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 “o...

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Published in:	Cell calcium (Edinburgh) Vol. 51; no. 2; pp. 107 - 116
Main Authors:	Thomsen, Alex Rojas Bie, Hvidtfeldt, Maja, Bräuner-Osborne, Hans
Format:	Journal Article
Language:	English
Published:	Netherlands 01-02-2012
Subjects:	Advanced Basic Science Aminoglycosides - pharmacology Animals Arrestin - genetics Arrestin - metabolism GTP-Binding Protein alpha Subunits, Gi-Go - genetics GTP-Binding Protein alpha Subunits, Gi-Go - metabolism GTP-Binding Protein alpha Subunits, Gq-G11 - genetics GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism HEK293 Cells Humans MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - physiology Mitogen-Activated Protein Kinase 3 - genetics Mitogen-Activated Protein Kinase 3 - metabolism Polyamines - pharmacology Rats Receptors, Calcium-Sensing - agonists Receptors, Calcium-Sensing - genetics Receptors, Calcium-Sensing - metabolism G protein-coupled receptor Cyclic AMP Calcium-sensing receptor Inositol phosphate Biased agonism ERK
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Summary:	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: 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0143-4160 1532-1991
DOI:	10.1016/j.ceca.2011.11.009