ACTIVATING MUTATIONS OF THE CA2-SENSING RECEPTOR()

The Ca2+-sensing receptor (CaR) is a member of the seven-transmembrane domain, G-protein-coupled receptor superfamily. It is expressed in pa rathyroid, kidney, and other tissues. In parathyroid, activation of th e CaR by extracellular Ca2+ negatively regulates the secretion of para thyroid hormone. In the the thick ascending limb of Henle's loop, rece ptor activation decreases renal reabsorption of Ca2+. Heterozygous ina ctivating mutations of the CaR cause familial benign hypocalciuric hyp ercalcemia while homozygous inactivating mutations cause neonatal seve re hyperparathyroidism. Conversely, activating mutations of the CaR ca use autosomal dominant and sporadic hypoparathyroidism. Affected indiv iduals have hypocalcemia which ranges from mild and asymptomatic to li fe-threatening. They also show a greater tendency to hypercalciuria th an do other patients with hypoparathyroidism. Most, but not all, of th e reported activating mutations occur in the amino-terminal, extracell ular domain of the receptor. When expressed in cultured cells, mutant receptors can show both increased receptor sensitivity to Ca2+ and inc reased maximal signal transduction capacity (C) 1998 Academic Press.