Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid

Abstract

Maintenance of a stable internal environment within complex organisms requires specialized cells that sense changes in the extracellular concentration of specific ions (such as Ca2+). Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion. The latter restores normocalcaemia by acting on kidney and bone. We now report the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor. The novel approximately 120K receptor shares limited similarity with the metabotropic glutamate receptors and features a large extracellular domain, containing clusters of acidic amino-acid residues possibly involved in calcium binding, coupled to a seven-membrane-spanning domain like those in the G-protein-coupled receptor superfamily.

The calcium-sensing receptor and 25-hydroxyvitamin D–1α-hydroxylase interact to modulate skeletal growth and bone turnover

“…E xtracellular calcium ([Ca 2þ ] e ) and the activated form of vitamin D [1,25(OH) 2 D] play important roles in modulating systemic calcium homeostasis. [Ca 2þ ] e activates a cation-sensing G protein-coupled receptor (CaSR) to modulate the concentrations of circulating parathyroid hormone (PTH) and to regulate renal calcium reabsorption.…”

“…[Ca 2þ ] e activates a cation-sensing G protein-coupled receptor (CaSR) to modulate the concentrations of circulating parathyroid hormone (PTH) and to regulate renal calcium reabsorption. (1) Gain-of-function mutations in the CASR gene in humans cause autosomal dominant hypocalcemia, a condition of mild to moderate hypocalcemia associated with suppression of PTH secretion that can be accompanied by hypercalciuria. (2) Loss-of-function mutations in the CASR gene cause familial benign hypocalciuric hypercalcemia in heterozygotes and neonatal severe hyperparathyroidism in homozygotes, both associated with increased PTH secretion and diminished renal calcium excretion but of differing severities.…”

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

“…1 Upon an increase in extracellular calcium, the receptor triggers intracellular signals that suppress PTH secretion. As an allosteric modulator, which enables the CASR to sense lower concentrations of extracellular calcium, the calcimimetic cinacalcet has been used in clinical practice to treat secondary hyperparathyroidism (sHPT), a common complication of chronic kidney disease (CKD), allowing for a decrease in the release of PTH with lower endogenous calcium levels.…”

Effects of propofol on intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism undergoing parathyroidectomy: a randomized control trial

“…12 In normal individuals, control of the PTH secretion is mediated by a direct interaction between extracellular calcium and the G protein-coupled calciumsensing receptors (CaRs) located on the parathyroid cell surface. 13 In patients with primary HPT, the number of CaRs is reduced on the surface of affected parathyroid gland cells, 14 but the function of an individual CaR is unchanged. This results in the PTH-Ca 2?…”