urotensin-II

{{Chembox

| ImageFile =Urotensin II.svg

| ImageSize =

| ImageAlt =

| IUPACName =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

| OtherNames =

|Section1={{Chembox Identifiers

| CASNo = 251293-28-4

| PubChem = 146158369

| ChEMBL = 437430

| ChemSpiderID = 24646295

| 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

| 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

| InChIKey = HFNHAPQMXICKCF-USJMABIRBM

| StdInChI = 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

| StdInChIKey = HFNHAPQMXICKCF-USJMABIRSA-N }}

|Section2={{Chembox Properties

| Formula = C₆₄H₈₅N₁₃O₁₈S₂

| MolarMass = 1388.6 g/mol

| Appearance =

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|Section3={{Chembox Hazards

| MainHazards =

| FlashPt =

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}}

Urotensin-II (U-II) is a peptide ligand that is the strongest known vasoconstrictor.{{cite journal | vauthors = 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 | title = 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 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 311 | issue = 1 | pages = 204–12 | date = Oct 2004 | pmid = 15146030 | doi = 10.1124/jpet.104.068320 | s2cid = 2011410 | department = (primary) }} Because of the involvement of the UII system in multiple biological systems such as the cardiovascular, nervous, endocrine, and renal,{{cite journal | vauthors = Douglas SA, Dhanak D, Johns DG | title = From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function | journal = Trends in Pharmacological Sciences | volume = 25 | issue = 2 | pages = 76–85 | date = Feb 2004 | pmid = 15102493 | doi = 10.1016/j.tips.2003.12.005 | department = (review) }}{{cite journal | vauthors = Vaudry H, Do Rego JC, Le Mevel JC, Chatenet D, Tostivint H, Fournier A, Tonon MC, Pelletier G, Conlon JM, Leprince J | title = Urotensin II, from fish to human | journal = Annals of the New York Academy of Sciences | volume = 1200 | pages = 53–66 | year = 2010 | issue = 1 | pmid = 20633133 | doi = 10.1111/j.1749-6632.2010.05514.x | bibcode = 2010NYASA1200...53V | s2cid = 25173513 | department = (review) }}{{cite journal | vauthors = Vaudry H, Leprince J, Chatenet D, Fournier A, Lambert DG, Le Mével JC, Ohlstein EH, Schwertani A, Tostivint H, Vaudry D | title = International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function | journal = Pharmacological Reviews | volume = 67 | issue = 1 | pages = 214–58 | year = 2015 | pmid = 25535277 | doi = 10.1124/pr.114.009480 | department = (review) | doi-access = free }} it represents a promising target for the development of new drugs.{{cite journal | vauthors = 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 | title = Structure-activity relationships of urotensin II and URP | journal = Peptides | volume = 29 | issue = 5 | pages = 658–73 | date = May 2008 | pmid = 17931747 | doi = 10.1016/j.peptides.2007.08.014 | s2cid = 23592090 | department = (review) }}

In humans, Urotensin-2 is encoded by the UTS2 gene.{{cite journal | vauthors = Coulouarn Y, Lihrmann I, Jegou S, Anouar Y, Tostivint H, Beauvillain JC, Conlon JM, Bern HA, Vaudry H | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 26 | pages = 15803–8 | date = Dec 1998 | pmid = 9861051 | pmc = 28125 | doi = 10.1073/pnas.95.26.15803 | bibcode = 1998PNAS...9515803C | doi-access = free }}{{cite journal | vauthors = 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 | title = Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 | journal = Nature | volume = 401 | issue = 6750 | pages = 282–6 | date = Sep 1999 | pmid = 10499587 | doi = 10.1038/45809 | bibcode = 1999Natur.401..282A | s2cid = 4564765 }}{{cite web | title = Entrez Gene: UTS2 urotensin 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10911}}

Discovery

U-II was initially isolated from the neurosecretory system of the Goby fish (Gillichthys mirabilis).{{cite journal | vauthors = Bern HA, Lederis K | title = A reference preparation for the study of active substances in the caudal neurosecretory system of teleosts | journal = The Journal of Endocrinology | volume = 45 | issue = 1 | pages = Suppl:xi–xii | date = Sep 1969 | pmid = 5347394 | department = (primary) }} 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.{{cite journal | vauthors = Sugo T, Murakami Y, Shimomura Y, Harada M, Abe M, Ishibashi Y, Kitada C, Miyajima N, Suzuki N, Mori M, Fujino M | title = Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain | journal = Biochemical and Biophysical Research Communications | volume = 310 | issue = 3 | pages = 860–8 | date = Oct 2003 | pmid = 14550283 | department = (review) | doi=10.1016/j.bbrc.2003.09.102}} 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.{{cite journal | vauthors = Nothacker HP, Clark S | title = From heart to mind. The urotensin II system and its evolving neurophysiological role | journal = The FEBS Journal | volume = 272 | issue = 22 | pages = 5694–702 | date = Nov 2005 | pmid = 16279935 | doi = 10.1111/j.1742-4658.2005.04983.x | department = (review) | doi-access = free }}

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).{{cite journal | vauthors = Clark SD, Nothacker HP, Wang Z, Saito Y, Leslie FM, Civelli O | title = The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat | journal = Brain Research | volume = 923 | issue = 1–2 | pages = 120–7 | date = Dec 2001 | pmid = 11743979 | doi = 10.1016/s0006-8993(01)03208-5| s2cid = 29248060 | department = (review) }} It is also found in rat astrocytes.{{cite journal | vauthors = 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 | title = Biochemical and functional characterization of high-affinity urotensin II receptors in rat cortical astrocytes | journal = Journal of Neurochemistry | volume = 99 | issue = 2 | pages = 582–95 | date = Oct 2006 | pmid = 16942596 | doi = 10.1111/j.1471-4159.2006.04130.x | s2cid = 21445345 | department = (primary) }}

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.{{cite journal | vauthors = do Rego JC, Leprince J, Scalbert E, Vaudry H, Costentin J | title = Behavioral actions of urotensin-II | journal = Peptides | volume = 29 | issue = 5 | pages = 838–44 | date = May 2008 | pmid = 18294732 | doi = 10.1016/j.peptides.2007.12.016 | s2cid = 207356571 | department = (review) }}

= 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.