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  • Review Article
  • Published:

Localization and function of the renal calcium-sensing receptor

Nature Reviews Nephrology volume 12, pages 414–425 (2016)Cite this article

Subjects

Key Points

  • A pivotal role for the renal calcium-sensing receptor (CaSR) in the control of divalent cation excretion in a parathyroid hormone-independent manner has been identified through tissue-specific CaSR ablation and pharmacological studies

  • A functional interaction between the CaSR and Claudin-14 in the thick ascending limb permits regulation of paracellular Ca2+ reabsorption

  • The CaSR fine tunes Ca2+, Mg2+, and Pi transport in the proximal tubule by integrating multiple inputs from divalent cation concentration, osmolarity, and urine acidification

  • Calcimimetics would be expected to increase urinary Ca2+ excretion by acting on the CaSR in the parathyroid glands and the kidney

  • Calcilytics represent a novel, promising avenue for the treatment of hypercalciuria, nephrolithiasis, and nephrocalcinosis

  • The CaSR and adenylyl cyclase type 6 are co-expressed in the nephron and act to sensitize hormones to extracellular Ca2+ and counteract hormone-induced increases in cAMP

Abstract

The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca2+) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca2+ sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca2+ (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function.

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Figure 1: Localization of the calcium-sensing receptor (CaSR) in the kidney tubule.
Figure 2: The calcium-sensing receptor (CaSR) confers high sensitivity to extracellular Ca2+ concentration by reducing the effects of distinct hormones that selectively act in selected nephron segments via the Gs-coupled receptor–ADCY6–cAMP signalling pathway.

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Acknowledgements

The authors acknowledge financial support from the Marie Curie Initial Training Network for the project “Multifaceted CaSR” (to D.R.) and Telethon funding for the project “Aquaporin-2 and calcium-sensing receptor: new players regulating water handling in familial hypercalciuria” (to G.V.). The authors are grateful to Drs Edward M. Brown, Dennis Brown and the late Steven Hebert for their mentorship and support, and for inspiring their work on the renal CaSR.

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  1. Division of Pathophysiology and Repair, School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK

    Daniela Riccardi

  2. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, Via Orabona 4, Bari, 70125, Italy

    Giovanna Valenti

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Both authors researched data for the article, provided a substantial contribution to discussions of the content, contributed equally to writing the article and to review and/or editing of the manuscript before submission.

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Riccardi, D., Valenti, G. Localization and function of the renal calcium-sensing receptor. Nat Rev Nephrol 12, 414–425 (2016). https://doi.org/10.1038/nrneph.2016.59

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