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

细胞外钙感应受体 (CaR) 通常与全身Ca(2) 稳态有关,但CaR也在许多其他组织中表达,包括朗格汉斯的胰岛。在本研究中,我们使用人类胰岛和胰岛素分泌细胞系 (MIN6) 来研究使用钙拟R-568 (一种在细胞外Ca(2) 的生理浓度下激活CaR的CaR激动剂) 激活CaR的作用。CaR激活在葡萄糖的亚刺激浓度下启动了人类胰岛和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。磷脂酶C或钙-钙调蛋白依赖性激酶的抑制剂可减少CaR诱导的胰岛素分泌,但蛋白激酶C抑制剂不能减少。CaR激活也与p42/44丝裂原活化蛋白激酶 (MAPK) 的激活有关,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被与胰岛素共同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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