We recently reported that a CB2R agonist,GW405833 (GW),reduced both the ACh-induced Ca2+ oscillations and the L-arginine-induced Ca2+ 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 Ca2+ signaling in acinar cells.Patch-clamp whole-cell recordings were applied to measure ACh-induced intracellular Ca2+ oscillations in pancreatic acinar cells acutely dissociated from wild-type (WT),CB1R knockout (KO),and CB2R KO mice,and the pharmacological effects of various cannabinoid ligands on the Ca2+ oscillations were examined.We found that all the 8 CB2R agonists tested inhibited ACh-induced Ca2+ oscillations.Among them,GW,JWH133,and GP1a caused potent inhibition with ICso values of 5.0,6.7,and 1.2 μmol/L,respectively.In CB2R KO mice or in the presence of a CB2R antagonist (AM630),the inhibitory effects of these 3 CB2R agonists were abolished,suggesting that they acted through the CB2Rs.The CB1R agonist ACEA also induced inhibition of Ca2+ oscillations that existed in CB1R KO mice and in the presence of a CB1R antagonist (AM251),suggesting a non-CB1 R effect.In WT,CB1 R KO,and CB2R KO mice,a nonselective CBR agonist,WIN55,212-2,inhibited Ca2+ oscillations,which was not mediated by CB1Rs or CB2Rs.The endogenous cannabinoid substance,2-arachidonoylglycerol (2-AG),did not show an inhibitory effect on Ca2+ oscillations.In conclusion,CB2R agonists play critical roles in modulating Ca2+ signals in mouse pancreatic acinar cells,while other cannabinoid ligands modulate Ca2+ oscillations in a heterogeneous manner through a CB receptor or non-CB-receptor mechanism.