The calcium-sensing receptor in hereditary disorders of calcium homeostasis

Inherited diseases of calcium homeostasis were described more than 30 years ago. Consecutively, the discovery of the calcium receptor (CaR) more than a decade ago, followed by the demonstration that familial diseases of hyper- and hypocalcemia, in some cases were caused by functionally important mutations in the CaR, highlighted the receptor's pivotal role in the maintenance of systemic calcium homeostasis. Mutations that change the receptor's affinity toward calcium induce illnesses of calcium homeostasis by changing the set-point for calcium-regulated PTH release as well as the renal handling of calcium. Gain-of-function mutations cause a form of autosomal dominant hypoparathyroidism (ADH); this rare disease exhibits a clinical spectrum from mild to much more severe and symptomatic hypocalcemia with relative or absolute hypercalciuria. Loss-of-function mutations produce PTH-dependent forms of hypercalcemia called familial hypocalciuric hypercalcemia (FHH) in their heterozygous state (one mutated allele) and neonatal severe primary hyperparathyroidism (NSPHT) in their homozygous or compound heterozygous forms (two mutated alleles). FHH is thought to occur with about 1% of the prevalence of primary hyperparathyroidism and is often a benign state of hypercalcemia with relatively low urinary calcium output. NSPHT, on the other hand, is a considerably more rare but severe form of hypercalcemia presenting in most cases during the first 6 months of life. Affected children become symptomatic early on in life with failure to thrive and severe hyperparathyroid bone disease and may even die if left untreated. Until recently treatment of this condition involved total or subtotal parathyroidectomy. Similar to the inherited diseases with mutations in the calcium-sensing receptor, autoimmune diseases with antibodies targeting the CaR have been recognized. This review will focus on the calcium-sensing receptor, including its molecular physiology, as well as its role in various diseases of calcium homeostasis that illuminate the receptor's role not only in pathophysiology but also in normal physiology. Lastly, we shall describe the CaR as a drug target with proven and potential applications.