Biased agonism of the calcium-sensing receptor

Alex Rojas Bie Thomsen, Maja Hvidtfeldt, Hans Bräuner-Osborne

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    79 Citations (Scopus)

    Abstract

    After the discovery of molecules modulating G protein-coupled receptors (GPCRs) that are able to selectively affect one signaling pathway over others for a specific GPCR, thereby "biasing" the signaling, it has become obvious that the original model of GPCRs existing in either an "on" or "off" conformation is too simple. The current explanation for this biased agonism is that GPCRs can adopt multiple active conformations stabilized by different molecules, and that each conformation affects intracellular signaling in a different way. In the present study we sought to investigate biased agonism of the calcium-sensing receptor (CaSR), by looking at 12 well-known orthosteric CaSR agonists in 3 different CaSR signaling pathways: G(q/11) protein, G(i/o) protein, and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Here we show that apart from G(q/11) and G(i/o) signaling, ERK1/2 is activated through recruitment of ß-arrestins. Next, by measuring activity of all three signaling pathways we found that barium, spermine, neomycin, and tobramycin act as biased agonist in terms of efficacy and/or potency. Finally, polyamines and aminoglycosides in general were biased in their potencies toward ERK1/2 signaling. In conclusion, the results of this study indicate that several active conformations of CaSR, stabilized by different molecules, exist, which affect intracellular signaling distinctly.
    Original languageEnglish
    JournalCell Calcium
    Volume51
    Issue number2
    Pages (from-to)107-116
    ISSN0143-4160
    DOIs
    Publication statusPublished - Feb 2012

    Bibliographical note

    Keywords: Calcium-sensing receptor; Biased agonism; G protein-coupled receptor; Inositol phosphate; Cyclic AMP; ERK

    Keywords

    • Former Faculty of Pharmaceutical Sciences

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