Optical control of cannabinoid receptor 2-mediated Ca2+ release enabled by 
synthesis of photoswitchable probes

Sarott, Roman C.; Viray, Alexander E. G.; Pfaff, Patrick; Sadybekov, Anastasiia; Rajic, Gabriela; Katritch, Vsevolod; Carreira, Erick M.; Frank, James A.

doi:10.1021/jacs.0c08926

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Optical control of cannabinoid receptor 2-mediated Ca2+ release enabled by synthesis of photoswitchable probes

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Sarott, Roman C.
Chemical Biology, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Sarott, R. C., Viray, A. E. G., Pfaff, P., Sadybekov, A., Rajic, G., Katritch, V., et al. (2021). Optical control of cannabinoid receptor 2-mediated Ca2+ release enabled by synthesis of photoswitchable probes. Journal of the American Chemical Society, 143(2), 736-743. doi:10.1021/jacs.0c08926.

Cite as: https://hdl.handle.net/21.11116/0000-000F-F428-1

Abstract

Cannabinoid receptor 2 (CB2) is a promising target for the treatment of neuroinflammation and other diseases. However, a lack of understanding of its complex signaling in cells and tissues complicates the therapeutic exploitation of CB2 as a drug target. We show for the first time that benchmark CB2 agonist HU308 increases cytosolic Ca2+ levels in AtT-20(CB2) cells via CB2 and phospholipase C. The synthesis of photoswitchable derivatives of HU308 from the common building block 3-OTf-HU308 enables optical control over this pathway with spatiotemporal precision, as demonstrated in a real-time Ca2+ fluorescence assay. Our findings reveal a novel messenger pathway by which HU308 and its derivatives affect cellular excitability, and they demonstrate the utility of chemical photoswitches to control and monitor CB2 signaling in real-time.