Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors
Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors
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DOI：
10.1096/fj.14-249771
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发表时间：
2014-12-01
期刊：
影响因子：
4.8
通讯作者：
Prezeau, Laurent
中科院分区：
文献类型：
--
作者：
Brule, Cedric;Perzo, Nicolas;Prezeau, Laurent
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 beta-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 beta-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 pEC(50)s 5-10 x higher, and did not or barely recruited beta-arrestin; urantide also failed to recruit beta-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 [Orn5] 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 beta-arrestin and G proteins, and between G-protein subtypes, which dictates the receptor's cellular responses.-Brule, C., Perzo, N., Joubert, J.-E., Sainsily, X., Leduc, R., Castel, H., Prezeau, L. Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors.
