TY - JOUR TI - Cannabidiol interactions with voltage-gated sodium channels AU - Sait, Lily Goodyer AU - Sula, Altin AU - Ghovanloo, Mohammad-Reza AU - Hollingworth, David AU - Ruben, Peter C AU - Wallace, BA A2 - Islas, Leon D A2 - Boudker, Olga A2 - Islas, Leon D VL - 9 PY - 2020 DA - 2020/10/22 SP - e58593 C1 - eLife 2020;9:e58593 DO - 10.7554/eLife.58593 UR - https://doi.org/10.7554/eLife.58593 AB - 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. KW - voltage -gated sodium channel KW - crystal structure KW - structure-function relationships KW - drug interations KW - electrophysiology KW - cannabidiol JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -