The Calcium Receptor in Health and Disease

Abstract

The recent cloning of a G-protein-coupled, extracellular calcium [(Ca²⁺)_e]-sensing receptor (CaR_G) from the parathyroid, kidney and brain of several species has clarified the molecular mechanisms underlying Ca²⁺-sensing by parathyroid and other cell types. It has long been suspected that such a receptor existed on parathyroid cells, coupled to intracellular second messengers through guanine nucleotide regulatory (G) protein which is able to recognize and respond to (Ca²⁺)_e. Recently, functional screening of a cDNA library constructed from bovine parathyroid 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 protein of 1,085 amino acids with three principal predicted structural domains. The CaR_G protein is present in chief parathyroid cells, in C cells of the thyroid, in the cortical thick ascending limb (TAL) and collecting duct of the kidney, and in discrete brain areas. CaR_G may play 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 Ca²⁺ reabsorption in TAL and water reabsorption in the collecting duct has been obtained. Mutations of the CaR_G gene are responsible for hereditary and familial parathyroid disorders, and a decrease in CaR_G expression has been documented in primary and secondary uremic hyperparathyroidism. The expression of CaR_G in several additional organs and tissues allows speculation on the potential involvement in other pathologies.