Biased agonism of the calcium-sensing receptor

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Biased agonism of the calcium-sensing receptor. / Thomsen, Alex Rojas Bie; Hvidtfeldt, Maja; Bräuner-Osborne, Hans.

In: Cell Calcium, Vol. 51, No. 2, 02.2012, p. 107-116.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Thomsen, ARB, Hvidtfeldt, M & Bräuner-Osborne, H 2012, 'Biased agonism of the calcium-sensing receptor', Cell Calcium, vol. 51, no. 2, pp. 107-116. https://doi.org/10.1016/j.ceca.2011.11.009

APA

Thomsen, A. R. B., Hvidtfeldt, M., & Bräuner-Osborne, H. (2012). Biased agonism of the calcium-sensing receptor. Cell Calcium, 51(2), 107-116. https://doi.org/10.1016/j.ceca.2011.11.009

Vancouver

Thomsen ARB, Hvidtfeldt M, Bräuner-Osborne H. Biased agonism of the calcium-sensing receptor. Cell Calcium. 2012 Feb;51(2):107-116. https://doi.org/10.1016/j.ceca.2011.11.009

Author

Thomsen, Alex Rojas Bie ; Hvidtfeldt, Maja ; Bräuner-Osborne, Hans. / Biased agonism of the calcium-sensing receptor. In: Cell Calcium. 2012 ; Vol. 51, No. 2. pp. 107-116.

Bibtex

@article{ff655b540d1b4a48801f79d4347ecfcd,
title = "Biased agonism of the calcium-sensing receptor",
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.",
keywords = "The Faculty of Pharmaceutical Sciences",
author = "Thomsen, {Alex Rojas Bie} and Maja Hvidtfeldt and Hans Br{\"a}uner-Osborne",
note = "Keywords: Calcium-sensing receptor; Biased agonism; G protein-coupled receptor; Inositol phosphate; Cyclic AMP; ERK",
year = "2012",
month = "2",
doi = "10.1016/j.ceca.2011.11.009",
language = "English",
volume = "51",
pages = "107--116",
journal = "Cell Calcium",
issn = "0143-4160",
publisher = "Churchill Livingstone",
number = "2",

}

RIS

TY - JOUR

T1 - Biased agonism of the calcium-sensing receptor

AU - Thomsen, Alex Rojas Bie

AU - Hvidtfeldt, Maja

AU - Bräuner-Osborne, Hans

N1 - Keywords: Calcium-sensing receptor; Biased agonism; G protein-coupled receptor; Inositol phosphate; Cyclic AMP; ERK

PY - 2012/2

Y1 - 2012/2

N2 - 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.

AB - 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.

KW - The Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.ceca.2011.11.009

DO - 10.1016/j.ceca.2011.11.009

M3 - Journal article

VL - 51

SP - 107

EP - 116

JO - Cell Calcium

JF - Cell Calcium

SN - 0143-4160

IS - 2

ER -

ID: 37586619