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Gene Review

UTS2  -  urotensin 2

Homo sapiens

Synonyms: PRO1068, U-II, UCN2, UII, UNQ525/PRO1068, ...
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Disease relevance of UTS2

  • These results strongly suggest that subjects with S89N in the UTS2 gene are more insulin-resistant and thus more susceptible to type 2 diabetes mellitus development [1].
  • Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates [2].
  • Urinary hUII concentrations from patients with essential hypertension and those with renal tubular abnormality, but not with glomerular diseases, were significantly greater than those from normal individuals [3].
  • U-II is proposed to contribute to human diseases including atherosclerosis, cardiac hypertrophy, pulmonary hypertension and tumour growth [4].
  • In conclusion, the in vivo efficacy of the specific UT receptor antagonist ACT-058362 reveals a role of endogenous U-II in renal ischemia [5].

Psychiatry related information on UTS2

  • Following ICV administration, hU-II (3-10 micrograms ICV) increased rearing and grooming, and increased motor activity in a familiar environment [6].
  • Recently, physiological data have provided further evidence that UII is indeed a modulator of REM sleep [7].

High impact information on UTS2

  • Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization [2].
  • The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far [2].
  • Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man [2].
  • Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities [2].
  • In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction [2].

Chemical compound and disease context of UTS2


Biological context of UTS2

  • The aim of this study is to investigate a possible contribution of SNPs in the UTS2 gene to the development of Type 2 diabetes [13].
  • For UTS2, the GGT haplotype (-605G, 143G and 3836T) was associated with higher plasma level of U-II and insulin, and higher homeostasis model assessment of insulin resistance index and beta-cell function [14].
  • The allele frequency of 89N was significantly higher in type 2 diabetic patients than in both elderly normal subjects (P = 0.0018) and subjects with normal glucose tolerance (P = 0.0011), whereas the allele frequency of T21M and -605G>A in the UTS2 gene and those of two SNPs in the GPR14 gene were essentially identical in these three groups [1].
  • The few structure-activity relationship studies reported to date attributed a critical role to this portion, with the Trp-Lys-Tyr motif appearing as the key determinant of U-II bioactivity [15].
  • On the basis of its spectrum of activities, hU-II has been suggested to modulate cardiovascular homeostasis and possibly to be involved in certain cardiovascular pathologies [16].

Anatomical context of UTS2

  • The resulting fractional excretion of hUII, exceeding the glomerular filtration rate, suggests a renal origin of urinary UII-LI. hUII mRNAs were abundantly expressed in the kidney and the right atrium, but far less so in the vasculature, whereas GPR14 mRNAs were equally and abundantly expressed in both cardiovascular and renal tissues [3].
  • Using immunohistochemistry we demonstrated U-II immunoreactivity in endothelial, smooth muscle and inflammatory cells of both carotid and aortic plaques, with a clear propensity for intimal staining [17].
  • In contrast, in humans U-II has emerged as a ubiquitious constrictor of both arteries and veins in vitro and elicits a reduction in blood flow in the forearm and skin microcirculation in vivo [4].
  • We found that lymphocytes were by far the largest producers of U-II mRNA [17].
  • We also extended our PCR analysis to include leukocyte expression of U-II and GPR14 [17].

Associations of UTS2 with chemical compounds

  • Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 [2].
  • Additionally, the effects of pre-treatment with the nitric oxide (NO) synthase blocker, nitro-l-arginine methyl ester (l-NAME), and the cyclooxygenase inhibitor, indomethacin, on the renal haemodynamic response to hU-II were studied in CHF rats [18].
  • The effect of U-II on the vascular system is variable, depending on species, vascular bed and calibre of the vessel [19].
  • Immunohistochemical studies showed intense UII peptide staining in diabetic tissue localized predominantly to tubular epithelial cells, and fluorescein-labeled ligand binding studies showed a similar tubular pattern of distribution [20].
  • [Bz-Phe(6)]U-II bound the receptor expressed in COS-7 cells with high affinity (IC(50) 0.7 nM) and was as potent as U-II in the agonist-induced production of inositol phosphate [21].

Physical interactions of UTS2


Regulatory relationships of UTS2

  • Radioligand binding analysis showed high affinity binding of UII to membrane preparations isolated from HEK293 cells stably expressing rat GPR14 [23].
  • 2. Although the somatostatin (SST) antagonist SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide) is purported to block U-II-induced contractions in rat isolated aorta, little is known about its specific pharmacological properties [24].
  • In TE-671 cells, U-II stimulated extracellular signal regulated kinase phosphorylation and increased c-fos mRNA expression [25].
  • Somatostatin receptor antagonists dose-dependently inhibited human urotensin II-induced Ca2+ transients in rat thoracic aorta rings [26].
  • URP was found to bind and activate the human or rat UII receptors (GPR14) and showed a hypotensive effect when administered to anesthetized rats [27].

Other interactions of UTS2

  • Urotensin-II is a neuropeptide "somatostatin-like" cyclic peptide, which was originally isolated from fish spinal cords, and which has recently been cloned from human [28].
  • Is urotensin-II the new endothelin [4]?
  • Accordingly, the present study sought to examine the expression and localization of UII and its receptor in kidney tissue from patients with diabetic nephropathy [20].
  • These data suggest that hUII is an autocrine/paracrine growth factor for renal epithelial cells via activation of both protein kinase C and ERK1/2 pathways as well as Ca(2+) influx via voltage-dependent Ca(2+) channels [29].
  • The synthesized compounds seem to be selective for the UII receptor as no activities were observed at the closely related SSTR3 and 5 receptors [30].

Analytical, diagnostic and therapeutic context of UTS2


  1. Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese. Suzuki, S., Wenyi, Z., Hirai, M., Hinokio, Y., Suzuki, C., Yamada, T., Yoshizumi, S., Suzuki, M., Tanizawa, Y., Matsutani, A., Oka, Y. Peptides (2004) [Pubmed]
  2. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Ames, R.S., Sarau, H.M., Chambers, J.K., Willette, R.N., Aiyar, N.V., Romanic, A.M., Louden, C.S., Foley, J.J., Sauermelch, C.F., Coatney, R.W., Ao, Z., Disa, J., Holmes, S.D., Stadel, J.M., Martin, J.D., Liu, W.S., Glover, G.I., Wilson, S., McNulty, D.E., Ellis, C.E., Elshourbagy, N.A., Shabon, U., Trill, J.J., Hay, D.W., Ohlstein, E.H., Bergsma, D.J., Douglas, S.A. Nature (1999) [Pubmed]
  3. Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues. Matsushita, M., Shichiri, M., Imai, T., Iwashina, M., Tanaka, H., Takasu, N., Hirata, Y. J. Hypertens. (2001) [Pubmed]
  4. Is urotensin-II the new endothelin? Maguire, J.J., Davenport, A.P. Br. J. Pharmacol. (2002) [Pubmed]
  5. 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. Clozel, M., Binkert, C., Birker-Robaczewska, M., Boukhadra, C., Ding, S.S., Fischli, W., Hess, P., Mathys, B., Morrison, K., Müller, C., Müller, C., Nayler, O., Qiu, C., Rey, M., Scherz, M.W., Velker, J., Weller, T., Xi, J.F., Ziltener, P. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  6. Central effects of urotensin-II following ICV administration in rats. Gartlon, J., Parker, F., Harrison, D.C., Douglas, S.A., Ashmeade, T.E., Riley, G.J., Hughes, Z.A., Taylor, S.G., Munton, R.P., Hagan, J.J., Hunter, J.A., Jones, D.N. Psychopharmacology (Berl.) (2001) [Pubmed]
  7. From heart to mind. The urotensin II system and its evolving neurophysiological role. Nothacker, H.P., Clark, S. FEBS J. (2005) [Pubmed]
  8. Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages. Watanabe, T., Suguro, T., Kanome, T., Sakamoto, Y., Kodate, S., Hagiwara, T., Hongo, S., Hirano, T., Adachi, M., Miyazaki, A. Hypertension (2005) [Pubmed]
  9. Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells. Djordjevic, T., BelAiba, R.S., Bonello, S., Pfeilschifter, J., Hess, J., Görlach, A. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  10. Urotensin II-induced hypotensive responses in Wistar-Kyoto (Wky) and spontaneously hypertensive (Shr) rats. Gendron, G., Gobeil, F., Bélanger, S., Gagnon, S., Regoli, D., D'Orléans-Juste, P. Peptides (2005) [Pubmed]
  11. Urotensin II acts centrally to increase epinephrine and ACTH release and cause potent inotropic and chronotropic actions. Watson, A.M., Lambert, G.W., Smith, K.J., May, C.N. Hypertension (2003) [Pubmed]
  12. Cellular and molecular basis of portal hypertension. Shah, V. Clinics in liver disease. (2001) [Pubmed]
  13. Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects. Wenyi, Z., Suzuki, S., Hirai, M., Hinokio, Y., Tanizawa, Y., Matsutani, A., Satoh, J., Oka, Y. Diabetologia (2003) [Pubmed]
  14. Haplotypes in the urotensin II gene and urotensin II receptor gene are associated with insulin resistance and impaired glucose tolerance. Ong, K.L., Wong, L.Y., Man, Y.B., Leung, R.Y., Song, Y.Q., Lam, K.S., Cheung, B.M. Peptides (2006) [Pubmed]
  15. Urotensin-II receptor peptide agonists. Carotenuto, A., Grieco, P., Novellino, E., Rovero, P. Medicinal research reviews. (2004) [Pubmed]
  16. Urotensin-II receptor antagonists. Carotenuto, A., Grieco, P., Rovero, P., Novellino, E. Current medicinal chemistry. (2006) [Pubmed]
  17. Increased expression of urotensin II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta. Bousette, N., Patel, L., Douglas, S.A., Ohlstein, E.H., Giaid, A. Atherosclerosis (2004) [Pubmed]
  18. Renal effects of human urotensin-II in rats with experimental congestive heart failure. Ovcharenko, E., Abassi, Z., Rubinstein, I., Kaballa, A., Hoffman, A., Winaver, J. Nephrol. Dial. Transplant. (2006) [Pubmed]
  19. Urotensin II: its function in health and its role in disease. Ong, K.L., Lam, K.S., Cheung, B.M. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. (2005) [Pubmed]
  20. Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy. Langham, R.G., Kelly, D.J., Gow, R.M., Zhang, Y., Dowling, J.K., Thomson, N.M., Gilbert, R.E. Am. J. Kidney Dis. (2004) [Pubmed]
  21. Photolabelling the rat urotensin II/GPR14 receptor identifies a ligand-binding site in the fourth transmembrane domain. Boucard, A.A., Sauvé, S.S., Guillemette, G., Escher, E., Leduc, R. Biochem. J. (2003) [Pubmed]
  22. Structural requirements at the N-terminus of urotensin II octapeptides. Coy, D.H., Rossowski, W.J., Cheng, B.L., Taylor, J.E. Peptides (2002) [Pubmed]
  23. Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Liu, Q., Pong, S.S., Zeng, Z., Zhang, Q., Howard, A.D., Williams, D.L., Davidoff, M., Wang, R., Austin, C.P., McDonald, T.P., Bai, C., George, S.R., Evans, J.F., Caskey, C.T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  24. Pharmacological characterization of SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide), a novel peptidic urotensin-II receptor antagonist. Behm, D.J., Herold, C.L., Ohlstein, E.H., Knight, S.D., Dhanak, D., Douglas, S.A. Br. J. Pharmacol. (2002) [Pubmed]
  25. The expression of urotensin II receptor (U2R) is up-regulated by interferon-gamma. Birker-Robaczewska, M., Boukhadra, C., Studer, R., Mueller, C., Binkert, C., Nayler, O. J. Recept. Signal Transduct. Res. (2003) [Pubmed]
  26. Human urotensin II-induced aorta ring contractions are mediated by protein kinase C, tyrosine kinases and Rho-kinase: inhibition by somatostatin receptor antagonists. Rossowski, W.J., Cheng, B.L., Taylor, J.E., Datta, R., Coy, D.H. Eur. J. Pharmacol. (2002) [Pubmed]
  27. Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain. Sugo, T., Murakami, Y., Shimomura, Y., Harada, M., Abe, M., Ishibashi, Y., Kitada, C., Miyajima, N., Suzuki, N., Mori, M., Fujino, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  28. Recent structure-activity studies of the peptide hormone urotensin-II, a potent vasoconstrictor. Grieco, P., Rovero, P., Novellino, E. Current medicinal chemistry. (2004) [Pubmed]
  29. Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1. Matsushita, M., Shichiri, M., Fukai, N., Ozawa, N., Yoshimoto, T., Takasu, N., Hirata, Y. Endocrinology (2003) [Pubmed]
  30. Isochromanone-based urotensin-II receptor agonists. Lehmann, F., Currier, E.A., Olsson, R., Hacksell, U., Luthman, K. Bioorg. Med. Chem. (2005) [Pubmed]
  31. Functional and binding characterizations of urotensin II-related peptides in human and rat urotensin II-receptor assay. Brkovic, A., Hattenberger, A., Kostenis, E., Klabunde, T., Flohr, S., Kurz, M., Bourgault, S., Fournier, A. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
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