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Clinical lessons from the calcium-sensing receptor

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 122–133 (2007)Cite this article

Abstract

The extracellular calcium ion (Ca2+e)-sensing receptor (CaR) enables key tissues that maintain Ca2+e homeostasis to sense changes in the Ca2+e concentration. These tissues respond to changes in Ca2+e with functional alterations that will help restore Ca2+e to normal. For instance, decreases in Ca2+e act via the CaR to stimulate secretion of parathyroid hormone—a Ca2+e-elevating hormone—and to increase renal tubular calcium reabsorption; each response helps promote normalization of Ca2+e levels. Further work is needed to determine whether the CaR regulates other parameters of renal function (e.g. 1,25-dihydroxyvitamin D3 synthesis, intestinal absorption of mineral ions, and/or bone turnover). Identification of the CaR has also elucidated the pathogenesis and pathophysiology of inherited disorders of mineral and electrolyte metabolism; moreover, acquired abnormalities of Ca2+e-sensing can result from autoimmunity to the CaR, and reduced CaR expression in the parathyroid may contribute to the abnormal parathyroid secretory control that is observed in primary and secondary hyperparathyroidism. Finally, calcimimetics—allosteric activators of the CaR—treat secondary hyperparathyroidism effectively in end-stage renal failure.

Key Points

  • Precise regulation of extracellular calcium is essential for life

  • The extracellular calcium-ion-sensing receptor (CaR) serves as a key sensor of the extracellular calcium concentration

  • The CaR promotes maintenance of extracellular calcium homeostasis by direct and/or indirect regulation of calcium transport in bone, kidney and intestine

  • Inherited and acquired disorders of calcium sensing can reset the serum calcium concentration either upward or downward

  • Pharmacologic activation of the CaR has provided an effective CaR-based small-molecule therapeutic for treating secondary hyperparathyroidism in patients with end-stage renal disease who are on dialysis

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Figure 1: Schematic diagram to illustrate the principal elements of extracellular calcium homeostasis.
Figure 2: Schematic of the extracellular calcium-ion-sensing receptor, showing the locations of activating and inactivating mutations and polymorphisms.

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  1. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, EBRC223, 221 Longwood Avenue, Boston, MA 02116, USA embrown@rics.bwh.harvard.edu

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  1. EM Brown is a Professor of Medicine in the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women's Hospital in Boston, MA, USA.,

    Edward M Brown

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The author has declared an association with Amgen; he receives royalties related to the sale of Sensipar® (cinacalcet hydrochloride).

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Brown, E. Clinical lessons from the calcium-sensing receptor. Nat Rev Endocrinol 3, 122–133 (2007). https://doi.org/10.1038/ncpendmet0388

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