TY - JOUR
T1 - Optical Control of Cannabinoid Receptor 2-Mediated Ca2+Release Enabled by Synthesis of Photoswitchable Probes
AU - Sarott, Roman C.
AU - Viray, Alexander E.G.
AU - Pfaff, Patrick
AU - Sadybekov, Anastasiia
AU - Rajic, Gabriela
AU - Katritch, Vsevolod
AU - Carreira, Erick M.
AU - Frank, James A.
N1 - Funding Information:
E.M.C gratefully acknowledges support by ETH Zürich. R.C.S and P.P. gratefully acknowledge funding from the Scholarship Fund of the Swiss Chemical Industry (SSCI). J.A.F., A.E.G.V., and G.R. acknowledge the Vollum Institute Fellowship for financial support.
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/1/20
Y1 - 2021/1/20
N2 - 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
AB - 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
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U2 - 10.1021/jacs.0c08926
DO - 10.1021/jacs.0c08926
M3 - Article
C2 - 33399457
AN - SCOPUS:85100078587
SN - 0002-7863
VL - 143
SP - 736
EP - 743
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 2
ER -