The calcium-sensing receptor in normal physiology and pathophysiology: A review

TY - JOUR

T1 - The calcium-sensing receptor in normal physiology and pathophysiology

T2 - A review

AU - Tfelt-Hansen, Jacob

AU - Brown, Edward M.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - The discovery of a G protein-coupled, calcium-sensing receptor (CaR) a decade ago and of diseases caused by CaR mutations provided unquestionable evidence of the CaR's critical role in the maintenance of systemic calcium homeostasis. On the cell membrane of the chief cells of the parathyroid glands, the CaR "senses" the extracellular calcium concentration and, subsequently, alters the release of parathyroid hormone (PTH). The CaR is likewise functionally expressed in bone, kidney, and gut-the three major calcium-translocating organs involved in calcium homeostasis. Intracellular signal pathways to which the CaR couples via its associated G proteins include phospholipase C (PLC), protein kinase B (AKT); and mitogen-activated protein kinases (MAPKs). The receptor is widely expressed in various tissues and regulates important cellular functions in addition to its role in maintaining systemic calcium homeostasis, i.e., protection against apoptosis, cellular proliferation, and membrane voltage. Functionally significant mutations in the receptor have been shown to induce diseases of calcium homeostasis owing to changes in the set point for calcium-regulated PTH release as well as alterations in the renal handling of calcium. Gain-of-function mutations cause hypocalcemia, whereas loss-of-function mutations produce hypercalcemia. Recent studies have shown that the latter clinical presentation can also be caused by inactivating autoantibodies directed against the CaR. Newly discovered type II allosteric activators of the CaR have been found to be effective as a medical treatment for renal secondary hyperparathyroidism.

AB - The discovery of a G protein-coupled, calcium-sensing receptor (CaR) a decade ago and of diseases caused by CaR mutations provided unquestionable evidence of the CaR's critical role in the maintenance of systemic calcium homeostasis. On the cell membrane of the chief cells of the parathyroid glands, the CaR "senses" the extracellular calcium concentration and, subsequently, alters the release of parathyroid hormone (PTH). The CaR is likewise functionally expressed in bone, kidney, and gut-the three major calcium-translocating organs involved in calcium homeostasis. Intracellular signal pathways to which the CaR couples via its associated G proteins include phospholipase C (PLC), protein kinase B (AKT); and mitogen-activated protein kinases (MAPKs). The receptor is widely expressed in various tissues and regulates important cellular functions in addition to its role in maintaining systemic calcium homeostasis, i.e., protection against apoptosis, cellular proliferation, and membrane voltage. Functionally significant mutations in the receptor have been shown to induce diseases of calcium homeostasis owing to changes in the set point for calcium-regulated PTH release as well as alterations in the renal handling of calcium. Gain-of-function mutations cause hypocalcemia, whereas loss-of-function mutations produce hypercalcemia. Recent studies have shown that the latter clinical presentation can also be caused by inactivating autoantibodies directed against the CaR. Newly discovered type II allosteric activators of the CaR have been found to be effective as a medical treatment for renal secondary hyperparathyroidism.

KW - Acquired hypoparathyroidism

KW - Autosomal dominant hypoparathyroidism

KW - Calcilytic

KW - Calcimimetic

KW - Calcium homeostasis

KW - Calcium-sensing receptor

KW - Familial hypocalciuric hypercalcemia

KW - G-protein

KW - Hyperparathyroidism

KW - Osteoporosis

UR - http://www.scopus.com/inward/record.url?scp=18244363907&partnerID=8YFLogxK

U2 - 10.1080/10408360590886606

DO - 10.1080/10408360590886606

M3 - Review

C2 - 15697170

AN - SCOPUS:18244363907

SN - 1040-8363

VL - 42

SP - 35

EP - 70

JO - Critical Reviews in Clinical Laboratory Sciences

JF - Critical Reviews in Clinical Laboratory Sciences

IS - 1

ER -