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 parathyroid, kidney, and other tissues. In parathyroid, activation of the CaR by extracellular Ca2+ negatively regulates the secretion of parathyroid hormone. In the the thick ascending limb of Henle's loop, receptor activation decreases renal reabsorption of Ca2+. Heterozygous inactivating mutations of the CaR cause familial benign hypocalciuric hypercalcemia while homozygous inactivating mutations cause neonatal severe hyperparathyroidism. Conversely, activating mutations of the CaR cause autosomal dominant and sporadic hypoparathyroidism. Affected individuals have hypocalcemia which ranges from mild and asymptomatic to life-threatening. They also show a greater tendency to hypercalciuria than do other patients with hypoparathyroidism. Most, but not all, of the reported activating mutations occur in the amino-terminal, extracellular domain of the receptor. When expressed in cultured cells, mutant receptors can show both increased receptor sensitivity to Ca2+ and increased maximal signal transduction capacity.