Insight into the role of urotensin II-related peptide tyrosine residue in UT activation

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

“…In the present study, neither UT-derived pepducin exhibited significant contractile action in rat aortic ring preparations. Since aortic ring contraction is in part mediated by intracellular calcium mobilization following activation of G q (22,23,43) and by the stimulation of the small GTPase RhoA following G 12 activation (60), the weak contractile potency of hUT-Pep2 and [Trp 1 , Leu 2 ]hUT-Pep3 could be explained by their inability to trigger sustained G 12 and/or G q activation. This is perhaps not surprising as receptor expression is low.…”

“…Contingent on their interactions with UT, UII and URP probably induce distinct UT conformational and dynamic changes that lead to divergent signaling profiles with both common and distinct biological activities (2,(17)(18)(19)(20)(21). Recent years have witnessed the emergence of useful molecules, with probe-dependent actions, that could shed light on the respective roles and importance of UII and URP under normal and pathological conditions (13,17,18,(22)(23)(24)(25)(26)(27).…”

New directions for urotensin II receptor ligands

“…G q and G 12 , of UII‐ and URP‐mediated aortic contraction were evaluated using BRET‐based biosensors. The contractile activity was then correlated with a loss of G q activation and the apparition of a significant signaling bias in favor of G 12 activation (9.95 ± 1.42 time compared to URP) . Therefore, enhancement of steric hindrance at this particular position in URP probably perturbs molecular microswitches involved in G q but not G 12 activation.…”

“…Interested in a better understanding of the role of this Tyr 6 residue in URP, our team performed a SAR study in which this residue was replaced by hydrophobic and constrained non‐natural amino‐acids . While the binding seems facilitated or at least not perturbed by the introduction of hydrophobic residues such as 4,4′‐biphenylalanine ([Bip 6 ]URP) or 4‐(phenylethynyl)‐phenylalanine ([Pep 6 ]URP, Figure ), such substitutions are detrimental for their vasocontractile action . Considering the fact that [Pep 6 ]URP has the same affinity than URP but a 22‐fold reduced contractile potency, two upstream pathways, i.e .…”

“…As demonstrated for other GPCR systems, functional selectivity, which can be triggered by subtle but specific conformational changes upon ligand binding, is dependent on the lipid composition of cell membrane, the palmitoylation of the C‐terminal domain of the receptor, or receptor oligomerization . While there is no definite proof of the involvement of such mechanisms in UII/URP functional selectivity, several lines of evidence are nonetheless pointing out the existence of UT oligomers, and their possible involvement in UII/URP functional selectivity . Altered UT signaling in response to UII or URP could therefore lead to distinct role for each peptide in the pathogenesis and progression of UT‐associated diseases including atherosclerosis, pulmonary arterial hypertension, heart failure, and cancer.…”