Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors. Issue 12 (2nd September 2014)

• Record Type: Journal Article
• Authors: Brulé, Cédric; Perzo, Nicolas; Joubert, Jane‐Eileen; Sainsily, Xavier; Leduc, Richard; Castel, Hélène; Prézeau, Laurent
• Is Part Of: FASEB journal. Volume 28:Issue 12(2014)
• Page Start: 5148
• Page End: 5162
• Publication Date: 2014-09-02
• Subjects: G‐protein‐coupled receptor -- partial agonism -- G‐protein signaling -- β‐arrestin signaling; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.14-249771
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : 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 Gi1, GoA, Gq, and G13, excluding Gs, 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 UII4–11 displayed the full profile; [Orn 8 ]UII and [Orn 5 ]URP activated G proteins, although with pEC50 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 Gi and Gq vs. Go pEC50 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