 and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV2 channel in apo and CBD-bound states in nanodiscs by cryo-electron microscopy. We show that CBD interacts with TRPV2 through a hydrophobic pocket located between S5 and S6 helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV2 structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV2 apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.

Data availability

cryoEM maps have been deposited in the Electron Microscopy Data Bank under the following accession codes: EMD-20677, EMD-20678, EMD-20686, EMD-20682The models built into the cryoEM maps have been deposited into the Protein Data Bank under the following accession codes: 6U84, 6U85, 6U8A, 6U88The maps and models analyzed in this study are included with the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Ruth A Pumroy

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  2. Amrita Samanta

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  3. Yuhang Liu

    Pfizer Research and Development, Groton, United States
    Competing interests
    Yuhang Liu, is affiliated with Pfizer Research and Development. The author has no financial interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6844-7480
  4. Taylor ET Hughes

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  5. Siyuan Zhao

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, United States
    Competing interests
    No competing interests declared.
  6. Yevgen Yudin

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, United States
    Competing interests
    No competing interests declared.
  7. Tibor Rohacs

    Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3580-2575
  8. Seungil Han

    Pfizer Research and Development, Groton, United States
    For correspondence
    seungil.han@pfizer.com
    Competing interests
    Seungil Han, is affiliated with Pfizer Research and Development. The author has no financial interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1070-3880
  9. Vera Y Moiseenkova-Bell

    Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    vmb@pennmedicine.upenn.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0589-4053

Funding

National Institutes of Health (R01GM129357)

  • Vera Y Moiseenkova-Bell

National Institutes of Health (R01GM103899)

  • Vera Y Moiseenkova-Bell

National Institutes of Health (R01 NS055159)

  • Tibor Rohacs

National Institutes of Health (R01GM093290)

  • Tibor Rohacs

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

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Version history

  1. Received: May 25, 2019
  2. Accepted: September 27, 2019
  3. Accepted Manuscript published: September 30, 2019 (version 1)
  4. Version of Record published: October 15, 2019 (version 2)

Copyright

© 2019, Pumroy 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. Ruth A Pumroy
  2. Amrita Samanta
  3. Yuhang Liu
  4. Taylor ET Hughes
  5. Siyuan Zhao
  6. Yevgen Yudin
  7. Tibor Rohacs
  8. Seungil Han
  9. Vera Y Moiseenkova-Bell
(2019)
Molecular mechanism of TRPV2 channel modulation by cannabidiol
eLife 8:e48792.
https://doi.org/10.7554/eLife.48792

Share this article

https://doi.org/10.7554/eLife.48792

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