The extracellular calcium-sensing receptor (CaR) is usually associated with systemic Ca(2+) homeostasis, but the CaR is also expressed in many other tissues, including pancreatic islets of Langerhans. In the present study, we have used human islets and an insulin-secreting cell line (MIN6) to investigate the effects of CaR activation using the calcimimetic R-568, a CaR agonist that activates the CaR at physiological concentrations of extracellular Ca(2+). CaR activation initiated a marked but transient insulin secretory response from both human islets and MIN6 cells at a sub-stimulatory concentration of glucose, and further enhanced glucose-induced insulin secretion. CaR-induced insulin secretion was reduced by inhibitors of phospholipase C or calcium-calmodulin-dependent kinases, but not by a protein kinase C inhibitor. CaR activation was also associated with an activation of p42/44 mitogen-activated protein kinases (MAPK), and CaR-induced insulin secretion was reduced by an inhibitor of p42/44 MAPK activation. We suggest that the beta-cell CaR is activated by divalent cations co-released with insulin, and that this may be an important mechanism of intra-islet communication between beta-cells.

译文

:细胞外钙敏感受体(CaR)通常与全身性Ca(2)稳态相关,但该CaR在许多其他组织中也表达,包括Langerhans的胰岛。在本研究中,我们已经使用人类胰岛和胰岛素分泌细胞系(MIN6)来研究使用拟钙剂R-568(CaR激动剂在生理浓度的细胞外Ca(2)激活CaR的CaR激活)的作用。 。 CaR激活在葡萄糖的亚刺激浓度下启动了来自人胰岛和MIN6细胞的显着但短暂的胰岛素分泌反应,并进一步增强了葡萄糖诱导的胰岛素分泌。 CaR诱导的胰岛素分泌通过磷脂酶C或钙钙调蛋白依赖性激酶的抑制剂降低,但不通过蛋白激酶C抑制剂降低。 CaR激活还与p42 / 44丝裂原激活的蛋白激酶(MAPK)激活相关,并且CaR诱导的胰岛素分泌被p42 / 44 MAPK激活的抑制剂减少。我们建议β细胞CaR被与胰岛素共释放的二价阳离子激活,这可能是β细胞之间胰岛内通讯的重要机制。

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