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Urotensin receptor C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [13,18,37]) 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]. 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 [9,27,30-31]. 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 [5,21]. 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 [35]. 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 [37].
Receptors
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UT receptor
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Further reading
* 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: 279-288. [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, 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]
References
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. Expl Ther., 306: 1200-1209. [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, Jegou 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: 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: 15803-15808. [PMID:9861051]
10. Croston GE, Olsson R, Currier EA, Burstein ES, Weiner D, Nash N, Severance D, Allenmark SG, Thunberg L, Ma JN, Mohell N, O'Dowd B, Brann MR, Hacksell U. (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: 4950-4953. [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, Buckley PT, Schmidt DB, Wixted WE, Widdowson K, Riley G, Jin J, Gallagher TF, Schmidt SJ, Ridgers L, Christmann LT, Keenan RM, Knight SD, Dhanak D. (2005) Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375. Br J Pharmacol, 145: 620-635. [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, Aiyar NV. (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: 9-22. [PMID:11976263]
17. Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T. (2002) Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II. J. Med. Chem., 45: 1799-1805. [PMID:11960491]
18. 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: 279-288. [PMID:15914470]
19. 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: 4391-4394. [PMID:12238917]
20. Jin J, Dhanak D, Knight SD, Widdowson K, Aiyar N, Naselsky D, Sarau HM, Foley JJ, Schmidt DB, Bennett CD, Wang B, Warren GL, Moore ML, Keenan RM, Rivero RA, Douglas SA. (2005) Aminoalkoxybenzyl pyrrolidines as novel human urotensin-II receptor antagonists. Bioorg Med Chem Lett, 15: 3229-3232. [PMID:15936190]
21. Kinney WA, Almond HR Jr, Qi J, Smith CE, Santulli RJ, de Garavilla L, Andrade-Gordon P, Cho DS, Everson AM, Feinstein MA, Leung PA, Maryanoff BE. (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: 2940-2944. [PMID:12203418]
22. Labarrere P, Chatenet D, Leprince J, Marionneau C, Loirand G, Tonon M-C, Dubesy C, Scalbert E, Pfeiffer B, Renard P, Calas B, Pacaud P, Vaudry H. (2003) Structure-activity relationships of human urotensin II and related analogues on rat aortic contraction. J. Enz. Inhib. Med. Chem., 18: 77-88. [PMID:12943190]
23. Lawson EC, Luci DK, Ghosh S, Kinney WA, Reynolds CH, Qi J, Smith CE, Wang Y, Minor LK, Haertlein BJ et al.. (2009) Nonpeptide urotensin-II receptor antagonists: a new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits. J. Med. Chem., 52 (23): 7432-45. [PMID:19731961]
24. 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]
25. 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]
26. 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]
27. Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams DL Jr, Davidoff M, Wang R, Austin CP, McDonald TP, Bai C, George SR, Evans JF, Caskey CT. (1999) Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem. Biophys. Res. Commun., 266: 174-178. [PMID:10581185]
28. 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: 441-446. [PMID:11015293]
29. 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]
30. Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y, Kurokawa T, Onda H, Nishimura O, Fujino M. (1999) Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14). Biochem. Biophys. Res. Commun., 265: 123-129. [PMID:10548501]
31. Nothacker H-P, 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: 383-385. [PMID:10559967]
32. 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]
33. 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]
34. 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]
35. 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]
36. 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: 752-759. [PMID:7733947]
37. 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]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Hubert Vaudry (Chairperson)
Alain Fournier
Adel Giaid
Henry Krum
David G. Lambert
Jérôme Leprince
Eliot H. Ohlstein
Hervé Tostivint
David Vaudry |
Other contributors:
Anthony P. Davenport
Stephen A. Douglas (Past chairperson)
Margaret R. MacLean
Walter G. Thomas
David J. Webb |
How to cite this family page
Database page citation:
Hubert Vaudry, Anthony P. Davenport, Stephen A. Douglas, Alain Fournier, Adel Giaid, Henry Krum, David G. Lambert, Jérôme Leprince, Margaret R. MacLean, Eliot H. Ohlstein, Walter G. Thomas, Hervé Tostivint, David Vaudry, David J. Webb. Urotensin receptor. Accessed on 23/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=65.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: G protein-coupled receptors. Br J Pharmacol. 174 Suppl 1: S17-S129.
In the human vasculature, human urotensin-II (UTS2, O95399) elicits both vasoconstrictor (pD2 9.3-10.1, [28]) and vasodilator (pIC50 10.3-10.4, [34]) responses.