Cannabidiol inhibits Na<sub>v</sub> channels through two distinct binding sites.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37330538.
- Also identified by DOI 10.1038/s41467-023-39307-6 and PMC identifier 10276812.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of proteins, but which targets are most relevant for clinical actions is still unclear. Here we show that CBD interacts with Na<sub>v</sub>1.7 channels at sub-micromolar concentrations in a state-dependent manner. Electrophysiological experiments show that CBD binds to the inactivated state of Na<sub>v</sub>1.7 channels with a dissociation constant of about 50 nM. The cryo-EM structure of CBD bound to Na<sub>v</sub>1.7 channels reveals two distinct binding sites. One is in the IV-I fenestration near the upper pore. The other binding site is directly next to the inactivated "wedged" position of the Ile/Phe/Met (IFM) motif on the short linker between repeats III and IV, which mediates fast inactivation. Consistent with producing a direct stabilization of the inactivated state, mutating residues in this binding site greatly reduced state-dependent binding of CBD. The identification of this binding site may enable design of compounds with improved properties compared to CBD itself.
Medical subject headings
- Cannabidiol
- Epilepsy