Cannabinoid inhibition of mechanosensitive K+ channels.

Cannabidiol (CBD) is a prominent non-psychoactive small molecule produced by cannabis plants used clinically as an antiepileptic. Here, we show CBD and other cannabinoids are potent inhibitors of mechanosensitive two-pore domain K+ (K2P) channels, including TRAAK and TREK-1 that contribute to spike propagation in myelinated axons. Five TRAAK mutations that cause epilepsy or the neurodevelopmental syndrome FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth) retain sensitivity to cannabinoid inhibition. A cryo-EM structure reveals CBD binds in the intracellular cavity of TREK-1 to sterically block ion conduction. These results show that cannabinoids and endogenous lipids compete for a common binding site to inhibit channel activity, identify mechanosensitive K2Ps as potential physiological targets of CBD, and suggest cannabinoids could counter gain-of-function in TRAAK channelopathies.