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Urotensin-II (U-II) is a peptide ligand that is now described as the strongest vasoconstrictor known to man^[1]. Because of the potential involvement of the UII system in multiple biological systems such as the cardiovascular, nervous, endocrine, and renal system it represents a good target for the development of new drugs^[2].

Discovery

U-II was initially isolated from the neurosecretory system of the Goby fish (Gillichthys mirabilis).^[3] For many years it was thought that U-II does not exhibit significant effects in mammalian systems; a view quickly overturned when it was demonstrated that Goby U-II produces slow relaxation of mouse anococcygeus muscle, in addition to contraction of rat artery segments. In 1998, the cDNA encoding a U-II precursor was cloned in humans, unequivocally demonstrating its existence in mammalian species.

Structure

The URP gene is located on chromosome 1p36^[4]. U-II peptide length can vary between different species because there is no specific cleavage site. In humans U-II length is 11 amino acids. The peptide sequence that is needed for biological function for both U-II and urotensin II-Related Peptide (URP) is known as the core. It is hexapeptide (-CYS-TYR-LYS-TRP-PHE-CYS-), and is connected at the two ends by a disulfide bond. Also just like URP the amino terminus can be modified without any loss in pharmacological activity suggesting that it is not needed for activation of the receptor. Unlike URP, U-II has an acidic amino acid (Glutamic or Aspartic) that precedes the core sequence. While the amino acid isn’t necessary for the activation of Urotensin II receptor the fact that it is still conserved means that it has some biological function that has not been discovered^[5].

Receptor

UII is an agonist for the UII receptor which is a G protein-coupled receptor that has the alpha subunit Gαq11. It activates PKC which then activates PLC which increases the intercellular calcium concentration. It is found in many peripheral tissues, blood vessels, and also the brainstem cholinergic neurons of the laterodorsal tegmental (LDT) and the pedunculopontine tegmental nuclei (PPT)^[6]. It is also found in rat astrocytes^[7].

Tissue Localization

Pre-pro U-II in both humans and rats are primarily expressed in the motorneurons of the brainstem and spinal cord although its is also found in small amounts in other parts of the brain as well including the frontal lobe and the medulla oblongata. In humans U-II mRNA is also found in other peripheral tissues such as the heart, kidneys, adrenal gland, placenta, spleen, and thymus.^[4]

Function

Central Nervous System (CNS)

When injected intracerebroventricularly (icv) U-II causes an increase in the corticotropin releasing factor by activating the hypothalamic paraventricular neurons. This leads to increased plasma levels of adrenocorticotropic hormones and adrenaline. Rats and mice exhibit many stress related behaviors when injected with U-II which were tested by the elevated plus maze which measures anxiety like effects,and the hole-board test which measures head dipping which is also an anxiety like behavior.

U-II when injected icv in rats also leads to cardiovascular responses including raising mean arterial pressure (MAP) and causing tachycardia. When the arcuate nucleus, and the paraventricular nucleus, two different areas of the brain which are known to control blood pressure were injected with U-II simultaneously they caused an increase in blood pressure. When the two areas were injected separately it was discovered that U-II affected the excitatory neurons in the paraventricular nucleus and the inhibitory neurons of the arcuate nucleus.

U-II when injected icv in the lateral ventricle in both rats and mice also stimulates locomotion in familiar environments. This experiment was also tested in rainbow trout (Oncorhynchus mykiss). In the trouts case the doses used to test this reaction were not enough to cause a significant increase in blood pressure meaning that U-II release could be important for survival in species.

Depression like behavior was also observed when U-II was injected in the brain by using the forced swim test and the tail hanging test which compares molecules that are known to cause depression like effects to each other.

Orexigenic behavior which is increased appetite and thirst were also observed through icv injection of U-II in rats.^[8]

Peripheral Tissue Effects

U-II has a variety of effects on different tissues. In blood vessels it can cause contraction. In rat pancreas U-II inhibits insulin secretion. It also affects the kidneys including sodium transport, lipid and glucose metabolism, and natriuretic effects. Its has been linked to cardiac fibrosis and hypertrophy, heart failure, renal dysfunction, and diabetes^[8].

References

^ Clozel, M; Binkert, C; Birker-Robaczewska, M; Boukhadra, C; Ding, SS; Fischli, W; Hess, P; Mathys, B; Morrison, K; Muller, C (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: 204-212. {{cite journal}}: |access-date= requires |url= (help)
^ Leprince, Jerome; Chatenet, David; Dubessy, Christophe; Fournier, Alan; Pfeiffer, Bruno; Scalbert, Elizabeth; Renard, Pierre; Pacaud, Pierre; Oulyadi, Hassan; Segalas-Milazzo, Isabelle; Guilhaudis, Laure; Davoust, Daniel; Tonon, Marie-Christine; Vaudry, Hubert. "Structure–activity relationships of urotensin II and URP". Peptides. 29: 658-673. {{cite journal}}: |access-date= requires |url= (help)
^ Bern HA, Lederis K (September 1969). "A reference preparation for the study of active substances in the caudal neurosecretory system of teleosts". J. Endocrinol. 45 (1): Suppl:xi–xii. PMID 5347394.
^ ^a ^b Sugo, Tsukasa; Murakami, Yuko; Shimomura, Yukio; Harada, Mioko; Michiko, Abe; Ishibashi, Yoshihiro; Kitada, Chieko; Miyajima, Nobuyuki; Suzuki, Nobuhiro; Mori, Masaaki; Fujino, Masahiko (24 October 2003). "Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain". Biochemical and Biophysical Research Communications. 310 (3): 860-868. {{cite journal}}: |access-date= requires |url= (help)
^ Nothacker HP, Clark S (2005). "From heart to mind. The urotensin II system and its evolving neurophysiological role". The FEBS Journal. 272 (22): 5694–702. doi:10.1111/j.1742-4658.2005.04983.x. PMID 16279935.
^ Clark SD, Nothacker HP, Wang Z, Saito Y, Leslie FM, Civelli O (2001). "The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat". Brain Research. 923 (1–2): 120–7. PMID 11743979.
^ Castel, H; Diallo, M; Chatnet, D; Leprince, J; Desrues, L; Schouft, MT (2006). "Biochemical and functional characterization of high-affinity urotensin-II receptors in rat cortical astrocytes". J Neurochem. 99: 582-595. {{cite journal}}: |access-date= requires |url= (help)
^ ^a ^b Rego, Jean-Claude; Leprince, Jerome; Scalbert, Elizabeth; Vaudry, Hubert; Costentin, Jean (2008). "Behavioral actions of urotensin-II". Peptides. 29: 838-844. {{cite journal}}: |access-date= requires |url= (help)

Zhou P, Li ZL, Tang CS (2002). "Regulative effect of human urotensin-II on cardiovascular system". Di Yi Jun Yi Da Xue Xue Bao. 22 (6): 566–8. PMID 12297490.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Maguire JJ, Davenport AP (2003). "Is urotensin-II the new endothelin?". Br. J. Pharmacol. 137 (5): 579–88. doi:10.1038/sj.bjp.0704924. PMC 1573544. PMID 12381671.
Balment RJ, Song W, Ashton N (2006). "Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation". Ann. N. Y. Acad. Sci. 1040: 66–73. doi:10.1196/annals.1327.007. PMID 15891007.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Zhu YC, Zhu YZ, Moore PK (2006). "The role of urotensin II in cardiovascular and renal physiology and diseases". Br. J. Pharmacol. 148 (7): 884–901. doi:10.1038/sj.bjp.0706800. PMC 1751922. PMID 16783414.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Ashton N (2006). "Renal and vascular actions of urotensin II". Kidney Int. 70 (4): 624–9. doi:10.1038/sj.ki.5001621. PMID 16807543.
Jaïs P, Terris B, Ruszniewski P, et al. (1997). "Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours". Eur. J. Clin. Invest. 27 (8): 639–44. doi:10.1046/j.1365-2362.1997.1740719.x. PMID 9279525.
Liu Q, Pong SS, Zeng Z, et al. (2000). "Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14". Biochem. Biophys. Res. Commun. 266 (1): 174–8. doi:10.1006/bbrc.1999.1796. PMID 10581185.
Zatelli MC, Tagliati F, Taylor JE, et al. (2001). "Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line tt". J. Clin. Endocrinol. Metab. 86 (5): 2161–9. doi:10.1210/jc.86.5.2161. PMID 11344221.
Matsushita M, Shichiri M, Imai T, et al. (2002). "Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues". J. Hypertens. 19 (12): 2185–90. doi:10.1097/00004872-200112000-00011. PMID 11725162.
Valdez GR, Inoue K, Koob GF, et al. (2002). "Human urocortin II: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide". Brain Res. 943 (1): 142–50. doi:10.1016/S0006-8993(02)02707-5. PMID 12088848.
Kinney WA, Almond Jr HR, Qi J, 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. doi:10.1002/1521-3773(20020816)41:16<2940::AID-ANIE2940>3.0.CO;2-M. PMID 12203418.
Dschietzig T, Bartsch C, Pregla R, et al. (2003). "Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure". Regul. Pept. 110 (1): 33–8. doi:10.1016/S0167-0115(02)00158-1. PMID 12468107.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Zhu F, Ji L, Luo B (2003). "[The role of urotensin II gene in the genetic susceptibility to type 2 diabetes in Chinese population]". Zhonghua Yi Xue Za Zhi. 82 (21): 1473–5. PMID 12509909.{{cite journal}}: CS1 maint: multiple names: authors list (link)
Russell FD, Meyers D, Galbraith AJ, et al. (2003). "Elevated plasma levels of human urotensin-II immunoreactivity in congestive heart failure". Am. J. Physiol. Heart Circ. Physiol. 285 (4): H1576–81. doi:10.1152/ajpheart.00217.2003. PMID 12791592.
Wenyi Z, Suzuki S, Hirai M, et al. (2004). "Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects". Diabetologia. 46 (7): 972–6. doi:10.1007/s00125-003-1145-1. PMID 12830381.

[1] Clozel, M; Binkert, C; Birker-Robaczewska, M; Boukhadra, C; Ding, SS; Fischli, W; Hess, P; Mathys, B; Morrison, K; Muller, C (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: 204-212. {{cite journal}}: |access-date= requires |url= (help)

[2] Leprince, Jerome; Chatenet, David; Dubessy, Christophe; Fournier, Alan; Pfeiffer, Bruno; Scalbert, Elizabeth; Renard, Pierre; Pacaud, Pierre; Oulyadi, Hassan; Segalas-Milazzo, Isabelle; Guilhaudis, Laure; Davoust, Daniel; Tonon, Marie-Christine; Vaudry, Hubert. "Structure–activity relationships of urotensin II and URP". Peptides. 29: 658-673. {{cite journal}}: |access-date= requires |url= (help)

[3] Bern HA, Lederis K (September 1969). "A reference preparation for the study of active substances in the caudal neurosecretory system of teleosts". J. Endocrinol. 45 (1): Suppl:xi–xii. PMID 5347394.

[:0-4] Sugo, Tsukasa; Murakami, Yuko; Shimomura, Yukio; Harada, Mioko; Michiko, Abe; Ishibashi, Yoshihiro; Kitada, Chieko; Miyajima, Nobuyuki; Suzuki, Nobuhiro; Mori, Masaaki; Fujino, Masahiko (24 October 2003). "Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain". Biochemical and Biophysical Research Communications. 310 (3): 860-868. {{cite journal}}: |access-date= requires |url= (help)

[pmid16279935-5] Nothacker HP, Clark S (2005). "From heart to mind. The urotensin II system and its evolving neurophysiological role". The FEBS Journal. 272 (22): 5694–702. doi:10.1111/j.1742-4658.2005.04983.x. PMID 16279935.

[pmid11743979-6] Clark SD, Nothacker HP, Wang Z, Saito Y, Leslie FM, Civelli O (2001). "The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat". Brain Research. 923 (1–2): 120–7. PMID 11743979.

[7] Castel, H; Diallo, M; Chatnet, D; Leprince, J; Desrues, L; Schouft, MT (2006). "Biochemical and functional characterization of high-affinity urotensin-II receptors in rat cortical astrocytes". J Neurochem. 99: 582-595. {{cite journal}}: |access-date= requires |url= (help)

[:1-8] Rego, Jean-Claude; Leprince, Jerome; Scalbert, Elizabeth; Vaudry, Hubert; Costentin, Jean (2008). "Behavioral actions of urotensin-II". Peptides. 29: 838-844. {{cite journal}}: |access-date= requires |url= (help)

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