Heterogeneity of cannabinoid ligand-induced modulations in intracellular Ca signals of mouse pancreatic acinar cells in vitro.

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