The calcium-sensing receptor: one of a kind

New Findings What is the topic of this review? The extracellular calcium-sensing receptor, CaSR, ensures whole-body Ca2+ homeostasis. Recent developments highlight the importance of the CaSR beyond mineral ion metabolism. This review focuses on novel roles and the use of CaSR-based therapeutics within the vasculature, the gut and the lung. What advances does it highlight? The ability of the CaSR to act as a multimodal chemosensor has led to the identification of signalling pathways that are ligand and cellular context dependent. Development of cell-specific CaSR modulators is now being harnessed to rescue aberrant CaSR function outside the extracellular Ca2+ homeostatic system. The extracellular calcium-sensing receptor, CaSR, is the first G protein-coupled receptor found to have an inorganic ion, calcium (Ca2+), as its physiological agonist. It is highly expressed in all organs involved in the regulation of mineral ion metabolism, namely the parathyroid gland, the kidney and bone. The CaSR is the master controller of extracellular Ca2+ concentration, as highlighted by the evidence that both inherited and acquired mutations in the CASR gene cause disturbances in mineral ion metabolism. CaSR positive allosteric modulators have been successfully employed in the clinic for over a decade to restore CaSR function, which is reduced in hyperparathyroidism secondary to kidney failure, while negative allosteric modulators are currently being tested in patients with hypocalcaemia with hypercalciuria due to gain-of-function CASR mutations. In addition to its expression within the bone–kidney–parathyroid axis, the CaSR can be found in other tissues, including but not limited to the gut, the vasculature and the lung. Here, the CaSR acts as a chemosensor, integrating signals deriving from nutrient availability, salinity, acidification and the presence of ubiquitous polyamines. Knowledge of what these stimuli are and of the cell-specific signalling responses they evoke is crucial to our understanding of the non-calciotropic roles of the CaSR in physiology and how these are affected in disease states