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We recently reported that a CB 2 R agonist, GW405833 (GW), reduced both the ACh-induced Ca 2+ oscillations and the L-arginine-induced Ca 2+ signal enhancement in mouse pancreatic acinar cells, suggesting that GW-induced inhibition may prevent the pathogenesis of acute pancreatitis. In this study, we aim to evaluate the effects of other cannabinoid ligands on Ca 2+ signaling in acinar cells. Patch-clamp whole-cell recordings were applied to measure ACh-induced intracellular Ca 2+ oscillations in pancreatic acinar cells acutely dissociated from wild-type (WT), CB 1 R knockout (KO), and CB 2 R KO mice, and the pharmacological effects of various cannabinoid ligands on the Ca 2+ oscillations were examined. We found that all the 8 CB 2 R agonists tested inhibited ACh-induced Ca 2+ oscillations. Among them, GW, JWH133, and GP1a caused potent inhibition with IC 50 values of 5.0, 6.7, and 1.2 μmol/L, respectively. In CB 2 R KO mice or in the presence of a CB 2 R antagonist (AM630), the inhibitory effects of these 3 CB 2 R agonists were abolished, suggesting that they acted through the CB 2 Rs. The CB 1 R agonist ACEA also induced inhibition of Ca 2+ oscillations that existed in CB 1 R KO mice and in the presence of a CB 1 R antagonist (AM251), suggesting a non-CB 1 R effect. In WT, CB 1 R KO, and CB 2 R KO mice, a nonselective CBR agonist, WIN55,212-2, inhibited Ca 2+ oscillations, which was not mediated by CB 1 Rs or CB 2 Rs. The endogenous cannabinoid substance, 2-arachidonoylglycerol (2-AG), did not show an inhibitory effect on Ca 2+ oscillations. In conclusion, CB 2 R agonists play critical roles in modulating Ca 2+ signals in mouse pancreatic acinar cells, while other cannabinoid ligands modulate Ca 2+ oscillations in a heterogeneous manner through a CB receptor or non-CB-receptor mechanism.

Heterogeneity of cannabinoid ligand-induced modulations in intracellular Ca2+ signals of mouse pancreatic acinar cells in vitro