THE CALCIUM RECEPTOR IN HEALTH AND DISEASE

The recent cloning of a G-protein-coupled, extracellular calcium [(Ca2 +)(e)]-sensing receptor (CaRG) from the parathyroid, kidney and brain of several species has clarified the molecular mechanisms underlying C a2+-sensing by parathyroid and other cell types. It has long been susp ected that such a receptor existed on parathyroid cells, coupled to in tracellular second messengers through guanine nucleotide regulatory (G ) protein which is able to recognize and respond to (Ca2+)(e). Recentl y, functional screening of a cDNA library constructed from bovine para thyroid mRNA led to the isolation of a 5.3-kb clone expressing maximal Ca2+-stimulated Cl- currents in oocytes. This 5.3-kb cDNA encodes a p rotein of 1,085 amino acids with three principal predicted structural domains. The CaRG protein is present in chief parathyroid cells, in C cells of the thyroid, in the cortical thick ascending limb (TAL) and c ollecting duct of the kidney, and in discrete brain areas. CaRG may pl ay several physiological roles. It is a central element in the control of both parathyroid and calcitonin secretion by (Ca2+)(e). Moreover, functional evidence for its participation in the regulation of renal C a2+ reabsorption in TAL and water reabsorption in the collecting duct has been obtained. Mutations of the CaRG gene are responsible for here ditary and familial parathyroid disorders, and a decrease in CaRG expr ession has been documented in primary and secondary uremic hyperparath yroidism. The expression of CaRG in several additional organs and tiss ues allows speculation on the potential involvement in other pathologi es.