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

Br J Pharmacol. 2013 Feb;168(4):807-21. doi: 10.1111/j.1476-5381.2012.02217.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Macaca fascicularis
  • Male
  • Peptide Hormones / antagonists & inhibitors*
  • Peptide Hormones / chemistry
  • Peptide Hormones / pharmacology*
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Transfection
  • Urotensins / antagonists & inhibitors*
  • Urotensins / pharmacology
  • Vasoconstriction / drug effects


  • Intracellular Signaling Peptides and Proteins
  • Peptide Hormones
  • Receptors, G-Protein-Coupled
  • UTS2B protein, human
  • UTS2R protein, human
  • Urotensins
  • urotensin II-related peptide, 2-amino-3-(1,1'-bipheny-4-yl)propanoic acid(4)-
  • urotensin II