Activation of the extracellular calcium-sensing receptor increases functional tethering between pancreatic β-cells

Abstract

The extracellular calcium-sensing receptor (CaR) enables cells to detect and respond to changes in extracellular calcium. Our previous studies have shown that the CaR is expressed by islet β-cells and that pharmacological activation of the islet CaR, using the calcimimetic R568, results in enhanced secretion of insulin. Epithelial (E)-cadherin (ECAD) is a trans-membrane protein whose extracellular domain forms calcium-dependent homodimers with cadherins expressed on neighbouring cells facilitating cell-to-cell adhesion. This not only serves to increase adhesive strength of the junction but also acts as a signalling ‘node’ for various proteins that can influence adhesiveness and/or initiate intracellular signalling events. It is well established that a down-regulation of E-cadherin reduces insulin secretion. We hypothesise that the extracellular calcium-sensing receptor modifies cell-to-cell adhesion within the pancreatic islet and predict that activating the receptor increases ECAD expression and function.