Urotensin-II

Overview: The urotensin-II (U-II) receptor (UT, nomenclature as agreed by NC-IUPHAR, see Douglas and Ohlstein, 2000; Foord et al., 2005) is activated by the endogenous dodecapeptide U-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish (Bern et al., 1985). 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 (Coulouarn et al., 1998; Liu et al., 1999; Mori et al., 1999; Nothacker et al., 1999). Human U-II (derived from ENSG00000049247), an 11-amino-acid peptide (Coulouarn et al., 1998), retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding (Kinney et al., 2002; Brkovic et al., 2003). This sequence is also conserved in the deduced amino-acid sequence of rat (14 amino-acids) and mouse (14 amino-acids) U-II, although the N-terminal is more divergent from the human sequence (Coulouarn et al., 1999). A second endogenous ligand for UT has been discovered in rat (Sugo and Mori, 2008). The urotensin II-related peptide (URP), an octapeptide, is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat URP are predicted for the mature mouse and human peptides.

Nomenclature	UT
Other names	GPR14, SENR, UR-IIR
Ensembl ID	ENSG00000181408
Principal transduction	Gq/11
Selective agonists	[Pen5]U-II-(4–11), U-II-(4–11), U-II (Grieco et al., 2002), AC7954 (Lehmann et al., 2005), FL104 and analogues (Lehmann et al., 2006; 2007;)
Selective antagonists	Urantide (8.3, Patacchini et al., 2003), SB706375 (7.5–8.0, Douglas et al., 2005), palosuran (pIC50 7.1, Clozel et al., 2004), SB611812 (6.6, Rakowski et al., 2005)
Probes	[125I]-hU-II (0.24 nM, Maguire et al., 2000)

In human vasculature, human U-II elicits both vasoconstrictor (pD₂ 9.3–10.1, Maguire et al., 2000) and vasodilator (pIC₅₀ 10.3–10.4, Stirrat et al., 2001) responses.

Glossary

Abbreviations:

[Pen⁵]U-II-(4-11]

[pencillamine, β,β-dimethylcysteine]⁵U-II-(4-11)

AC7954

3-(4-chlorophenyl)-3-(2-dimethyl-aminoethyl)-isochroman-1-one HCl

FL104

(+)N-(1-[4-chlorophenyl]-3-dimethylaminopropyl)-4-phenylbenzamide oxalate

palosuran

1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulphate, also known as ACT058362

SB611812

2,6-dichloro-N-(4-chloro-3-{[2-(dimethylamino)ethyl]oxy}phenyl)-4-(trifluoromethyl)benzenesulfonamide

SB706375

2-bromo-4,5-dimethoxy-N-[3-(R)-1-methyl-pyrrolidin-3-yloxy)-4-trifluromethyl-phenyl]-benzenesulphonamide HCl

urantide

[Pen⁵,DTrp⁷,Orn⁸]hU-II(4-11)

Further Reading

Desai N, Sajjad J, Frishman WH (2008). Urotensin II: a new pharmacologic target in the treatment of cardiovascular disease. Cardiol Rev16: 142–153.

Douglas SA, Ohlstein EH (2000). Urotensin receptors. In: Girdlestone D (ed.). The IUPHAR Receptor Compendium of Receptor Characterization and Classification. IUPHAR Media Ltd.: London, pp. 365–372.

Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. (2005). International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev57: 279–288.

Lescot E, Bureau R, Rault S (2008). Nonpeptide Urotensin-II receptor agonists and antagonists: review and structure-activity relationships. Peptides29: 680–690.

Leprince J, Chatenet D, Dubessy C, Fournier A, Pfeiffer B, Scalbert E et al. (2008). Structure-activity relationships of urotensin II and URP. Peptides29: 658–673.

Ong KL, Wong LY, Cheung BM (2008). The role of urotensin II in the metabolic syndrome. Peptides29: 859–867.

Proulx CD, Holleran BJ, Lavigne P, Escher E, Guillemette G, Leduc R (2008). Biological properties and functional determinants of the urotensin II receptor. Peptides29: 691–699.