title: Discovery of new antagonists aimed at discriminating UII and URP-mediated biological activities: insight into UII and URP receptor activation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratoire d'études moléculaires et pharmacologiques des peptides, Université du Québec, INRS-Institut Armand-Frappier, Ville de Laval, QC, Canada. david.chatenet@iaf.inrs.ca
authors.forename: D
authors.initials: D
authors.lastname: Chatenet
authors.forename: M
authors.initials: M
authors.lastname: Létourneau
authors.forename: Q T
authors.initials: QT
authors.lastname: Nguyen
authors.forename: N D
authors.initials: ND
authors.lastname: Doan
authors.forename: J
authors.initials: J
authors.lastname: Dupuis
authors.forename: A
authors.initials: A
authors.lastname: Fournier
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008252:Macaca fascicularis; D008297:Male; D036361:Peptide Hormones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014579:Urotensins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; C479080:UTS2B protein, human; C121697:UTS2R protein, human; D014579:Urotensins; C570602:urotensin II-related peptide, 2-amino-3-(1,1'-bipheny-4-yl)propanoic acid(4)-; C029677:urotensin II