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Discovery of new antagonists aimed at discriminating UII and URP-mediated biological activities: insight into UII and URP receptor activation.

Abstract : BACKGROUND AND PURPOSE: Recent evidence suggested that urotensin II (UII) and its paralog peptide UII-related peptide (URP) might exert common but also divergent physiological actions. Unfortunately, none of the existing antagonists were designed to discriminate specific UII- or URP-associated actions, and our understanding, on how these two endogenous peptides can trigger different, but also common responses, is limited. EXPERIMENTAL APPROACH: Ex vivo rat and monkey aortic ring contraction as well as dissociation kinetics studies using transfected CHO cells expressing the human urotensin (UT) receptors were used in this study. KEY RESULTS: Ex vivo rat and monkey aortic ring contraction studies revealed the propensity of [Pep(4)]URP to decrease the maximal response of human UII (hUII) without any significant change in potency, whereas no effect was noticeable on the URP-induced vasoconstriction. Dissociation experiments demonstrated the ability of [Pep(4)]URP to increase the dissociation rate of hUII, but not URP. Surprisingly, URP, an equipotent UII paralog, was also able to accelerate the dissociation rate of membrane-bound (125)I-hUII, whereas hUII had no noticeable effect on URP dissociation kinetics. Further experiments suggested that an interaction between the glutamic residue at position 1 of hUII and the UT receptor seems to be critical to induce conformational changes associated with agonistic activation. Finally, we demonstrated that the N-terminal domain of the rat UII isoform was able to act as a specific antagonist of the URP-associated actions. CONCLUSION: Such compounds, that is [Pep(4)]URP and rUII(1-7), should prove to be useful as new pharmacological tools to decipher the specific role of UII and URP in vitro but also in vivo.
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https://hal-riip.archives-ouvertes.fr/pasteur-00819041
Contributor : Charles M. Dozois <>
Submitted on : Monday, April 29, 2013 - 10:19:28 PM
Last modification on : Monday, July 20, 2020 - 12:33:14 PM

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D. Chatenet, M. Létourneau, Q. T. Nguyen, N. D. Doan, J. Dupuis, et al.. Discovery of new antagonists aimed at discriminating UII and URP-mediated biological activities: insight into UII and URP receptor activation.. British Journal of Pharmacology, Wiley, 2013, 168 (4), pp.807-21. ⟨10.1111/j.1476-5381.2012.02217.x⟩. ⟨pasteur-00819041⟩

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