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: Gq/11 protein, Gi/o protein, and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Here we show that apart from Gq/11 and Gi/o signaling, ERK1/2 is activated through recruitment of β-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: Gq/11 protein, Gi/o protein, and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Here we show that apart from Gq/11 and Gi/o signaling, ERK1/2 is activated through recruitment of β-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 - Former Faculty of Pharmaceutical Sciences
U2 - 10.1016/j.ceca.2011.11.009
DO - 10.1016/j.ceca.2011.11.009
M3 - Journal article
C2 - 22192592
SN - 0143-4160
VL - 51
SP - 107
EP - 116
JO - Cell Calcium
JF - Cell Calcium
IS - 2
ER -