Cannabidiol Interactions with Voltage-Gated Sodium Channels
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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, showing 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 illuminate why the closely-related psychoactive compound THC may not bind to 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 with sodium channels.
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###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on June 8, 2020, follows.
Summary
Cannabidiol (CBD) has been recently approved for treatment of epilepsy. Some of CBD anti-epileptic properties might be due to CBD inhibition of voltage-gated sodium channels but the molecular mechanism of such inhibition is unknown. Sait et al. studied the molecular bases of CBD inhibition using X-ray crystallography in application to the bacterial sodium channel NavMs. The authors solved NavMS structures in the apo state and in complex with CBD and based on structural comparison, identified CBD binding sites and proposed the molecular mechanism of sodium channel inhibition by CBD. The crystal structures are of high quality and among the best published structures of sodium channels, and the study is …
###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on June 8, 2020, follows.
Summary
Cannabidiol (CBD) has been recently approved for treatment of epilepsy. Some of CBD anti-epileptic properties might be due to CBD inhibition of voltage-gated sodium channels but the molecular mechanism of such inhibition is unknown. Sait et al. studied the molecular bases of CBD inhibition using X-ray crystallography in application to the bacterial sodium channel NavMs. The authors solved NavMS structures in the apo state and in complex with CBD and based on structural comparison, identified CBD binding sites and proposed the molecular mechanism of sodium channel inhibition by CBD. The crystal structures are of high quality and among the best published structures of sodium channels, and the study is without doubt of high importance.
This is a solid manuscript from an experienced group that reports structural insights into cannabidiol interactions with the voltage-gated sodium channel NavM. The manuscript is easy to read, well-executed, and reveals interesting data.
Essential Revisions
The weakness of this study is the lack of functional data that would greatly complement the excellent structural results. Electrophysiological data showing the interaction of CBD with NavMs should be obtained and presented. This should be a very easy experiment to perform. CBD has been show to block the NachBac sodium channel, but there is no record in the literature that shows that CBD also blocks NavMs.
This is a fundamental experiment that should be included in a revised version of the paper. It will also be of great interest to test the results of their structure by mutating appropriate sodium channel residues (e.g. in Nav1.1) and measure changes in cannabidiol interaction.
Similarly, discussion of the different ways CBD and THC bind to NavMs (page 6) would greatly benefit from a comparison of the physiological effects of these two compounds. Does THC block NavMs and if it does, what is Kd/IC50 for THC compared to CBD?
Electron density observed at the CBD site in the apo state structure needs to be shown side by side with the density for CBD in the structure obtained in the presence of CBD (a supplementary figure would suffice). Along these lines, it might be a good idea to add a brief discussion on how physiologically relevant is the apo state density. For example, if this site is always occupied by a lipid in physiological conditions, the channel would never open.
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