Optical Control of Cannabinoid Receptor 2-Mediated Ca2+ Release Enabled by Synthesis of Photoswitchable Probes

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

Automated summary

CB2 receptor is a promising target for treating neuroinflammation and other diseases, but the lack of understanding of its complex signaling complicates therapeutic exploitation. A study demonstrates how the CB2 agonist HU308 affects cytosolic Ca2+ levels in cells and tissues, and shows the utility of chemical photoswitches for real-time control and monitoring of CB2 signaling.