Urotensin-II explained

Urotensin-II (U-II) is a peptide ligand that is the strongest known vasoconstrictor.^[1] Because of the involvement of the UII system in multiple biological systems such as the cardiovascular, nervous, endocrine, and renal,^{[2] [3] [4]} it represents a promising target for the development of new drugs.^[5]

In humans, Urotensin-2 is encoded by the UTS2 gene.^{[6] [7] [8]}

Discovery

U-II was initially isolated from the neurosecretory system of the Goby fish (Gillichthys mirabilis).^[9] 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 genes for Pre-pro U-II were found in mammals proving that the peptide U-II did exist in mammals.

Structure

The U-II gene is located on chromosome 1p36.^[10] U-II peptide length varies between species due to the specific cleaving sites located at different spots depending on the species. 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 is not necessary for the activation of urotensin II receptor the fact that it is conserved in different species suggests that it has a biological function that has not been discovered.^[11]

Receptor

U-II is an agonist for the urotensin-II receptor which is a G protein-coupled receptor that primarily activates 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).^[12] It is also found in rat astrocytes.^[13]

Tissue localization

Pre-pro U-II in both humans and rats are primarily expressed in the motorneurons of the brainstem and spinal cord although it 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.

Function

Central nervous system

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 both rats and mice also stimulates locomotion in familiar environments. This experiment was also tested in rainbow trout (Oncorhynchus mykiss) where a stimulatory effect was also observed..

Depression-like behavior was also observed when U-II was injected in the brain by using the forced swim test and the tail suspension test which are used to compare molecules that are thought to cause anti-depressive-like effects.

Orexigenic behavior which is increased appetite and thirst were also observed after icv injection of U-II in rats.^[14]

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. It has been linked to cardiac fibrosis and hypertrophy, heart failure, renal dysfunction, and diabetes.

Further reading

• Zhou P, Li ZL, Tang CS . Regulative effect of human urotensin-II on cardiovascular system . Di 1 Jun Yi da Xue Xue Bao = Academic Journal of the First Medical College of PLA . 22 . 6 . 566–8 . Jun 2002 . 12297490 .
• Maguire JJ, Davenport AP . Is urotensin-II the new endothelin? . British Journal of Pharmacology . 137 . 5 . 579–88 . Nov 2002 . 12381671 . 1573544 . 10.1038/sj.bjp.0704924 .
• Balment RJ, Song W, Ashton N . Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation . Annals of the New York Academy of Sciences . 1040 . 66–73 . Apr 2005 . 1 . 15891007 . 10.1196/annals.1327.007 . 2005NYASA1040...66B . 44360612 .
• Zhu YC, Zhu YZ, Moore PK . The role of urotensin II in cardiovascular and renal physiology and diseases . British Journal of Pharmacology . 148 . 7 . 884–901 . Aug 2006 . 16783414 . 1751922 . 10.1038/sj.bjp.0706800 .
• Ashton N . Renal and vascular actions of urotensin II . Kidney International . 70 . 4 . 624–9 . Aug 2006 . 16807543 . 10.1038/sj.ki.5001621 . free .
• Jaïs P, Terris B, Ruszniewski P, LeRomancer M, Reyl-Desmars F, Vissuzaine C, Cadiot G, Mignon M, Lewin MJ . Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours . European Journal of Clinical Investigation . 27 . 8 . 639–44 . Aug 1997 . 9279525 . 10.1046/j.1365-2362.1997.1740719.x . 23503397 .
• Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams DL, Davidoff M, Wang R, Austin CP, McDonald TP, Bai C, George SR, Evans JF, Caskey CT . Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14 . Biochemical and Biophysical Research Communications . 266 . 1 . 174–8 . Dec 1999 . 10581185 . 10.1006/bbrc.1999.1796 .
• Zatelli MC, Tagliati F, Taylor JE, Rossi R, Culler MD, degli Uberti EC . Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line tt . The Journal of Clinical Endocrinology and Metabolism . 86 . 5 . 2161–9 . May 2001 . 10.1210/jcem.86.5.7489 . 11344221 . free .
• Matsushita M, Shichiri M, Imai T, Iwashina M, Tanaka H, Takasu N, Hirata Y . Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues . Journal of Hypertension . 19 . 12 . 2185–90 . Dec 2001 . 11725162 . 10.1097/00004872-200112000-00011 . 37723397 .
• Valdez GR, Inoue K, Koob GF, Rivier J, Vale W, Zorrilla EP . Human urocortin II: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide . Brain Research . 943 . 1 . 142–50 . Jul 2002 . 12088848 . 10.1016/S0006-8993(02)02707-5 . 25952175 .
• Kinney WA, Almond Jr HR, Qi J, Smith CE, Santulli RJ, de Garavilla L, Andrade-Gordon P, Cho DS, Everson AM, Feinstein MA, Leung PA, Maryanoff BE . Structure-function analysis of urotensin II and its use in the construction of a ligand-receptor working model . Angewandte Chemie . 41 . 16 . 2940–4 . Aug 2002 . 12203418 . 10.1002/1521-3773(20020816)41:16<2940::AID-ANIE2940>3.0.CO;2-M .
• Dschietzig T, Bartsch C, Pregla R, Zurbrügg HR, Armbruster FP, Richter C, Laule M, Romeyke E, Neubert C, Voelter W, Baumann G, Stangl K . Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure . Regulatory Peptides . 110 . 1 . 33–8 . Dec 2002 . 12468107 . 10.1016/S0167-0115(02)00158-1 . 8874326 .
• Zhu F, Ji L, Luo B . [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 . Nov 2002 . 12509909 .
• Russell FD, Meyers D, Galbraith AJ, Bett N, Toth I, Kearns P, Molenaar P . Elevated plasma levels of human urotensin-II immunoreactivity in congestive heart failure . American Journal of Physiology. Heart and Circulatory Physiology . 285 . 4 . H1576-81 . Oct 2003 . 12791592 . 10.1152/ajpheart.00217.2003 .
• Wenyi Z, Suzuki S, Hirai M, Hinokio Y, Tanizawa Y, Matsutani A, Satoh J, Oka Y . Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects . Diabetologia . 46 . 7 . 972–6 . Jul 2003 . 12830381 . 10.1007/s00125-003-1145-1 . free .

Notes and References

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2. Douglas SA, Dhanak D, Johns DG . From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function . Trends in Pharmacological Sciences . 25 . 2 . 76–85 . Feb 2004 . 15102493 . 10.1016/j.tips.2003.12.005 . (review) .
3. Vaudry H, Do Rego JC, Le Mevel JC, Chatenet D, Tostivint H, Fournier A, Tonon MC, Pelletier G, Conlon JM, Leprince J . Urotensin II, from fish to human . Annals of the New York Academy of Sciences . 1200 . 53–66 . 2010 . 1 . 20633133 . 10.1111/j.1749-6632.2010.05514.x . 2010NYASA1200...53V . 25173513 . (review) .
4. Vaudry H, Leprince J, Chatenet D, Fournier A, Lambert DG, Le Mével JC, Ohlstein EH, Schwertani A, Tostivint H, Vaudry D . International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function . Pharmacological Reviews . 67 . 1 . 214–58 . 2015 . 25535277 . 10.1124/pr.114.009480 . (review) . free .
5. Leprince J, Chatenet D, Dubessy C, Fournier A, Pfeiffer B, Scalbert E, Renard P, Pacaud P, Oulyadi H, Ségalas-Milazzo I, Guilhaudis L, Davoust D, Tonon MC, Vaudry H . Structure-activity relationships of urotensin II and URP . Peptides . 29 . 5 . 658–73 . May 2008 . 17931747 . 10.1016/j.peptides.2007.08.014 . 23592090 . (review) .
6. Coulouarn Y, Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC, Conlon JM, Bern HA, Vaudry H . 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 . Proceedings of the National Academy of Sciences of the United States of America . 95 . 26 . 15803–8 . Dec 1998 . 9861051 . 28125 . 10.1073/pnas.95.26.15803 . 1998PNAS...9515803C . free .
7. Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD, Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Ohlstein EH, Bergsma DJ, Douglas SA . Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 . Nature . 401 . 6750 . 282–6 . Sep 1999 . 10499587 . 10.1038/45809 . 1999Natur.401..282A . 4564765 .
8. Web site: Entrez Gene: UTS2 urotensin 2.
9. Bern HA, Lederis K . A reference preparation for the study of active substances in the caudal neurosecretory system of teleosts . The Journal of Endocrinology . 45 . 1 . Suppl:xi–xii . Sep 1969 . 5347394 . (primary) .
10. Sugo T, Murakami Y, Shimomura Y, Harada M, Abe M, Ishibashi Y, Kitada C, Miyajima N, Suzuki N, Mori M, Fujino M . Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain . Biochemical and Biophysical Research Communications . 310 . 3 . 860–8 . Oct 2003 . 14550283 . (review) . 10.1016/j.bbrc.2003.09.102.
11. Nothacker HP, Clark S . From heart to mind. The urotensin II system and its evolving neurophysiological role . The FEBS Journal . 272 . 22 . 5694–702 . Nov 2005 . 16279935 . 10.1111/j.1742-4658.2005.04983.x . (review) . free .
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13. Castel H, Diallo M, Chatenet D, Leprince J, Desrues L, Schouft MT, Fontaine M, Dubessy C, Lihrmann I, Scalbert E, Malagon M, Vaudry H, Tonon MC, Gandolfo P . Biochemical and functional characterization of high-affinity urotensin II receptors in rat cortical astrocytes . Journal of Neurochemistry . 99 . 2 . 582–95 . Oct 2006 . 16942596 . 10.1111/j.1471-4159.2006.04130.x . 21445345 . (primary) .
14. do Rego JC, Leprince J, Scalbert E, Vaudry H, Costentin J . Behavioral actions of urotensin-II . Peptides . 29 . 5 . 838–44 . May 2008 . 18294732 . 10.1016/j.peptides.2007.12.016 . 207356571 . (review) .