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Optical Control of Cannabinoid Receptor 2–Mediated Ca2+ Release Enabled By Synthesis of Photoswitchable Probes
ChemRxiv Pub Date : 2020-07-28 , DOI: 10.26434/chemrxiv.12722498.v1
Roman Sarott , Alexander E.G. Viray , Patrick Pfaff , Anastasiia Sadybekov , Gabriela Rajic , Vsevolod Katritch , Erick Carreira , James Frank

Cannabinoid receptor 2 (CB2) is a promising target for the treatment of neuroinflammation and other diseases. Howev-er, lack of understanding of its complex signaling in cells and tissues complicates its therapeutic targeting. For the first time we show that HU308 increases cytosolic Ca2+ levels in mammalian cells via CB2 and phospholipase C. We report the synthesis of pho-toswitchable derivatives of CB2 agonist HU308, azo-HU308s, from central building block 3-OTf-HU308. Azo-HU308s enable optical control over CB2 activity with spatiotemporal precision, as demonstrated in real-time Ca2+ fluorescence imaging. Our findings reveal a novel messenger pathway by which HU308 and its derivatives can affect cellular excitability, and demonstrate the utility of chemical photoswitches to control CB2 signaling in real time.

中文翻译:

大麻受体2介导的Ca2 +释放的光学控制,通过光开关探针的合成实现。

大麻素受体2(CB2)是治疗神经炎症和其他疾病的有希望的靶标。然而,缺乏对其在细胞和组织中复杂信号转导的理解,使其靶向治疗复杂化。首次显示,HU308通过CB2和磷脂酶C增加哺乳动物细胞中的胞质Ca 2+水平。我们报道了CB2激动剂HU308偶氮-HU308s的可光转换衍生物的合成,其中心结构单元3-OTf-HU308 。Azo-HU308s能够以时空精度对CB2活性进行光学控制,如实时Ca 2+荧光成像。我们的发现揭示了HU308及其衍生物可影响细胞兴奋性的新型信使途径,并证明了化学光开关可实时控制CB2信号传导。
更新日期:2020-07-28
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