Cannabidiol interactions with voltage-gated sodium channels
- Birkbeck College, University of London, United Kingdom
- 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
Mohammad-Reza Ghovanloo
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.
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Cannabidiol interactions with voltage-gated sodium channels
eLife 9:e58593.
https://doi.org/10.7554/eLife.58593
