Cannabidiol activates neuronal Kv7 channels

Niday, Z.; Heckman, L.; Jo, S.; Zhang, H.-X. B.; Fujita, A.; Shim, J.; Pandey, R.; Al Jandal, H.; Jayakar, S.; Smith, J. A.; Woolf, C. J.; Bean, B. P.

doi:10.1101/2021.08.20.457154

bioRxiv · 10.1101/2021.08.20.457154

Cannabidiol activates neuronal Kv7 channels

Niday, Z.·Heckman, L.·Jo, S.·Zhang, H.-X. B.·Fujita, A.·Shim, J.·Pandey, R.·Al Jandal, H.·Jayakar, S.·Smith, J. A.·Woolf, C. J.·Bean, B. P.

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Abstract

Cannabidiol (CBD), a chemical found in the Cannabis sativa plant, is a clinically effective antiepileptic drug whose mechanism of action is unknown. Using a fluorescence-based thallium flux assay, we performed a large-scale screen and found enhancement of flux through heterologously-expressed human Kv7.2/7.3 channels by CBD. Using patch clamp recordings, we found that CBD at low concentrations activates Kv7.2/7.3 channels at subthreshold voltages, with 100 nM CBD producing a doubling of current at -50 mV. CBD shifted the voltage-dependence of channels in the hyperpolarizing direction, producing a shift in the midpoint of activation by [~]-14 mV at 300 nM. CBD also effectively enhanced native M-current in both mouse superior cervical ganglion neurons and rat hippocampal neurons. The potent enhancement of Kv2/7.3 channels by CBD seems likely to contribute to its effectiveness as an antiepileptic drug by reducing neuronal hyperexcitability.

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Niday, Z., Heckman, L., Jo, S., Zhang, H.-X. B., Fujita, A., Shim, J., Pandey, R., Al Jandal, H., Jayakar, S., Smith, J. A., Woolf, C. J., Bean, B. P.. 2021-08-21. Cannabidiol activates neuronal Kv7 channels. https://doi.org/10.1101/2021.08.20.457154

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