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      The Calcium Receptor in Health and Disease

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          The recent cloning of a G-protein-coupled, extracellular calcium [(Ca<sup>2+</sup>)<sub>e</sub>]-sensing receptor (CaR<sub>G</sub>) from the parathyroid, kidney and brain of several species has clarified the molecular mechanisms underlying Ca<sup>2+</sup>-sensing by parathyroid and other cell types. It has long been suspected that such a receptor existed on parathyroid cells, coupled to intracellular second messengers through guanine nucleotide regulatory (G) protein which is able to recognize and respond to (Ca<sup>2+</sup>)<sub>e</sub>. Recently, functional screening of a cDNA library constructed from bovine parathyroid mRNA led to the isolation of a 5.3-kb clone expressing maximal Ca<sup>2+</sup>-stimulated Cl<sup>–</sup> currents in oocytes. This 5.3-kb cDNA encodes a protein of 1,085 amino acids with three principal predicted structural domains. The CaR<sub>G</sub> protein is present in chief parathyroid cells, in C cells of the thyroid, in the cortical thick ascending limb (TAL) and collecting duct of the kidney, and in discrete brain areas. CaR<sub>G</sub> may play several physiological roles. It is a central element in the control of both parathyroid and calcitonin secretion by (Ca<sup>2+</sup>)<sub>e</sub>. Moreover, functional evidence for its participation in the regulation of renal Ca<sup>2+</sup> reabsorption in TAL and water reabsorption in the collecting duct has been obtained. Mutations of the CaR<sub>G</sub> gene are responsible for hereditary and familial parathyroid disorders, and a decrease in CaR<sub>G</sub> expression has been documented in primary and secondary uremic hyperparathyroidism. The expression of CaR<sub>G</sub> in several additional organs and tissues allows speculation on the potential involvement in other pathologies.

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          Most cited references 12

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          Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

          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.
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            The metabotropic glutamate receptors: Structure and functions

             R. Duvoisin,  J-P Pin (1995)
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              Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs.

              Parathyroid cells express a cell surface receptor, coupled to the mobilization of intracellular Ca2+, that is activated by increases in the concentration of extracellular Ca2+ and by a variety of other cations. This "Ca2+ receptor" (CaR) serves as the primary physiological regulator of parathyroid hormone secretion. Alterations in the CaR have been proposed to underlie the increases in Ca2+ set-point seen in primary hyperparathyroidism due to parathyroid adenoma. We have isolated human CaR cDNAs from an adenomatous parathyroid gland. The cloned receptor, expressed in Xenopus oocytes, responds to extracellular application of physiologically relevant concentrations of Ca2+ and other CaR agonists. The rank order of potency of CaR agonists displayed by the native receptor (Gd3+ > neomycin B > Ca2+ > Mg2+) is maintained by the expressed receptor. The nucleotide sequence of the human CaR cDNA predicts a protein of 1078 amino acids with high sequence similarity to a bovine CaR, and displays seven putative membrane-spanning regions common to G protein-coupled receptors. The deduced protein sequence shows potential sites for N-linked glycosylation and phosphorylation by protein kinase C and has a low level of sequence similarity to the metabotropic glutamate receptors. Comparison of the cDNA sequence to that of the normal human CaR gene showed no alteration in the coding region sequence of the CaR in this particular instance of parathyroid adenoma. Human cDNA clones with differing 5'-untranslated regions were isolated, suggesting alternative splicing of the parathyroid CaR mRNA. A rare variant cDNA clone representing a 10 amino acid insertion into the extracellular domain was also isolated. Northern blot analysis of normal and adenomatous parathyroid gland mRNA identified a predominant transcript of approximately 5.4 kilobases, and less abundant transcripts of approximately 10, 4.8 and 4.2 kilobases in RNA from the adenoma. While there is no evidence for alteration of the primary amino acid sequence of the CaR in this adenoma, modulation of CaR biosynthesis through alternative RNA processing may play a role in set-point alterations.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                June 1998
                22 May 1998
                : 6
                : 3
                : 171-179
                Unité 90 INSERM et Département de Néphrologie, Hôpital Necker Paris, France
                20520 Exp Nephrol 1998;6:171–179
                © 1998 S. Karger AG, Basel

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                Figures: 2, Tables: 1, References: 76, Pages: 9
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20520
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