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Review ArticleMINIREVIEW

Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications

Zuzana Saidak, Michel Brazier, Saïd Kamel and Romuald Mentaverri
Molecular Pharmacology December 2009, 76 (6) 1131-1144; DOI: https://doi.org/10.1124/mol.109.058784
Zuzana Saidak
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Michel Brazier
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Saïd Kamel
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Romuald Mentaverri
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Abstract

The calcium-sensing receptor (CaR) belongs to the G protein-coupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain. The primary physiological function of the CaR is the maintenance of constant blood Ca2+ levels, as a result of its ability to sense very small changes in extracellular Ca2+ (Ca2+o). Nevertheless, in addition to being expressed in tissues involved in Ca2+o homeostasis, the CaR is also expressed in tissues not involved in mineral homeostasis, suggestive of additional physiological functions. Numerous agonists and modulators of the CaR are now known in addition to Ca2+o, including various divalent and trivalent cations, aromatic l-amino acids, polyamines, and aminoglycoside antibiotics. The signaling of the CaR is also regulated by extracellular pH and ionic strength. The activated CaR couples mainly to the phospholipase Cβ and extracellular signal-regulated kinase 1/2 signaling pathways, and it decreases intracellular cAMP levels, leading to various physiological effects. The recent identification of synthetic allosteric modulators of the CaR has opened up a new field of research possibilities. Calcimimetics and calcilytics, which increase and decrease agonist signaling via the CaR, respectively, may facilitate the manipulation of the CaR and thus aid in further investigations of its precise signaling. These allosteric modulators, as well as strontium, have been demonstrated to have therapeutic potential for the treatment of disorders involving the CaR. This review discusses the various agonists and modulators of the CaR, differences in their binding and signaling, and their roles as therapeutics in various diseases.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.058784

  • ABBREVIATIONS:

    CaR
    Ca2+-sensing receptor
    GPCR
    G protein-coupled receptor
    TM
    transmembrane
    ECD
    extracellular N-terminal domain
    VFTM
    Venus Flytrap Domain Motif
    PLC
    phospholipase C
    IP3
    inositol 1,4,5-triphosphate
    MAPK
    mitogen-activated protein kinase
    PTH
    parathyroid hormone
    HPT
    hyperparathyroidism
    FHH
    familial hypocalciuric hypercalcemia
    NSHPT
    neonatal severe hyperparathyroidism
    ADH
    autosomal dominant hypocalcemia
    pHo
    extracellular pH
    HEK
    human embryonic kidney
    NPS 2143
    N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
    NPS R-568
    N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
    ERK
    extracellular signal-regulated kinase
    AGA
    aminoglycoside antibiotic
    Calhex 231
    N(1)-(4-chlorobenzoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane
    GPRC6A
    G protein-coupled receptor, family C, group 6, member A
    G cells
    antral gastrin cells.

    • Received June 23, 2009.
    • Accepted September 24, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (6)
Molecular Pharmacology
Vol. 76, Issue 6
1 Dec 2009
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Review ArticleMINIREVIEW

Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications

Zuzana Saidak, Michel Brazier, Saïd Kamel and Romuald Mentaverri
Molecular Pharmacology December 1, 2009, 76 (6) 1131-1144; DOI: https://doi.org/10.1124/mol.109.058784

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Review ArticleMINIREVIEW

Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications

Zuzana Saidak, Michel Brazier, Saïd Kamel and Romuald Mentaverri
Molecular Pharmacology December 1, 2009, 76 (6) 1131-1144; DOI: https://doi.org/10.1124/mol.109.058784
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