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The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases

Abstract

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and β-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.

Key points

  • The Ca2+-sensing receptor (CaSR) is a family C G protein-coupled receptor that is expressed on the cell surface as a dimer and signals via G proteins and β-arrestin.

  • The CaSR regulates bone and mineral metabolism by influencing parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation.

  • Germline CASR, GNA11 and AP2S1 mutations cause calcitropic disorders such as familial hypocalciuric hypercalcaemia and/or autosomal dominant hypocalcaemia.

  • In noncalcitropic tissues, the CaSR influences biological processes including gastrointestinal nutrient sensing, secretion of insulin and enteroendocrine hormones, vascular tone and wound healing.

  • Abnormal expression or function of the CaSR is associated with primary and secondary hyperparathyroidism, ischaemic brain injury, cardiovascular disease, asthma and cancers of the breast, prostate and colon.

  • CaSR-targeted calcimimetic and calcilytic drugs have therapeutic potential for calcitropic and noncalcitropic diseases.

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Fig. 1: Role of the CaSR in extracellular Ca2+ homeostasis.
Fig. 2: CaSR signalling and trafficking.
Fig. 3: Disruption of a salt bridge within the CaSR transmembrane domain causes biased signalling.
Fig. 4: Physiological roles and disease associations of the CaSR.

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Acknowledgements

The authors are supported by a Wellcome Trust Investigator Award (106995/Z/15/Z, to R.V.T.), a National Institute for Health Research Senior Investigator Award (NF-SI-0514-10091, to R.V.T.), UK Medical Research Council programme grants (G9825289 and G1000467, to R.V.T.), the European Commission Seventh Framework Programme (FP7-264663, to R.V.T. and E.K.), the Horizon 2020 Programme of the European Union (Project ID 675228, to F.M.H., E.K., M.L.B. and R.V.T.), the Austrian Science Fund (P29948-B28, to E.K.), the Vienna Science and Technology Fund (LS12-047, to E.K.), a US National Institute of Health Research Award (R01AR067291, to W.C.) and a Department of Veteran Affairs Merit Review Grant (I01 BX003453-01A2, to W.C.).

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F.M.H., E.K. and W.C. researched data for the article, provided substantial contribution to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. M.L.B. and R.V.T. provided substantial contribution to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Maria Luisa Brandi or Rajesh V. Thakker.

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F.M.H. and R.V.T. have received grant funding from NPS–Shire Pharmaceuticals and GlaxoSmithKline for studies involving the use of Ca2+-sensing receptor allosteric inhibitors. The other authors declare no competing interests.

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Hannan, F.M., Kallay, E., Chang, W. et al. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol 15, 33–51 (2019). https://doi.org/10.1038/s41574-018-0115-0

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