Optical Control of Cannabinoid Receptor 2-Mediated Ca <sup>2+</sup> Release Enabled by Synthesis of Photoswitchable Probes
Roman C. Sarott, Alexander E. G. Viray, Patrick Pfaff, Anastasiia Sadybekov, Gabriela Rajic, Vsevolod Katritch, Erick M. Carreira, James A. Frank
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