The Photoswitchable Cannabinoid Azo -HU308 Enables Optical Control of Ca 2+ Signaling in Pancreatic β-Cells via a Non-CB2 TRPC Channel Mechanism
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Background and Purpose
Ca 2+ plays a critical role in regulating insulin secretion from pancreatic β-cells, a process modulated by various cell surface receptors, including cannabinoid receptors (CBRs). However, our understanding of cannabinoid signaling in β-cells is complicated by the intricate pharmacology of cannabinoid ligands and their inherent hydrophobicity, which hinders precise control of receptor activation. This study aims to investigate the effects of the light-activatable CB2 receptor agonist, azo -HU308, on β-cell Ca 2+ dynamics.
Experimental Approach
We employ fluorescent Ca 2+ imaging in INS-1 832/13 (INS-1) β-cells to measure Ca 2+ transients induced by azo -HU308 and photoactivation with UV-A light. We then apply a pharmacological screen using a various CBR and TRP channel antagonists to determine the mechanism by which azo -HU308 enables optical control of β-cell Ca 2+ levels.
Key Results
We observed that azo- HU308 triggers a robust increase in intracellular Ca 2+ when isomerized to the cis -form with UV-A light. The effect was repeatable over multiple cycles of irradiation and gradually desensitized on each sequential UV-light pulse. A pharmacological screen determined that the Ca 2+ increase was not due to CB2 receptor activation and Ca 2+ release from intracellular stores, but rather influx of extracellular Ca 2+ through TRPC channels.
Conclusions and Implications
azo- HU308 enables robust, repeatable stimulation of Ca 2+ in INS-1 pancreatic β-cells when triggered by UV-A light. This study presents a novel tool to optically control β-cell Ca 2+ dynamics, and sheds light on a new mechanism by which synthetic cannabinoids affect Ca 2+ signaling through non-GPCR targets.
