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 IC50 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-CB1R effect. In WT, CB1R 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.

中文翻译：

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大麻素配体诱导的体外小鼠胰腺腺泡细胞内 Ca2+ 信号调节的异质性。

我们最近报道了 CB2R 激动剂 GW405833 (GW) 在小鼠胰腺腺泡细胞中降低了 ACh 诱导的 Ca2+ 振荡和 L-精氨酸诱导的 Ca2+ 信号增强，表明 GW 诱导的抑制可能预防急性胰腺炎的发病机制. 在这项研究中，我们旨在评估其他大麻素配体对腺泡细胞中 Ca2+ 信号传导的影响。膜片钳全细胞记录用于测量 ACh 诱导的与野生型 (WT)、CB1R 敲除 (KO) 和 CB2R KO 小鼠急性分离的胰腺腺泡细胞中的细胞内 Ca2+ 振荡，以及各种大麻素配体的药理作用对 Ca2+ 振荡进行了检查。我们发现测试的所有 8 种 CB2R 激动剂都抑制了 ACh 诱导的 Ca2+ 振荡。其中，GW、JWH133、和 GP1a 产生有效的抑制作用，IC50 值分别为 5.0、6.7 和 1.2 μmol/L。在 CB2R KO 小鼠或存在 CB2R 拮抗剂 (AM630) 的情况下，这 3 种 CB2R 激动剂的抑制作用被消除，表明它们通过 CB2R 起作用。CB1R 激动剂 ACEA 还诱导抑制存在于 CB1R KO 小鼠和存在 CB1R 拮抗剂 (AM251) 的 Ca2+ 振荡，表明非 CB1R 效应。在 WT、CB1R KO 和 CB2R KO 小鼠中，非选择性 CBR 激动剂 WIN55,212-2 抑制了不受 CB1R 或 CB2R 介导的 Ca2+ 振荡。内源性大麻素物质 2-花生四烯酰甘油 (2-AG) 对 Ca2+ 振荡没有显示抑制作用。总之，CB2R 激动剂在调节小鼠胰腺腺泡细胞中的 Ca2+ 信号中起关键作用，