The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics

The extracellular calcium (Ca(o)2+)-sensing receptor (CaR) enables the parathyroid glands and other CaR-expressing cells to sense alterations in the level of Ca(o)2+ and to respond with changes in function that are directed at normalizing the blood calcium concentration. In addition to the parathyroid gland, the kidney is a key site for Ca(o)2(+)-sensing that enables it to make physiologically relevant alterations in divalent cation and water metabolism. Several disorders of Ca(o)2(+)-sensing arise from inherited or acquired abnormalities that "reset" the serum calcium concentration upward or downward. Inactivating mutations produce a benign form of hypercalcemia when present in the heterozygous state, termed Familial Hypocalciuric Hypercalcemia (FHH), while homozygous mutations produce a much more severe hypercalcemic disorder resulting from marked hyperparathyroidism, called Neonatal Severe Hyperparathyroidism (NSHPT). Activating mutations cause a hypocalcemic syndrome of varying severity, termed autosomal dominant hypocalcemia or hypoparathyroidism. Inactivating or activating antibodies directed at the CaR produce the expected hyper- or hypocalcemic syndromes, respectively. "Calcimimetic" CaR activators and "calcilytic" CaR antagonists have been developed. The calcimimetics are currently in use for controlling severe hyperparathyroidism in patients receiving dialysis treatment for end stage renal disease or with parathyroid cancer. Calcilytics are being evaluated as a means of inducing a "pulse" in the circulating parathyroid hormone (PTH) concentration, which would mimic that resulting from injection of PTH, an established anabolic form of treatment for osteoporosis.