The photoswitchable cannabinoid azo-HU308 enables optical control of Ca²⁺ dynamics in INS-1 β-cells via off-target...

Intracellular Ca²⁺ regulates insulin secretion from pancreatic β-cells and is influenced by cannabinoid signaling. However, the hydrophobicity and complex pharmacology of cannabinoid ligands prevent precision receptor targeting, limiting our understanding of their roles in modulating insulin release. Here, we use fluorescent Ca²⁺ imaging to examine how the light-activatable CB2 receptor agonist azo-HU308 modulates Ca²⁺ dynamics in INS-1 β-cells. UV-A photoactivation of azo-HU308 triggered robust, repeatable Ca²⁺ transients, and pharmacological profiling revealed this effect was independent of CB2 receptor activation but was instead mediated by extracellular Ca²⁺ influx through TRPC channels. These findings position azo-HU308 as a novel optical tool for controlling β-cell Ca²⁺ levels and highlight a non-GPCR pathway by which synthetic cannabinoids can modulate Ca²⁺ dynamics in excitable cells.