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Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors
Author(s) -
Brulé Cédric,
Perzo Nicolas,
Joubert JaneEileen,
Sainsily Xavier,
Leduc Richard,
Castel Hélène,
Prézeau Laurent
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-249771
Subject(s) - urotensin ii , g protein coupled receptor , receptor , microbiology and biotechnology , heterotrimeric g protein , förster resonance energy transfer , signal transduction , agonist , g protein , phosphorylation , hek 293 cells , chemistry , biology , biochemistry , physics , quantum mechanics , fluorescence
Biased agonism by G‐protein‐coupled receptor ligands has opened up strategies for targeted physiological or therapeutic actions. We hypothesized that urotensin II (UII)‐derived peptides displayed unexpected physiological effects because of such biased signaling on the UII human urotensin (hUT) receptor. We determined the coupling to G proteins and β‐arrestins of the UII‐activated hUT receptor expressed in HEK293 using bioluminescence resonance energy transfer (BRET) biosensors, as well as the production of IP1‐3 and cAMP using homogenous time‐resolved Forster resonance energy transfer (FRET) (HTRF)‐based assays. The activated receptor coupled to G i1 , G oA , G q , and G 13 , excluding G s , and recruited β‐arrestins 1 and 2. Integration of these pathways led to a 2‐phase kinetic phosphorylation of ERK1/2 kinases. The tested peptides induced three different profiles: UII, urotensin‐related peptide (URP), and UII 4–11 displayed the full profile; [Orn 8 ]UII and [Orn 5 ]URP activated G proteins, although with pEC 50 s 5‐10× higher, and did not or barely recruited β‐arrestin; urantide also failed to recruit β‐arrestin but displayed a reversed rank order for G i and G q vs. G o pEC 50 s (–8.79±0.20, –8.43±0.21, and –7.86±0.36, respectively, for urantide, –7.87±0.10, –7.23±0.27, and –8.55±0.19, respectively, for [Orn 5 ]URP) and was a partial agonist of all G‐protein pathways. Interestingly, the peptides differently modulated cell survival but similarly induced cell migration and adhesion. Thus, we demonstrate biased signaling between β‐arrestin and G proteins, and between G‐protein subtypes, which dictates the receptor's cellular responses.—Brulé, C., Perzo, N., Joubert, J.‐E., Sainsily, X., Leduc, R., Castel, H., Prézeau, L., Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors. FASEB J. 28, 5148–5162 (2014). www.fasebj.org