Calcium-sensing receptor: roles in and beyond systemic calcium homeostasis

The cloning of a Ca2+(0)-sensing receptor (CaR) from parathyroid and kidney, coupled with the identification of inherited disorders in Ca2+(0)-sensing resulting from inactivating or activating mutations of this CaR, has provided substantial insights into how Ca2+(0) is regulated at a systemic level. The CaR plays a central role in mediating, on one hand, the inhibitory effect of Ca2+(0) on parathyroid hormone (PTH) secretion and, on the other, the stimulatory action of Ca2+(0) on calcitonin secretion, which provide for a sophisticated, bi-directional regulation of the secretion of calciotropic hormones mediated by the same receptor. Indeed Ca2+(0) itself can be viewed as a calciotropic 'hormone' acting, along with PTH and calcinotin (CT), on its target tissues involved in mineral ion homeostasis, particularly the kidney. In the kidney, Ca2+zero, acting via the CaR, controls renal handling of divalent mineral ions in the cortical thick ascending limb (CTAL) and perhaps also in the distal convoluted tubule (DCT). In CTAL the CaR not only affects renal calcium handling indirectly by modulating the secretion of PTH but also directly at the level of the tubule, where it is localized on the same basolateal surface of the cells where the PTH receptor is located. Moreover, renal CaRs likely subserve important functions involved in integrating mineral ion metabolism with the homeostasis of water and, perhaps, monovalent cations (e.g., elevating Ca2+(0) produces a CaR-mediated inhibition of NaCl reabsorption in the CTAL). More recent data, however, accumulated since the cloning of the CaR, have suggested additional roles of the receptor in cells uninvolved in mineral ion metabolism. Examples include the brain, intestine and skin, where the receptor may regulate, respectively, the activities of ion channels and probably other neuronal functions, proliferation of the cells of the colonic crypts and differentiation of keratinocytes, presumably in response to local changes in Ca2+(0). It is also possible that the the CaR responds to other endogenous agonists, either polyvalent agonists, such as Mg2+(0) or organic polycations, including spermine or even protamine. Finally additional studies are needed to determine whether there are additional members of a putative family of structurally-related ion-sensing GPCRs, such as that apparently present in osteoblasts that sense Ca2+(0) and, perhaps, in other cell types that recognize additional ions [e.g., Cd2+(0) in dermal fibroblasts (Smith et al., 1989)].