A role for the extracellular calcium-sensing receptor in cell-cell communication in pancreatic islets of langerhans.

BACKGROUND The extracellular calcium-sensing receptor (CaR) is expressed in many tissues that are not associated with Ca(2+) homeostasis, including the endocrine cells in pancreatic islets of Langerhans. We have demonstrated previously that pharmacological activation of the CaR stimulates insulin secretion from islet beta-cells and insulin-secreting MIN6 cells. METHODS In the present study we have investigated the effects of CaR activation on MIN6 cell proliferation and have used shRNA-mediated CaR knockdown to determine whether the CaR is involved in the regulation of insulin secretion via cell-cell communication. RESULTS CaR activation caused the phosphorylation and activation of the p42/44 MAPK signalling cascade, and this activation was prevented by the shRNA-induced down-regulation of CaR mRNA expression. CaR activation also resulted in increased proliferation of MIN6 cells, consistent with the known role of the p42/44 MAPK system in the regulation of beta-cell proliferation. Down-regulation of CaR expression had no detectable effects on glucose-induced insulin secretion from MIN6 cells maintained as monolayers, but blocked the increases in insulin secretion that were observed when the cells were configured as three-dimensional islet-like structures (pseudoislets), consistent with a role for the CaR in cell-cell communication in pseudoislets. CONCLUSION It is well established that islet function is dependent on communication between islet cells and the results of this study suggest that the CaR is required for beta-cell to beta-cell interactions within islet-like structures.