The Calcium-Sensing Receptor and the Parathyroid: Past, Present, Future

Overview

Journal Front Physiol

Date 2016 Dec 27

PMID 28018229

Citations 35

Authors

Arthur D Conigrave

Affiliations

Soon will be listed here.

Abstract

Parathyroid hormone (PTH) defends the extracellular fluid from hypocalcemia and has powerful and well-documented actions on the skeleton and renal tubular system. To achieve a satisfactory stable plasma calcium level, the secretion of PTH, and the resulting serum PTH level, is titrated carefully to the prevailing plasma ionized Ca concentration via a Ca sensing mechanism that mediates feedback inhibition of PTH secretion. Herein, I consider the properties of the parathyroid Ca sensing mechanism, the identity of the Ca sensor, the intracellular biochemical mechanisms that it controls, the manner of its integration with other components of the PTH secretion control mechanism, and its modulation by other nutrients. Together the well-established, recently elucidated, and yet-to-be discovered elements of the story constitute the past, present, and future of the parathyroid and its calcium-sensing receptor (CaSR).

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References

Riccardi D, Traebert M, Ward D, Kaissling B, Biber J, Hebert S . Dietary phosphate and parathyroid hormone alter the expression of the calcium-sensing receptor (CaR) and the Na+-dependent Pi transporter (NaPi-2) in the rat proximal tubule. Pflugers Arch. 2001; 441(2-3):379-87. DOI: 10.1007/s004240000436. View

Shoback D, Membreno L, McGhee J . High calcium and other divalent cations increase inositol trisphosphate in bovine parathyroid cells. Endocrinology. 1988; 123(1):382-9. DOI: 10.1210/endo-123-1-382. View

Imanishi Y, Kawata T, Kenko T, Wada M, Nagano N, Miki T . Cinacalcet HCl suppresses Cyclin D1 oncogene-derived parathyroid cell proliferation in a murine model for primary hyperparathyroidism. Calcif Tissue Int. 2011; 89(1):29-35. DOI: 10.1007/s00223-011-9490-4. View

Tsuchiya D, Kunishima N, Kamiya N, Jingami H, Morikawa K . Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+. Proc Natl Acad Sci U S A. 2002; 99(5):2660-5. PMC: 122404. DOI: 10.1073/pnas.052708599. View

Pollak M, Brown E, Chou Y, Hebert S, Marx S, Steinmann B . Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993; 75(7):1297-303. DOI: 10.1016/0092-8674(93)90617-y. View

Brown E, Broadus A, Brennan M, Gardner D, Marx S, Spiegel A . Direct comparison in vivo and in vitro of suppressibility of parathyroid function by calcium in primary hyperparathyroidism. J Clin Endocrinol Metab. 1979; 48(4):604-10. DOI: 10.1210/jcem-48-4-604. View

Thakker R . Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium. 2004; 35(3):275-82. DOI: 10.1016/j.ceca.2003.10.010. View

Windeck R, Brown E, Gardner D, Aurbach G . Effect of gastrointestinal hormones on isolated bovine parathyroid cells. Endocrinology. 1978; 103(6):2020-6. DOI: 10.1210/endo-103-6-2020. View

Walter S, Baruch A, Dong J, Tomlinson J, Alexander S, Janes J . Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. J Pharmacol Exp Ther. 2013; 346(2):229-40. DOI: 10.1124/jpet.113.204834. View

10.

Brown E, Leombruno R, Thatcher J, Burrowes M . The acute secretory response to alterations in extracellular calcium concentration and dopamine in perifused bovine parathyroid cells. Endocrinology. 1985; 116(3):1123-32. DOI: 10.1210/endo-116-3-1123. View

11.

Ba J, Brown D, Friedman P . Calcium-sensing receptor regulation of PTH-inhibitable proximal tubule phosphate transport. Am J Physiol Renal Physiol. 2003; 285(6):F1233-43. DOI: 10.1152/ajprenal.00249.2003. View

12.

Ray K, Northup J . Evidence for distinct cation and calcimimetic compound (NPS 568) recognition domains in the transmembrane regions of the human Ca2+ receptor. J Biol Chem. 2002; 277(21):18908-13. DOI: 10.1074/jbc.M202113200. View

13.

Maccallum W, Voegtlin C . ON THE RELATION OF TETANY TO THE PARATHYROID GLANDS AND TO CALCIUM METABOLISM. J Exp Med. 2009; 11(1):118-51. PMC: 2124703. DOI: 10.1084/jem.11.1.118. View

14.

Kemp E, Gavalas N, Akhtar S, Krohn K, Pallais J, Brown E . Mapping of human autoantibody binding sites on the calcium-sensing receptor. J Bone Miner Res. 2009; 25(1):132-40. PMC: 3153323. DOI: 10.1359/jbmr.090703. View

15.

Moe S, Cunningham J, Bommer J, Adler S, Rosansky S, Urena-Torres P . Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant. 2005; 20(10):2186-93. DOI: 10.1093/ndt/gfh966. View

16.

Egbuna O, Brown E . Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol. 2008; 22(1):129-48. PMC: 2364635. DOI: 10.1016/j.berh.2007.11.006. View

17.

Riccardi D, Valenti G . Localization and function of the renal calcium-sensing receptor. Nat Rev Nephrol. 2016; 12(7):414-25. DOI: 10.1038/nrneph.2016.59. View

18.

Gardner D, Brown E, Attie M, Aurbach G . Prostaglandin-mediated stimulation of adenosine 3',5'-monophosphate accumulation and parathyroid hormone release in dispersed human parathyroid cells. J Clin Endocrinol Metab. 1980; 51(1):20-5. DOI: 10.1210/jcem-51-1-20. View

19.

Pallais J, Kifor O, Chen Y, Slovik D, Brown E . Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor. N Engl J Med. 2004; 351(4):362-9. DOI: 10.1056/NEJMoa040008. View

20.

Breitwieser G . Minireview: the intimate link between calcium sensing receptor trafficking and signaling: implications for disorders of calcium homeostasis. Mol Endocrinol. 2012; 26(9):1482-95. PMC: 5416969. DOI: 10.1210/me.2011-1370. View