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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
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1131)

Abstract

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.

Keywords

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

Abbreviations

1,25D3

1α,25-dihydroxyvitamin D3

AC

Adenylate cyclase

ADH

Autosomal dominant hypocalcaemia

AP2

Adaptor protein-2

cAMP

Cyclic adenosine monophosphate

Ca2+

Calcium

CaSR

Calcium-sensing receptor

CR

Cysteine rich domain

[Ca2+]o

Extracellular calcium concentration

Ca2+i

Intracellular calcium

[Ca2+]i

Intracellular calcium concentration

CKD

Chronic kidney disease

DAG

Diacylglycerol

ECD

Extracellular domain

ER

Endoplasmic reticulum

ERK

Extracellular signal-regulated kinase

FHH

Familial hypocalciuric hypercalcaemia

GABA

Gamma-aminobutyric acid

GAPs

GTPase-activating proteins

GEFs

Guanine nucleotide exchange factors

GDIs

Guanine nucleotide dissociation inhibitors

GPCR

G protein-coupled receptor

GRKs

G protein-coupled receptor kinases

GSK3

Glycogen synthase kinase-3

HEK

Human embryonic kidney

HEK-CaSR

HEK293 cells stably expressing the CaSR

ICD

Intracellular domain

IGF-1

Insulin-like growth factor 1

IP3

Inositol 1,4,5-trisphosphate

JNK

C-Jun amino-terminal kinases

mGlu

Metabotropic glutamate receptor

NAM

Negative allosteric modulator

LB

Lobe-shaped domain

MAPKs

Mitogen-activated protein kinases

NAM

Negative allosteric modulator

NSHPT

Neonatal severe hyperparathyroidism

NKCC2

Na-K-Cl cotransporter 2

PA

Phosphatidic acid

PAM

Positive allosteric modulator

PDEs

Phosphodiesterases

Pi

Inorganic phosphate

PI3Ks

Phosphoinositide 3-kinases

PIP2

Phosphatidylinositol 4,5-bisphosphate

PKA

Protein Kinase A

PKB

Protein Kinase B

PKC

Protein Kinase C

PLA2

Phospholipase A2

PLC

Phospholipase C

PLD

Phospholipase D

PreProPTH

Prepro-parathyroid hormone

PT

Parathyroid

PTH

Parathyroid hormone

PTHrP

Parathyroid hormone-related protein

PTx

Pertussis-toxin

RGS

Regulator of G protein signalling

RAMPs

Receptor activity-modifying proteins

TMD

Transmembrane domain

TAS1R

Taste 1 receptors

VFD

Venus flytrap domain

Notes

Acknowledgements

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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