1. Structural Biology and Molecular Biophysics

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
https://doi.org/10.7554/eLife.58593
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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.

Metrics

  • 5,688
    views
  • 490
    downloads
  • 43
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.58593

Categories and tags

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics

    Genetic code expansion, click chemistry, and light-activated PI3K reveal details of membrane protein trafficking downstream of receptor tyrosine kinases

    Duk-Su Koh, Anastasiia Stratiievska ... Sharona E Gordon
    Tools and Resources

    Ligands such as insulin, epidermal growth factor, platelet-derived growth factor, and nerve growth factor (NGF) initiate signals at the cell membrane by binding to receptor tyrosine kinases (RTKs). Along with G-protein-coupled receptors, RTKs are the main platforms for transducing extracellular signals into intracellular signals. Studying RTK signaling has been a challenge, however, due to the multiple signaling pathways to which RTKs typically are coupled, including MAP/ERK, PLCγ, and Class 1A phosphoinositide 3-kinases (PI3K). The multi-pronged RTK signaling has been a barrier to isolating the effects of any one downstream pathway. Here, we used optogenetic activation of PI3K to decouple its activation from other RTK signaling pathways. In this context, we used genetic code expansion to introduce a click chemistry noncanonical amino acid into the extracellular side of membrane proteins. Applying a cell-impermeant click chemistry fluorophore allowed us to visualize delivery of membrane proteins to the plasma membrane in real time. Using these approaches, we demonstrate that activation of PI3K, without activating other pathways downstream of RTK signaling, is sufficient to traffic the TRPV1 ion channels and insulin receptors to the plasma membrane.

    1. Structural Biology and Molecular Biophysics

    Nuclear Receptors: A new mode of inhibition

    Andrew D Huber, Taosheng Chen
    Insight

    Complementary structural biology approaches reveal how an agonist and a covalent inhibitor simultaneously bind to a nuclear receptor.

    1. Structural Biology and Molecular Biophysics

    Decoupling of the onset of anharmonicity between a protein and its surface water around 200 K

    Lirong Zheng, Bingxin Zhou ... Liang Hong
    Short Report

    The protein dynamical transition at ~200 K, where the biomolecule transforms from a harmonic, non-functional form to an anharmonic, functional state, has been thought to be slaved to the thermal activation of dynamics in its surface hydration water. Here, by selectively probing the dynamics of protein and hydration water using elastic neutron scattering and isotopic labeling, we found that the onset of anharmonicity in the two components around 200 K is decoupled. The one in protein is an intrinsic transition, whose characteristic temperature is independent of the instrumental resolution time, but varies with the biomolecular structure and the amount of hydration, while the one of water is merely a resolution effect.