Cannabidiol interactions with voltage-gated sodium channels

  1. Lily Goodyer Sait
  2. Altin Sula
  3. Mohammad-Reza Ghovanloo
  4. David Hollingworth
  5. Peter C Ruben
  6. Bonnie A Wallace  Is a corresponding author
  1. Birkbeck College, University of London, United Kingdom
  2. Simon Fraser University, Canada

Abstract

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, and electrophysiology to show the functional effects of binding CBD to these channels. CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies suggest why the closely-related psychoactive compound tetrahydrocannabinol may not have the same effects on these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD interactions with sodium channels.

Data availability

Coordinates and Diffraction data have been deposited in the PDB under PDB6YZ2, and PDB6YZ0.All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Lily Goodyer Sait

    Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Altin Sula

    Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Mohammad-Reza Ghovanloo

    Simon Fraser University, Burnaby, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2171-0744
  4. David Hollingworth

    Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter C Ruben

    Simon Fraser University, Burnaby, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7877-5178
  6. Bonnie A Wallace

    Institute of Structural and Molecular Biology, Birkbeck College, University of London, London, United Kingdom
    For correspondence
    b.wallace@mail.cryst.bbk.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9649-5092

Funding

Biotechnology and Biological Sciences Research Council (BB/L006790)

  • Bonnie A Wallace

Biotechnology and Biological Sciences Research Council (BB/R001294)

  • Bonnie A Wallace

Medical Research Council (Studentship)

  • Lily Goodyer Sait

Natural Science and Engineering Research Council of Canada (RGPIN03920)

  • Peter C Ruben

Rare Disease Foundation (00000)

  • Peter C Ruben

Natural Science and Engineering Research Council of Canada (CGS-D:535333-2019)

  • Mohammad-Reza Ghovanloo

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

Publication history

  1. Received: May 5, 2020
  2. Accepted: October 15, 2020
  3. Accepted Manuscript published: October 22, 2020 (version 1)
  4. Version of Record published: November 4, 2020 (version 2)

Copyright

© 2020, Sait 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. Lily Goodyer Sait
  2. Altin Sula
  3. Mohammad-Reza Ghovanloo
  4. David Hollingworth
  5. Peter C Ruben
  6. Bonnie A Wallace
(2020)
Cannabidiol interactions with voltage-gated sodium channels
eLife 9:e58593.
https://doi.org/10.7554/eLife.58593
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