CALCIUM-SENSING RECEPTOR - ROLES IN AND BEYOND SYSTEMIC CALCIUM HOMEOSTASIS

The cloning of a Ca-0(2+)-sensing receptor (CaR) from parathyroid and kidney, coupled with the identification of inherited disorders in Ca-0 (2+)-sensing resulting from inactivating or activating mutations of th is Can, has provided substantial insights into how Ca-0(2+) is regulat ed at a systemic level. The CaR plays a central role in mediating, on one hand, the inhibitory effect of Ca-0(2+) on parathyroid hormone (PT H) secretion and, on the other, the stimulatory action of Ca-0(2+) on calcitonin secretion, which provide for a sophisticated, bi-directiona l regulation of the secretion of calciotropic hormones mediated by the same receptor. Indeed Ca-0(2+) itself can be viewed as a calciotropic 'hormone' acting, along with PTH and calcinotin (CT), on its target t issues involved in mineral ion homeostasis, particularly the kidney. I n the kidney, Ca-0(2+), 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 n ot only affects renal calcium handling indirectly by modulating the se cretion of PTH but also directly at the level of the tubule, where it is localized on the same basolateral surface of the cells where the PT H receptor is located. Moreover, renal CaRs likely subserve important functions involved in integrating mineral ion metabolism with the home ostasis of water and, perhaps, monovalent cations (e.g., elevating Ca- 0(2+) produces a CaR-mediated inhibition of NaCl reabsorption in the C TAL). More recent data, however, accumulated since the cloning of the CaR, have suggested additional roles of the receptor in cells uninvolv ed in mineral ion metabolism. Examples include the brain, intestine an d skin, where the receptor may regulate, respectively, the activities of ion channels and probably other neuronal functions, proliferation o f the cells of the colonic crypts and differentiation of keratinocytes , presumably in response to local changes in Ca-0(2+). It is also poss ible that the CaR responds to other endogenous agonists, either polyva lent agonists, such as Mg-0(2+) or organic polycations, including sper mine or even protamine. Finally additional studies are needed to deter mine whether there are additional members of a putative family of stru cturally-related ion-sensing GPCRs, such as that apparently present in osteoblasts that sense Ca-0(2+) and, perhaps, in other cell types tha t recognize additional ions [e.g., Cd-0(2+) in dermal fibroblasts (Smi th ef al., 1989)].