The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [13,17,36]) is activated by the endogenous dodecapeptide urotensin-II (UTS2, O95399), originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [3,35]. Several structural forms of U-II exist in fish and amphibians. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [9,24,27-28]. Human urotensin-II (UTS2, O95399), an 11-amino-acid peptide [9], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [5,19]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [8]. A second endogenous ligand for the UT has been discovered in rat [33]. This is the urotensin II-related peptide (UTS2B, Q765I0), an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide (UTS2B, Q765I0) are predicted for the mature mouse and human peptides [15]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [36].

In the human vasculature, human urotensin-II (UTS2, O95399) elicits both vasoconstrictor (pD₂ 9.3-10.1, [25]) and vasodilator (pIC₅₀ 10.3-10.4, [32]) responses.

* Key recommended reading is highlighted with an asterisk

Desai N, Sajjad J, Frishman WH. (2008) Urotensin II: a new pharmacologic target in the treatment of cardiovascular disease. Cardiol Rev, 16 (3): 142-53. [PMID:18414185]

Douglas SA Ohlstein EH. (2000) Urotensin receptors. In The IUPHAR Receptor Compendium of Receptor Characterization and Classification. Edited by Girdlestone D (IUPHAR Media Ltd) 365-372.

* Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol. Rev., 57 (2): 279-88. [PMID:15914470]

Guidolin D, Albertin G, Ribatti D. (2010) Urotensin-II as an angiogenic factor. Peptides, 31 (6): 1219-24. [PMID:20346384]

* Hunt BD, Ng LL, Lambert DG. (2010) A rat brain atlas of urotensin-II receptor expression and a review of central urotensin-II effects. Naunyn Schmiedebergs Arch. Pharmacol., 382 (1): 1-31. [PMID:20422157]

Leprince J, Chatenet D, Dubessy C, Fournier A, Pfeiffer B, Scalbert E, Renard P, Pacaud P, Oulyadi H, Ségalas-Milazzo I et al.. (2008) Structure-activity relationships of urotensin II and URP. Peptides, 29 (5): 658-73. [PMID:17931747]

* Maryanoff BE, Kinney WA. (2010) Urotensin-II receptor modulators as potential drugs. J. Med. Chem., 53 (7): 2695-708. [PMID:20043680]

Ong KL, Wong LY, Cheung BM. (2008) The role of urotensin II in the metabolic syndrome. Peptides, 29 (5): 859-67. [PMID:17610998]

Proulx CD, Holleran BJ, Lavigne P, Escher E, Guillemette G, Leduc R. (2008) Biological properties and functional determinants of the urotensin II receptor. Peptides, 29 (5): 691-9. [PMID:18155322]

* Ross B, McKendy K, Giaid A. (2010) Role of urotensin II in health and disease. Am. J. Physiol. Regul. Integr. Comp. Physiol., 298 (5): R1156-72. [PMID:20421634]

* Vaudry H, Leprince J, Chatenet D, Fournier A, Lambert DG, Le Mével JC, Ohlstein EH, Schwertani A, Tostivint H, Vaudry D. (2015) International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function. Pharmacol. Rev., 67 (1): 214-58. [PMID:25535277]

1. Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW et al.. (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature, 401 (6750): 282-6. [PMID:10499587]

2. Bandholtz S, Erdmann S, von Hacht JL, Exner S, Krause G, Kleinau G, Grötzinger C. (2016) Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist. J. Med. Chem., 59 (22): 10100-10112. [PMID:27791374]

3. Bern HA, Pearson D, Larson BA, Nishioka RS. (1985) Neurohormones from fish tails: the caudal neurosecretory system. I: "Urophysiology" and the caudal neurosecretory system of fishes. Recent Prog. Horm. Res., 41: 533-552. [PMID:2864726]

4. Bourguignon-Bellefroid C, Wilkin JM, Joris B, Aplin RT, Houssier C, Prendergast FG, Van Beeumen J, Ghuysen JM, Frère JM. (1992) Importance of the two tryptophan residues in the Streptomyces R61 exocellular DD-peptidase. Biochem. J., 282 ( Pt 2): 361-7. [PMID:1546952]

5. Brkovic A, Hattenberger A, Kostenis E, Klabunde T, Flohr S, Kurz M, Bourgault S, Fournier A. (2003) Functional and binding characterizations of urotensin II-related peptides in human and rat urotensin II-receptor assay. J. Pharmacol. Exp. Ther., 306 (3): 1200-9. [PMID:12807997]

6. Chatenet D, Dubessy C, Boularan C, Scalbert E, Pfeiffer B, Renard P, Lihrmann I, Pacaud P, Tonon MC, Vaudry H et al.. (2006) Structure-activity relationships of a novel series of urotensin II analogues: identification of a urotensin II antagonist. J. Med. Chem., 49 (24): 7234-8. [PMID:17125276]

7. Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C et al.. (2004) Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin System. J. Pharmacol. Exp. Ther., 311 (1): 204-12. [PMID:15146030]

8. Coulouarn Y, Jégou S, Tostivint H, Vaudry H, Lihrmann I. (1999) Cloning, sequence analysis and tissue distribution of the mouse and rat urotensin II precursors. FEBS Lett., 457 (1): 28-32. [PMID:10486557]

9. Coulouarn Y, Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC, Conlon JM, Bern HA, Vaudry H. (1998) Cloning of the cDNA encoding the urotensin II precursor in frog and human reveals intense expression of the urotensin II gene in motoneurons of the spinal cord. Proc. Natl. Acad. Sci. U.S.A., 95 (26): 15803-8. [PMID:9861051]

10. Croston GE, Olsson R, Currier EA, Burstein ES, Weiner D, Nash N, Severance D, Allenmark SG, Thunberg L, Ma JN et al.. (2002) Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954). J. Med. Chem., 45 (23): 4950-3. [PMID:12408704]

11. Diallo M, Jarry M, Desrues L, Castel H, Chatenet D, Leprince J, Vaudry H, Tonon MC, Gandolfo P. (2008) [Orn5]URP acts as a pure antagonist of urotensinergic receptors in rat cortical astrocytes. Peptides, 29 (5): 813-9. [PMID:18082287]

12. Doan ND, Nguyen TT, Létourneau M, Turcotte K, Fournier A, Chatenet D. (2012) Biochemical and pharmacological characterization of nuclear urotensin-II binding sites in rat heart. Br. J. Pharmacol., 166 (1): 243-57. [PMID:22044114]

13. Douglas SA Ohlstein EH. (2000) Urotensin receptors. In The IUPHAR Receptor Compendium of Receptor Characterization and Classification. Edited by Girdlestone D (IUPHAR Media Ltd) 365-372.

14. Douglas SA, Behm DJ, Aiyar NV, Naselsky D, Disa J, Brooks DP, Ohlstein EH, Gleason JG, Sarau HM, Foley JJ et al.. (2005) Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375. Br. J. Pharmacol., 145 (5): 620-35. [PMID:15852036]

15. Dubessy C, Cartier D, Lectez B, Bucharles C, Chartrel N, Montero-Hadjadje M, Bizet P, Chatenet D, Tostivint H, Scalbert E et al.. (2008) Characterization of urotensin II, distribution of urotensin II, urotensin II-related peptide and UT receptor mRNAs in mouse: evidence of urotensin II at the neuromuscular junction. J. Neurochem., 107 (2): 361-74. [PMID:18710417]

16. Elshourbagy NA, Douglas SA, Shabon U, Harrison S, Duddy G, Sechler JL, Ao Z, Maleeff BE, Naselsky D, Disa J et al.. (2002) Molecular and pharmacological characterization of genes encoding urotensin-II peptides and their cognate G-protein-coupled receptors from the mouse and monkey. Br. J. Pharmacol., 136 (1): 9-22. [PMID:11976263]

17. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol. Rev., 57 (2): 279-88. [PMID:15914470]

18. Grieco P, Carotenuto A, Campiglia P, Zampelli E, Patacchini R, Maggi CA, Novellino E, Rovero P. (2002) A new, potent urotensin II receptor peptide agonist containing a Pen residue at the disulfide bridge. J. Med. Chem., 45 (20): 4391-4. [PMID:12238917]

19. Kinney WA, Almond Jr HR, Qi J, Smith CE, Santulli RJ, de Garavilla L, Andrade-Gordon P, Cho DS, Everson AM, Feinstein MA et al.. (2002) Structure-function analysis of urotensin II and its use in the construction of a ligand-receptor working model. Angew. Chem. Int. Ed. Engl., 41 (16): 2940-4. [PMID:12203418]

20. Labarrère P, Chatenet D, Leprince J, Marionneau C, Loirand G, Tonon MC, Dubessy C, Scalbert E, Pfeiffer B, Renard P et al.. (2003) Structure-activity relationships of human urotensin II and related analogues on rat aortic ring contraction. J Enzyme Inhib Med Chem, 18 (2): 77-88. [PMID:12943190]

21. Lehmann F, Currier EA, Clemons B, Hansen LK, Olsson R, Hacksell U, Luthman K. (2009) Novel and potent small-molecule urotensin II receptor agonists. Bioorg. Med. Chem., 17 (13): 4657-65. [PMID:19481466]

22. Lehmann F, Currier EA, Olsson R, Hacksell U, Luthman K. (2005) Isochromanone-based urotensin-II receptor agonists. Bioorg. Med. Chem., 13 (8): 3057-68. [PMID:15781415]

23. Lehmann F, Lake L, Currier EA, Olsson R, Hacksell U, Luthman K. (2007) Design, parallel synthesis and SAR of novel urotensin II receptor agonists. Eur J Med Chem, 42 (2): 276-85. [PMID:17112638]

24. Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams Jr DL, Davidoff M, Wang R, Austin CP, McDonald TP et al.. (1999) Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem. Biophys. Res. Commun., 266 (1): 174-8. [PMID:10581185]

25. Maguire JJ, Kuc RE, Davenport AP. (2000) Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br. J. Pharmacol., 131 (3): 441-6. [PMID:11015293]

26. Marchese A, Heiber M, Nguyen T, Heng HH, Saldivia VR, Cheng R, Murphy PM, Tsui LC, Shi X, Gregor P et al.. (1995) Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors. Genomics, 29 (2): 335-44. [PMID:8666380]

27. Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y, Kurokawa T, Onda H et al.. (1999) Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14). Biochem. Biophys. Res. Commun., 265 (1): 123-9. [PMID:10548501]

28. Nothacker HP, Wang Z, McNeill AM, Saito Y, Merten S, O'Dowd B, Duckles SP, Civelli O. (1999) Identification of the natural ligand of an orphan G-protein-coupled receptor involved in the regulation of vasoconstriction. Nat. Cell Biol., 1 (6): 383-5. [PMID:10559967]

29. Ozoux ML, Briand V, Pelat M, Barbe F, Schaeffer P, Beauverger P, Poirier B, Guillon JM, Petit F, Altenburger JM et al.. (2020) Potential Therapeutic Value of Urotensin II Receptor Antagonist in Chronic Kidney Disease and Associated Comorbidities. J. Pharmacol. Exp. Ther., 374 (1): 24-37. [PMID:32332113]

30. Patacchini R, Santicioli P, Giuliani S, Grieco P, Novellino E, Rovero P, Maggi CA. (2003) Urantide, an ultrapotent urotensin II antagonist peptide in the rat aorta. Br. J. Pharmacol., 140: 1155-1158. [PMID:14645137]

31. Rakowski E, Hassan GS, Dhanak D, Ohlstein EH, Douglas SA, Giaid A. (2005) A role for urotensin II in restenosis following balloon angioplasty: use of a selective UT receptor blocker. J. Mol. Cell. Cardiol., 39 (5): 785-91. [PMID:16171813]

32. Stirrat A, Gallagher M, Douglas SA, Ohlstein EH, Berry C, Kirk A, Richardson M, MacLean MR. (2001) Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries. Am. J. Physiol. Heart Circ. Physiol., 280 (2): H925-8. [PMID:11158995]

33. Sugo T, Mori M. (2008) Another ligand fishing for G protein-coupled receptor 14. Discovery of urotensin II-related peptide in the rat brain. Peptides, 29 (5): 809-12. [PMID:17628210]

34. Tal M, Ammar DA, Karpuj M, Krizhanovsky V, Naim M, Thompson DA. (1995) A novel putative neuropeptide receptor expressed in neural tissue, including sensory epithelia. Biochem. Biophys. Res. Commun., 209 (2): 752-9. [PMID:7733947]

35. Vaudry H, Do Rego JC, Le Mevel JC, Chatenet D, Tostivint H, Fournier A, Tonon MC, Pelletier G, Conlon JM, Leprince J. (2010) Urotensin II, from fish to human. Ann. N. Y. Acad. Sci., 1200: 53-66. [PMID:20633133]

36. Vaudry H, Leprince J, Chatenet D, Fournier A, Lambert DG, Le Mével JC, Ohlstein EH, Schwertani A, Tostivint H, Vaudry D. (2015) International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function. Pharmacol. Rev., 67 (1): 214-58. [PMID:25535277]

Subcommittee members: Hubert Vaudry (Chairperson) Inserm U982 Institute for Research and Innovation in Biomedicine (IRIB) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Team Neurotrophic Factors and Neuronal Differentiation Associated International Laboratory Samuel de Champlain Regional Platform for Cell Imaging of Haute-Normandie (PRIMACEN) Normandy University F-76000 Rouen, France Alain Fournier INRS-Institut Armand-Frappier Université du Québec 531 boulevard des Prairies Ville de Laval Québec H7V 1B7 Canada Adel Giaid Division of Cardiology Montreal General Hospital McGill University Health Center Montreal Quebec Canada Henry Krum Centre of Cardiovascular Research and Education in Therapeutics Department of Epidemiology & Preventive Medicine Monash University Alfred Hospital Victoria Australia David G. Lambert University Department of Cardiovascular Sciences (Pharmacology and Therapeutics Group) Division of Anaesthesia Critical Care and Pain Management University of Leicester Leicester Royal Infirmary Leicester LE1 5WW UK Jérôme Leprince Inserm U982 Institute for Research and Innovation in Biomedicine (IRIB) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Team Neurotrophic Factors and Neuronal Differentiation Associated International Laboratory Samuel de Champlain Regional Platform for Cell Imaging of Haute-Normandie (PRIMACEN) Normandy University F-76000 Rouen, France Eliot H. Ohlstein Chief Scientific Officer Velicept Therapeutics 101 Lindenwood Dr Malvern PA 19355 USA Adjunct Professor in Pharmacology Drexel University College of Medicine Hervé Tostivint UMR 7221 CNRS/MNHN Evolution des Régulations Endocriniennes Muséum National d’Histoire Naturelle 75231 Paris France David Vaudry INSERM Unit 982 Institute for Research and Innovation in Biomedicine (IRIB) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Team Neurotrophic Factors and Neuronal Differentiation Associated International Laboratory Samuel de Champlain Regional Platform for Cell Imaging of Haute-Normandy (PRIMACEN) Normandy University F-76821 Mont-Saint-Aignan, France

Other contributors: Anthony P. Davenport Experimental Medicine and Immunotherapeutics University of Cambridge Level 6, Addenbrooke's Centre for Clinical Investigation (ACCI) Box 110, Addenbrooke's Hospital Cambridge, CB2 0QQ UK Stephen A. Douglas (Past chairperson) Discovery Translational Medicine S-2321 Wyeth Research 500 Arcola Road Collegeville PA 19426 USA Margaret R. MacLean Professor of Pulmonary Pharmacology Room 417 West Medical Building IBLS Glasgow University Glasgow G12 8QQ Scotland Walter G. Thomas School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia David J. Webb Centre for Cardiovascular Science Department of Medical Sciences The University of Edinburgh The Queen's Medical Research Institute 3rd Floor East, Room E3.22 47 Little France Crescent Edinburgh EH16 4TJ UK