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.

Metrics

  • 4,844
    Page views
  • 424
    Downloads
  • 23
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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

Further reading

    1. Structural Biology and Molecular Biophysics
    Hirohide Takahashi, Toshiki Yamada ... Erkan Karakas
    Research Article Updated

    Volume-regulated anion channels (VRACs) mediate volume regulatory Cl- and organic solute efflux from vertebrate cells. VRACs are heteromeric assemblies of LRRC8A-E proteins with unknown stoichiometries. Homomeric LRRC8A and LRRC8D channels have a small pore, hexameric structure. However, these channels are either non-functional or exhibit abnormal regulation and pharmacology, limiting their utility for structure-function analyses. We circumvented these limitations by developing novel homomeric LRRC8 chimeric channels with functional properties consistent with those of native VRAC/LRRC8 channels. We demonstrate here that the LRRC8C-LRRC8A(IL125) chimera comprising LRRC8C and 25 amino acids unique to the first intracellular loop (IL1) of LRRC8A has a heptameric structure like that of homologous pannexin channels. Unlike homomeric LRRC8A and LRRC8D channels, heptameric LRRC8C-LRRC8A(IL125) channels have a large-diameter pore similar to that estimated for native VRACs, exhibit normal DCPIB pharmacology, and have higher permeability to large organic anions. Lipid-like densities are located between LRRC8C-LRRC8A(IL125) subunits and occlude the channel pore. Our findings provide new insights into VRAC/LRRC8 channel structure and suggest that lipids may play important roles in channel gating and regulation.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Sean M Braet, Theresa SC Buckley ... Ganesh S Anand
    Research Article Updated

    SARS-CoV-2 emergent variants are characterized by increased viral fitness and each shows multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied to track changes in S dynamics from multiple SARS-CoV-2 variants. Our results highlight large differences across variants at two loci with impacts on S dynamics and stability. A significant enhancement in stabilization first occurred with the emergence of D614G S followed by smaller, progressive stabilization in subsequent variants. Stabilization preceded altered dynamics in the N-terminal domain, wherein Omicron BA.1 S showed the largest magnitude increases relative to other preceding variants. Changes in stabilization and dynamics resulting from S mutations detail the evolutionary trajectory of S in emerging variants. These carry major implications for SARS-CoV-2 viral fitness and offer new insights into variant-specific therapeutic development.