Urotensin-II

Urotensin-II (U-II) is a peptide ligand that is the strongest known vasoconstrictor.^[5] Because of the involvement of the UII system in multiple biological systems such as the cardiovascular, nervous, endocrine, and renal,^[6][7][8] it represents a promising target for the development of new drugs.^[9]

UTS2
Identifiers
Aliases	UTS2, PRO1068, U-II, UCN2, UII, urotensin 2
External IDs	OMIM: 604097; MGI: 1346329; HomoloGene: 4939; GeneCards: UTS2; OMA:UTS2 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.23 Start 7,843,083 bp[1] End 7,853,512 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 E2 Start 151,081,554 bp[2] End 151,086,267 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle gonad right adrenal cortex granulocyte lymph node left adrenal cortex rectum epithelium of colon mononuclear cell mucosa of transverse colon Top expressed in lumbar subsegment of spinal cord facial motor nucleus anterior horn of spinal cord motor neuron neural layer of retina cerebellar cortex spermatid neural tube skeletal muscle tissue lip More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hormone activity signaling receptor binding Cellular component extracellular region extracellular space Biological process muscle contraction regulation of blood pressure chemical synaptic transmission blood vessel diameter maintenance regulation of signaling receptor activity G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10911 24111 Ensembl ENSG00000049247 ENSMUSG00000028963 UniProt O95399 Q9QZQ3 RefSeq (mRNA) NM_006786 NM_021995 NM_011910 RefSeq (protein) NP_006777 NP_068835 NP_036040 Location (UCSC) Chr 1: 7.84 – 7.85 Mb Chr 4: 151.08 – 151.09 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Urotensin-II

Names
IUPAC name L-α-glutamyl-L-threonyl-L-prolyl-L-α-aspartyl-L-cysteinyl-L-phenylalanyl-L-tryptophyl-L-lysyl-L-tyrosyl-L-cysteinyl-L-valine (5→10)-disulfide
Identifiers
CAS Number	251293-28-4
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL437430
ChemSpider	24646295
PubChem CID	146158369
InChI InChI=1S/C64H85N13O18S2/c1-33(2)52(64(94)95)75-61(91)48-32-97-96-31-47(73-59(89)46(29-51(82)83)72-62(92)49-17-11-25-77(49)63(93)53(34(3)78)76-54(84)40(66)22-23-50(80)81)60(90)70-43(26-35-12-5-4-6-13-35)56(86)71-45(28-37-30-67-41-15-8-7-14-39(37)41)58(88)68-42(16-9-10-24-65)55(85)69-44(57(87)74-48)27-36-18-20-38(79)21-19-36/h4-8,12-15,18-21,30,33-34,40,42-49,52-53,67,78-79H,9-11,16-17,22-29,31-32,65-66H2,1-3H3,(H,68,88)(H,69,85)(H,70,90)(H,71,86)(H,72,92)(H,73,89)(H,74,87)(H,75,91)(H,76,84)(H,80,81)(H,82,83)(H,94,95)/t34-,40+,42+,43+,44+,45+,46+,47+,48+,49+,52+,53+/m1/s1 Key: HFNHAPQMXICKCF-USJMABIRSA-N InChI=1/C64H85N13O18S2/c1-33(2)52(64(94)95)75-61(91)48-32-97-96-31-47(73-59(89)46(29-51(82)83)72-62(92)49-17-11-25-77(49)63(93)53(34(3)78)76-54(84)40(66)22-23-50(80)81)60(90)70-43(26-35-12-5-4-6-13-35)56(86)71-45(28-37-30-67-41-15-8-7-14-39(37)41)58(88)68-42(16-9-10-24-65)55(85)69-44(57(87)74-48)27-36-18-20-38(79)21-19-36/h4-8,12-15,18-21,30,33-34,40,42-49,52-53,67,78-79H,9-11,16-17,22-29,31-32,65-66H2,1-3H3,(H,68,88)(H,69,85)(H,70,90)(H,71,86)(H,72,92)(H,73,89)(H,74,87)(H,75,91)(H,76,84)(H,80,81)(H,82,83)(H,94,95)/t34-,40+,42+,43+,44+,45+,46+,47+,48+,49+,52+,53+/m1/s1 Key: HFNHAPQMXICKCF-USJMABIRBM
SMILES C[C@H]([C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H]2CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC2=O)Cc3ccccc3)Cc4c[nH]c5c4cccc5)CCCCN)Cc6ccc(cc6)O)C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O
Properties
Chemical formula	C64H85N13O18S2
Molar mass	1388.6 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

In humans, Urotensin-2 is encoded by the UTS2 gene.^[10][11][12]

Discovery

U-II was initially isolated from the neurosecretory system of the Goby fish (Gillichthys mirabilis).^[13] 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.^[14]

Structure

The U-II gene is located on chromosome 1p36.^[15] 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.^[14]

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 cytosolic 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).^[16] It is also found in rat astrocytes.^[17]

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.^[15]

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.^[18]

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.^[18]

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.^[18]

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.^[18]

References

1. GRCh38: Ensembl release 89: ENSG00000049247 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028963 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C, Müller C, Nayler O, Qiu C, Rey M, Scherz MW, Velker J, Weller T, Xi JF, Ziltener P (Oct 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". (primary). The Journal of Pharmacology and Experimental Therapeutics. 311 (1): 204–12. doi:10.1124/jpet.104.068320. PMID 15146030. S2CID 2011410.
6. Douglas SA, Dhanak D, Johns DG (Feb 2004). "From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function". (review). Trends in Pharmacological Sciences. 25 (2): 76–85. doi:10.1016/j.tips.2003.12.005. PMID 15102493.
7. 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". (review). Annals of the New York Academy of Sciences. 1200 (1): 53–66. Bibcode:2010NYASA1200...53V. doi:10.1111/j.1749-6632.2010.05514.x. PMID 20633133. S2CID 25173513.
8. 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". (review). Pharmacological Reviews. 67 (1): 214–58. doi:10.1124/pr.114.009480. PMID 25535277.
9. 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 (May 2008). "Structure-activity relationships of urotensin II and URP". (review). Peptides. 29 (5): 658–73. doi:10.1016/j.peptides.2007.08.014. PMID 17931747. S2CID 23592090.
10. Coulouarn Y, Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC, Conlon JM, Bern HA, Vaudry H (Dec 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". Proceedings of the National Academy of Sciences of the United States of America. 95 (26): 15803–8. Bibcode:1998PNAS...9515803C. doi:10.1073/pnas.95.26.15803. PMC 28125. PMID 9861051.
11. 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 (Sep 1999). "Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14". Nature. 401 (6750): 282–6. Bibcode:1999Natur.401..282A. doi:10.1038/45809. PMID 10499587. S2CID 4564765.
12. "Entrez Gene: UTS2 urotensin 2".
13. Bern HA, Lederis K (Sep 1969). "A reference preparation for the study of active substances in the caudal neurosecretory system of teleosts". (primary). The Journal of Endocrinology. 45 (1): Suppl:xi–xii. PMID 5347394.
14. Nothacker HP, Clark S (Nov 2005). "From heart to mind. The urotensin II system and its evolving neurophysiological role". (review). The FEBS Journal. 272 (22): 5694–702. doi:10.1111/j.1742-4658.2005.04983.x. PMID 16279935.
15. Sugo T, Murakami Y, Shimomura Y, Harada M, Abe M, Ishibashi Y, Kitada C, Miyajima N, Suzuki N, Mori M, Fujino M (Oct 2003). "Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain". (review). Biochemical and Biophysical Research Communications. 310 (3): 860–8. doi:10.1016/j.bbrc.2003.09.102. PMID 14550283.
16. Clark SD, Nothacker HP, Wang Z, Saito Y, Leslie FM, Civelli O (Dec 2001). "The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat". (review). Brain Research. 923 (1–2): 120–7. doi:10.1016/s0006-8993(01)03208-5. PMID 11743979. S2CID 29248060.
17. 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 (Oct 2006). "Biochemical and functional characterization of high-affinity urotensin II receptors in rat cortical astrocytes". (primary). Journal of Neurochemistry. 99 (2): 582–95. doi:10.1111/j.1471-4159.2006.04130.x. PMID 16942596. S2CID 21445345.
18. do Rego JC, Leprince J, Scalbert E, Vaudry H, Costentin J (May 2008). "Behavioral actions of urotensin-II". (review). Peptides. 29 (5): 838–44. doi:10.1016/j.peptides.2007.12.016. PMID 18294732. S2CID 207356571.

Further reading

• Zhou P, Li ZL, Tang CS (Jun 2002). "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. PMID 12297490.
• Maguire JJ, Davenport AP (Nov 2002). "Is urotensin-II the new endothelin?". British Journal of Pharmacology. 137 (5): 579–88. doi:10.1038/sj.bjp.0704924. PMC 1573544. PMID 12381671.
• Balment RJ, Song W, Ashton N (Apr 2005). "Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation". Annals of the New York Academy of Sciences. 1040 (1): 66–73. Bibcode:2005NYASA1040...66B. doi:10.1196/annals.1327.007. PMID 15891007. S2CID 44360612.
• Zhu YC, Zhu YZ, Moore PK (Aug 2006). "The role of urotensin II in cardiovascular and renal physiology and diseases". British Journal of Pharmacology. 148 (7): 884–901. doi:10.1038/sj.bjp.0706800. PMC 1751922. PMID 16783414.
• Ashton N (Aug 2006). "Renal and vascular actions of urotensin II". Kidney International. 70 (4): 624–9. doi:10.1038/sj.ki.5001621. PMID 16807543.
• Jaïs P, Terris B, Ruszniewski P, LeRomancer M, Reyl-Desmars F, Vissuzaine C, Cadiot G, Mignon M, Lewin MJ (Aug 1997). "Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours". European Journal of Clinical Investigation. 27 (8): 639–44. doi:10.1046/j.1365-2362.1997.1740719.x. PMID 9279525. S2CID 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 (Dec 1999). "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. doi:10.1006/bbrc.1999.1796. PMID 10581185.
• Zatelli MC, Tagliati F, Taylor JE, Rossi R, Culler MD, degli Uberti EC (May 2001). "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. doi:10.1210/jcem.86.5.7489. PMID 11344221.
• Matsushita M, Shichiri M, Imai T, Iwashina M, Tanaka H, Takasu N, Hirata Y (Dec 2001). "Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues". Journal of Hypertension. 19 (12): 2185–90. doi:10.1097/00004872-200112000-00011. PMID 11725162. S2CID 37723397.
• Valdez GR, Inoue K, Koob GF, Rivier J, Vale W, Zorrilla EP (Jul 2002). "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. doi:10.1016/S0006-8993(02)02707-5. PMID 12088848. S2CID 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 (Aug 2002). "Structure-function analysis of urotensin II and its use in the construction of a ligand-receptor working model". Angewandte Chemie. 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, Zurbrügg HR, Armbruster FP, Richter C, Laule M, Romeyke E, Neubert C, Voelter W, Baumann G, Stangl K (Dec 2002). "Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure". Regulatory Peptides. 110 (1): 33–8. doi:10.1016/S0167-0115(02)00158-1. PMID 12468107. S2CID 8874326.
• Zhu F, Ji L, Luo B (Nov 2002). "[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.
• Russell FD, Meyers D, Galbraith AJ, Bett N, Toth I, Kearns P, Molenaar P (Oct 2003). "Elevated plasma levels of human urotensin-II immunoreactivity in congestive heart failure". American Journal of Physiology. Heart and Circulatory Physiology. 285 (4): H1576-81. doi:10.1152/ajpheart.00217.2003. PMID 12791592.
• Wenyi Z, Suzuki S, Hirai M, Hinokio Y, Tanizawa Y, Matsutani A, Satoh J, Oka Y (Jul 2003). "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.