Gray Elizabeth, Muller Dany, Squires Paul E, Asare-Anane Henry, Huang Guo-Cai, Amiel Stephanie, Persaud Shanta J, Jones Peter M
Beta Cell Development and Function Group, Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King's College London, Hodgkin Building HB2.10N, Guy's Campus, London SE1 9UL, UK.
J Endocrinol. 2006 Sep;190(3):703-10. doi: 10.1677/joe.1.06891.
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.
细胞外钙敏感受体（CaR）通常与全身钙（Ca2+）稳态相关，但CaR也在许多其他组织中表达，包括胰岛。在本研究中，我们使用人胰岛和胰岛素分泌细胞系（MIN6），利用拟钙剂R-568（一种在细胞外Ca2+生理浓度下激活CaR的CaR激动剂）来研究CaR激活的作用。在亚刺激浓度的葡萄糖条件下，CaR激活引发了人胰岛和MIN6细胞显著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或钙调蛋白依赖性激酶抑制剂可降低CaR诱导的胰岛素分泌，但蛋白激酶C抑制剂则无此作用。CaR激活还与p42/44丝裂原活化蛋白激酶（MAPK）的激活相关，并且p42/44 MAPK激活抑制剂可降低CaR诱导的胰岛素分泌。我们认为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细胞间胰岛内通讯的重要机制。
