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bioRxiv · 10.1101/2024.12.09.627564

Cannabinoid inhibition of mechanosensitive K+ channels

Docter, T.·Sorum, B.·Deshmane, R.·Doubravsky, C.·Brohawn, S. G.
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Abstract

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. SummaryWe discover cannabinoids inhibit mechanosensitive K+ channels including mutants that cause disease and reveal the mechanism for channel block.

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Docter, T., Sorum, B., Deshmane, R., Doubravsky, C., Brohawn, S. G.. 2024-12-10. Cannabinoid inhibition of mechanosensitive K+ channels. https://doi.org/10.1101/2024.12.09.627564

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