Calcium Signaling pp 1031-1063 | Cite as

Sensing Extracellular Calcium – An Insight into the Structure and Function of the Calcium-Sensing Receptor (CaSR)

  • Sergei Chavez-Abiega
  • Iris Mos
  • Patricia P. Centeno
  • Taha Elajnaf
  • Wolfgang Schlattl
  • Donald T. Ward
  • Joachim Goedhart
  • Enikö KallayEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1131)


The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a key role in calcium homeostasis, by sensing free calcium levels in blood and regulating parathyroid hormone secretion in response. The CaSR is highly expressed in parathyroid gland and kidney where its role is well characterised, but also in other tissues where its function remains to be determined. The CaSR can be activated by a variety of endogenous ligands, as well as by synthetic modulators such as Cinacalcet, used in the clinic to treat secondary hyperparathyroidism in patients with chronic kidney disease. The CaSR couples to multiple G proteins, in a tissue-specific manner, activating several signalling pathways and thus regulating diverse intracellular events. The multifaceted nature of this receptor makes it a valuable therapeutic target for calciotropic and non-calciotropic diseases. It is therefore essential to understand the complexity behind the pharmacology, trafficking, and signalling characteristics of this receptor. This review provides an overview of the latest knowledge about the CaSR and discusses future hot topics in this field.


Extracellular calcium Parathyroid hormone G protein-coupled receptor G proteins Biased signalling Calcimimetics Calcilytics Allosteric modulators Orthosteric ligands Cellular trafficking 



1α,25-dihydroxyvitamin D3


Adenylate cyclase


Autosomal dominant hypocalcaemia


Adaptor protein-2


Cyclic adenosine monophosphate




Calcium-sensing receptor


Cysteine rich domain


Extracellular calcium concentration


Intracellular calcium


Intracellular calcium concentration


Chronic kidney disease




Extracellular domain


Endoplasmic reticulum


Extracellular signal-regulated kinase


Familial hypocalciuric hypercalcaemia


Gamma-aminobutyric acid


GTPase-activating proteins


Guanine nucleotide exchange factors


Guanine nucleotide dissociation inhibitors


G protein-coupled receptor


G protein-coupled receptor kinases


Glycogen synthase kinase-3


Human embryonic kidney


HEK293 cells stably expressing the CaSR


Intracellular domain


Insulin-like growth factor 1


Inositol 1,4,5-trisphosphate


C-Jun amino-terminal kinases


Metabotropic glutamate receptor


Negative allosteric modulator


Lobe-shaped domain


Mitogen-activated protein kinases


Negative allosteric modulator


Neonatal severe hyperparathyroidism


Na-K-Cl cotransporter 2


Phosphatidic acid


Positive allosteric modulator




Inorganic phosphate


Phosphoinositide 3-kinases


Phosphatidylinositol 4,5-bisphosphate


Protein Kinase A


Protein Kinase B


Protein Kinase C


Phospholipase A2


Phospholipase C


Phospholipase D


Prepro-parathyroid hormone




Parathyroid hormone


Parathyroid hormone-related protein




Regulator of G protein signalling


Receptor activity-modifying proteins


Transmembrane domain


Taste 1 receptors


Venus flytrap domain



The authors thank Hans Bräuner-Osborne for critical review of the manuscript. The authors of this chapter have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 675228 (CaSR Biomedicine).


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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Sergei Chavez-Abiega
    • 1
    • 6
  • Iris Mos
    • 2
  • Patricia P. Centeno
    • 3
  • Taha Elajnaf
    • 4
  • Wolfgang Schlattl
    • 5
  • Donald T. Ward
    • 3
  • Joachim Goedhart
    • 6
  • Enikö Kallay
    • 4
    Email author
  1. 1.Systems Bioinformatics, Amsterdam Institute for Molecules, Medicines, and SystemsVU UniversityAmsterdamThe Netherlands
  2. 2.Department of Drug Design and Pharmacology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK
  4. 4.Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology & ImmunologyMedical University of ViennaViennaAustria
  5. 5.Computer Science DepartmentUniversity of Torino; S.A.F.AN. BIOINFORMATICSTorinoItaly
  6. 6.Section of Molecular Cytology, van Leeuwenhoek Centre for Advanced Microscopy, Swammerdam Institute for Life SciencesUniversity of AmsterdamAmsterdamThe Netherlands

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