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Research ArticleCellular and Molecular

Strontium Is a Biased Agonist of the Calcium-Sensing Receptor in Rat Medullary Thyroid Carcinoma 6-23 Cells

Alex Rojas Bie Thomsen, Jesper Worm, Stine Engesgaard Jacobsen, Martin Stahlhut, Markus Latta and Hans Bräuner-Osborne
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 638-649; DOI: https://doi.org/10.1124/jpet.112.197210
Alex Rojas Bie Thomsen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.R.B.T., S.E.J., H.B.-O.); and LEO Pharma A/S, Ballerup, Denmark (A.R.B.T., J.W., M.S., M.L.)
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Jesper Worm
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.R.B.T., S.E.J., H.B.-O.); and LEO Pharma A/S, Ballerup, Denmark (A.R.B.T., J.W., M.S., M.L.)
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Stine Engesgaard Jacobsen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.R.B.T., S.E.J., H.B.-O.); and LEO Pharma A/S, Ballerup, Denmark (A.R.B.T., J.W., M.S., M.L.)
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Martin Stahlhut
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.R.B.T., S.E.J., H.B.-O.); and LEO Pharma A/S, Ballerup, Denmark (A.R.B.T., J.W., M.S., M.L.)
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Markus Latta
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.R.B.T., S.E.J., H.B.-O.); and LEO Pharma A/S, Ballerup, Denmark (A.R.B.T., J.W., M.S., M.L.)
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Hans Bräuner-Osborne
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (A.R.B.T., S.E.J., H.B.-O.); and LEO Pharma A/S, Ballerup, Denmark (A.R.B.T., J.W., M.S., M.L.)
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Abstract

The calcium-sensing receptor (CaSR)-specific allosteric modulator cinacalcet has revolutionized the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. However, its application is limited to patients with end-stage renal disease because of hypocalcemic side effects presumably caused by CaSR-mediated calcitonin secretion from thyroid parafollicular C-cells. These hypocalcemic side effects might be dampened by compounds that bias the signaling of CaSR, causing similar therapeutic effects as cinacalcet without stimulating calcitonin secretion. Because biased signaling of CaSR is poorly understood, the objective of the present study was to investigate biased signaling of CaSR by using rat medullary thyroid carcinoma 6-23 cells as a model of thyroid parafollicular C-cells. By doing concentration-response experiments we focused on the ability of two well known CaSR agonists, calcium and strontium, to activate six different signaling entities: Gq/11 signaling, Gi/o signaling, Gs signaling, extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, intracellular calcium ([Ca2+]i) mobilization, and calcitonin secretion. The experiments showed that strontium biases CaSR signaling toward ERK1/2 signaling and possibly another pathway independent of Gq/11 signaling and [Ca2+]i mobilization. It is noteworthy that the potency of strontium-stimulated calcitonin secretion was elevated compared with calcium. Combining these results with experiments investigating signaling pathway components involved in calcitonin secretion, we found that the enhanced potency of strontium-mediated calcitonin secretion was caused by a different signaling pattern than that produced by calcium. Together, our results suggest that calcitonin secretion can be affected by CaSR-stimulated signaling bias, which may be used to develop novel drugs for the treatment of secondary hyperparathyroidism.

Footnotes

  • This work has been financially supported by LEO Pharma A/S and grants from the Drug Research Academy, Aase og Ejner Danielsens Fond, and Beckett-Fonden.

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

    http://dx.doi.org/10.1124/jpet.112.197210.

  • ABBREVIATIONS:

    CaSR
    calcium-sensing receptor
    GPCR
    G protein-coupled receptor
    PTH
    parathyroid hormone
    [Ca2+]e
    extracellular calcium
    [Sr2+]e
    extracellular strontium
    [Ca2+]i
    intracellular calcium
    DMEM
    Dulbecco's modified Eagle's medium
    DPBS
    Dulbecco's phosphate-buffered saline
    HBSS
    Hanks' balanced salt solution
    D609
    O-tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate
    LY294002
    2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
    PD98059
    2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
    ET-18-OCH3
    1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine
    2-APB
    2-aminoethoxydiphenyl borate
    U73122
    1-[6-[((17β)-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl]-1H-pyrrole-2,5-dione
    BAPTA-AM
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester)
    IBMX
    3-isobutyl-1-methylxanthine
    Calhex 231
    4-chloro-N-[(1S,2S)-2-[[(1R)-1-(1-naphthalenyl)ethyl]amino]cyclohexyl]-benzamide hydrochloride
    TR-FRET
    time-resolved-fluorescence resonance energy transfer
    IP1
    inositol monophosphate
    BF
    bias factor
    pBF
    potency BF
    IP3
    inositol 1,4,5-triphosphate
    PI-PLC
    phosphatidylinositol-specific phospholipase C
    PC-PLC
    phosphatidylcholine-specific phospholipase C
    AC
    adenylate cyclase
    ERK1/2
    extracellular signal-regulated kinases 1/2
    HEK
    human embryonic kidney
    PI3-K
    phosphatidylinositol 3-kinase
    ANOVA
    analysis of variance
    DMSO
    dimethyl sulfoxide
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    bp
    base pairs
    MEK1
    mitogen-activated protein kinase kinase 1
    NPS-R568
    N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
    NPS-2143
    N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine.

  • Received June 7, 2012.
  • Accepted August 30, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleCellular and Molecular

Strontium Is a Biased Agonist of the CaSR in 6–23 Cells

Alex Rojas Bie Thomsen, Jesper Worm, Stine Engesgaard Jacobsen, Martin Stahlhut, Markus Latta and Hans Bräuner-Osborne
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 638-649; DOI: https://doi.org/10.1124/jpet.112.197210

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Research ArticleCellular and Molecular

Strontium Is a Biased Agonist of the CaSR in 6–23 Cells

Alex Rojas Bie Thomsen, Jesper Worm, Stine Engesgaard Jacobsen, Martin Stahlhut, Markus Latta and Hans Bräuner-Osborne
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 638-649; DOI: https://doi.org/10.1124/jpet.112.197210
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