4.3 Article

Biased agonism of the calcium-sensing receptor

期刊

CELL CALCIUM
卷 51, 期 2, 页码 107-116

出版社

CHURCHILL LIVINGSTONE
DOI: 10.1016/j.ceca.2011.11.009

关键词

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

资金

  1. Drug Research Academy
  2. Aase og Ejner Danielsens Fond
  3. Beckett-Fonden

向作者/读者索取更多资源

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/0) protein, and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Here we show that apart from G(q/11) and G(i/0) signaling, ERK1/2 is activated through recruitment of beta-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. (C) 2011 Elsevier Ltd. All rights reserved.

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