# The photoswitchable cannabinoid azo‐HU308 enables optical control of Ca2+ dynamics in INS‐1 β‐cells via off‐target effects on TRPC channels

## TL;DR

A light-sensitive cannabinoid compound triggers calcium influx in pancreatic cells through TRPC channels, not via its intended receptor.

## Contribution

Azo-HU308 is a novel optical tool for controlling calcium levels in β-cells via TRPC channels, bypassing CB2 receptors.

## Key findings

- UV-A activation of azo-HU308 induces repeatable Ca2+ transients in INS-1 β-cells.
- The effect is mediated by TRPC channels and extracellular Ca2+ influx, not CB2 receptor activation.

## Abstract

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.

Light activation of the photoswitchable cannabinoid ligand azo‐HU308 triggers Ca2+ influx in pancreatic β‐cells through TRPC channels, independent of CB2 cannabinoid receptors. This reveals a non‐GPCR pathway for cannabinoid modulation of β‐cell Ca2+ dynamics and establishes azo‐HU308 as an optical tool to study cannabinoid signaling through TRP channels in excitable cells.