Cannabidiol interactions with voltage-gated sodium channels

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for the 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 chan...

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Bibliographic Details
Published in:eLife 2020-10, Vol.9
Main Authors: Sait, Lily Goodyer, Sula, Altin, Ghovanloo, Mohammad-Reza, Hollingworth, David, Ruben, Peter C, Wallace, B A
Format: Article
Language:English
Subjects:
Analysis
Binding Sites
Cannabidiol
Cannabidiol - metabolism
Cannabidiol - pharmacology
crystal structure
Crystallography, X-Ray
drug interations
Electrophysiology
Marijuana
Protein Conformation
Sequence Alignment
Structural Biology and Molecular Biophysics
structure-function relationships
voltage -gated sodium channel
Voltage-Gated Sodium Channels - chemistry
Voltage-Gated Sodium Channels - drug effects
Voltage-Gated Sodium Channels - genetics
Voltage-Gated Sodium Channels - metabolism
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Summary:Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for the 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.58593