Chemistry:Urotensin-II
 Generic protein structure example |
| |
| 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 | |
3D model (JSmol)
|
|
| ChEMBL | |
| ChemSpider | |
PubChem CID
|
|
| |
| |
| Properties | |
| 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 | |
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.[10]
Structure
The U-II gene is located on chromosome 1p36.[11] 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.[10]
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.[11]
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.[14]
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.[14]
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.[14]
References
- ↑ "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". The Journal of Pharmacology and Experimental Therapeutics 311 (1): 204–12. Oct 2004. doi:10.1124/jpet.104.068320. PMID 15146030.
- ↑ "From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function". Trends in Pharmacological Sciences 25 (2): 76–85. Feb 2004. doi:10.1016/j.tips.2003.12.005. PMID 15102493.
- ↑ "Urotensin II, from fish to human". Annals of the New York Academy of Sciences 1200 (1): 53–66. 2010. doi:10.1111/j.1749-6632.2010.05514.x. PMID 20633133. Bibcode: 2010NYASA1200...53V.
- ↑ "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. doi:10.1124/pr.114.009480. PMID 25535277.
- ↑ "Structure-activity relationships of urotensin II and URP". Peptides 29 (5): 658–73. May 2008. doi:10.1016/j.peptides.2007.08.014. PMID 17931747.
- ↑ "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. doi:10.1073/pnas.95.26.15803. PMID 9861051. Bibcode: 1998PNAS...9515803C.
- ↑ "Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14". Nature 401 (6750): 282–6. Sep 1999. doi:10.1038/45809. PMID 10499587. Bibcode: 1999Natur.401..282A.
- ↑ "Entrez Gene: UTS2 urotensin 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10911.
- ↑ "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. PMID 5347394.
- ↑ 10.0 10.1 "From heart to mind. The urotensin II system and its evolving neurophysiological role". The FEBS Journal 272 (22): 5694–702. Nov 2005. doi:10.1111/j.1742-4658.2005.04983.x. PMID 16279935.
- ↑ 11.0 11.1 "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. doi:10.1016/j.bbrc.2003.09.102. PMID 14550283.
- ↑ "The urotensin II receptor is expressed in the cholinergic mesopontine tegmentum of the rat". Brain Research 923 (1–2): 120–7. Dec 2001. doi:10.1016/s0006-8993(01)03208-5. PMID 11743979.
- ↑ "Biochemical and functional characterization of high-affinity urotensin II receptors in rat cortical astrocytes". Journal of Neurochemistry 99 (2): 582–95. Oct 2006. doi:10.1111/j.1471-4159.2006.04130.x. PMID 16942596.
- ↑ 14.0 14.1 14.2 14.3 "Behavioral actions of urotensin-II". Peptides 29 (5): 838–44. May 2008. doi:10.1016/j.peptides.2007.12.016. PMID 18294732.
Further reading
- "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. PMID 12297490.
- "Is urotensin-II the new endothelin?". British Journal of Pharmacology 137 (5): 579–88. Nov 2002. doi:10.1038/sj.bjp.0704924. PMID 12381671.
- "Urotensin II: ancient hormone with new functions in vertebrate body fluid regulation". Annals of the New York Academy of Sciences 1040 (1): 66–73. Apr 2005. doi:10.1196/annals.1327.007. PMID 15891007. Bibcode: 2005NYASA1040...66B.
- "The role of urotensin II in cardiovascular and renal physiology and diseases". British Journal of Pharmacology 148 (7): 884–901. Aug 2006. doi:10.1038/sj.bjp.0706800. PMID 16783414.
- "Renal and vascular actions of urotensin II". Kidney International 70 (4): 624–9. Aug 2006. doi:10.1038/sj.ki.5001621. PMID 16807543.
- "Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours". European Journal of Clinical Investigation 27 (8): 639–44. Aug 1997. doi:10.1046/j.1365-2362.1997.1740719.x. PMID 9279525.
- "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. doi:10.1006/bbrc.1999.1796. PMID 10581185.
- "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. doi:10.1210/jcem.86.5.7489. PMID 11344221.
- "Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues". Journal of Hypertension 19 (12): 2185–90. Dec 2001. doi:10.1097/00004872-200112000-00011. PMID 11725162.
- "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. doi:10.1016/S0006-8993(02)02707-5. PMID 12088848.
- "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. doi:10.1002/1521-3773(20020816)41:16<2940::AID-ANIE2940>3.0.CO;2-M. PMID 12203418.
- "Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure". Regulatory Peptides 110 (1): 33–8. Dec 2002. doi:10.1016/S0167-0115(02)00158-1. PMID 12468107.
- "[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. PMID 12509909.
- "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. doi:10.1152/ajpheart.00217.2003. PMID 12791592.
- "Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects". Diabetologia 46 (7): 972–6. Jul 2003. doi:10.1007/s00125-003-1145-1. PMID 12830381.
 |  |
