Abstract

In addition to its central role controlling systemic calcium homeostasis, the extracellular calcium-sensing receptor (CaSR) can be found on multiple cell types not associated with controlling plasma calcium. The endocrine pancreas is one such tissue, and it is apparent that the receptor plays an important role in regulating β-cell function. During exocytosis, divalent cations are coreleased with insulin and their concentration within the restricted intercellular compartments of the pancreatic islet increases sufficiently to activate the CaSR on neighboring cells. Acute and chronic activation of the receptor has multiple effects on the β-cell, from increasing cadherin-based cell–cell adhesion to directly altering the expression and function of various potassium and voltage-dependent calcium channels. The promiscuous activation of multiple binding partners improves cell adhesion, cell coupling, and cell-to-cell communication within the islet and is the basis for the effect of the CaSR on β-cell function and improved glucose responsiveness.