Lipidated peptides derived from intracellular loops 2 and 3 of the urotensin II receptor act as biased allosteric ligands

• Published in: The Journal of biological chemistry Vol. 297; no. 3; p. 101057
• Main Authors: Nassour, Hassan, Hoang, Tuan Anh, Martin, Ryan D., Dallagnol, Juliana C.C., Billard, Étienne, Létourneau, Myriam, Novellino, Ettore, Carotenuto, Alfonso, Allen, Bruce G., Tanny, Jason C., Fournier, Alain, Hébert, Terence E., Chatenet, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2021; American Society for Biochemistry and Molecular Biology
• Subjects: allosteric modulators; Allosteric Regulation; Cell Proliferation; cellular signaling; G-protein-coupled receptors; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Ligands; lipidated peptides; pepducins; Peptide Hormones - chemistry; Peptide Hormones - genetics; Peptide Hormones - metabolism; Peptides - chemistry; Peptides - metabolism; Protein Conformation, alpha-Helical; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; urotensin II receptor; DIEA; TOCSY; HEK 293 cells; G-protein-coupled receptors; pepducins; URP; Fmoc; urotensin II receptor; DMF; UT; BRET; BOP; MALDI-TOF; DCM; lipidated peptides; RP-HPLC; TSP; NMR; DQF-COSY; UII; DPC; allosteric modulators; cellular signaling; 7TMR; GPCR; NOESY; CHO cells
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.101057

Over the last decade, the urotensinergic system, composed of one G protein-coupled receptor and two endogenous ligands, has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases. Indeed, this system is associated with various biomarkers of cardiovascular dysfunctions and is involved in changes in cardiac contractility, fibrosis, and hypertrophy contributing, like the angiotensinergic system, to the pathogenesis and progression of heart failure. Significant investment has been made toward the development of clinically relevant UT ligands for therapeutic intervention, but with little or no success to date. This system therefore remains to be therapeutically exploited. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics; therefore, pepducins derived from the human urotensin II receptor might represent unique tools to generate signaling bias and study hUT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of the receptor (hUT-Pep2 and [Trp1, Leu2]hUT-Pep3, respectively), were synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp1, Leu2]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and, to a lesser extent, IP1 production, and stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate human urotensin II (hUII)- and urotensin II-related peptide (URP)-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue for the design of allosteric ligands selectively targeting hUT signaling potentially.