The urotensin-2 receptor (UR-II-R) also known as GPR14 is a class A rhodopsin family G protein coupled-receptor (GPCR) that is 386 amino acids long which binds primarily to the neuropeptide urotensin II.[1] The receptor quickly rose to prominence when it was found that when activated by urotensin II it induced the most potent vasoconstriction effect ever seen.[5] While the precise function of the urotensin II receptor is not fully known it has been linked to cardiovascular effects, stress, and REM sleep.
Ligands
There are two known endogenous agonists for the urotensin II receptor. One is urotensin II whose mRNA is found in a variety of tissues including the brain and also blood vessels. It is a potent vasoconstrictor and can increase REM cycles. The other is urotensin II-Related Peptide (URP) which is found in a variety of tissues as well although at less concentrations then urotensin II. The one exception is in human reproductive tissue where the levels of URP are much higher than urotensin II.
Cellular Pathway
Activation protein kinase C
Urotensin II Receptor interacts with the G Protein whose alpha subunit is Gαq11 which is mainly involved in activating Protein Kinase C (PKC). This then activates phospholipase C which increases the intercellular amount of calcium through the activation of IP3 which is an intracellular molecule that acts as secondary messenger. IP3 will then release calcium which then activates PKC.
When the urotensin II receptor is activated it also promotes beta arrestin translocation. Beta arrestin is important for ceasing the response of a receptor to a stimuli. Beta arrestin also brings with it other proteins that internalize the receptor which also helps in desensitizing the cell to the stimuli.[6]
Tissue distribution
Based on RT-PCR techniques the urotensin II receptor appears to be expressed throughout the entire brain.[7] On the other hand, when using in situ hybridization technique which is less sensitive but provides more information of the anatomical location urotensin II receptor mRNA was shown to be restricted to the brainstemcholinergic neurons of the laterodorsal tegmental (LDT) and the pedunculopontine tegmental nuclei (PPT) both of which are important for REM sleep.[8] These two different results are because urotensin II receptor can also be found in blood vessels which is what the sensitive RT-PCR technique was likely detecting. Urotensin II receptors are also found in the cholinergic neurons of the spinal cord indicating some type of motor function.
Urotensin II receptors have also been found in other peripheral tissues and blood vessels. This suggests some effects on the cardiovascular system.
Function
CNS
When the urotensin II receptor is activated through an intracerebroventricular (icv) injection of urotensin II it causes an increase of corticotropin releasing factor through the activation of the hypothalamic paraventricular neurons (PVN) which lead to increased plasma levels of adrenocorticotropic hormones. C-fos levels which go up whenever there is an increase in neural activity were detected in the brain 20 minutes after the urotensin II was injected. The stimulation of the PVN by the activation of urotensin II receptor means that it directly affects the hypothalamus pituitary axis (HPA) which is important in the regulation of many important body functions.[9] Rats also exhibit many stress related behaviors when injected with urotensin II such as pacing and fidgeting in familiar environments.
REM sleep is controlled by the cholinergic neurons in the PPT and LDT. Local injection of urotensin II into the PPT to leads to increased REM sleep episodes where the firing of the cholinergic neurons was observed through electrophysiological studies. The studies also showed there was no effect on the non-cholinergic neurons. Wakefulness and slow wave sleep were not affected by the activation of the urotensin II receptor.[10]
Cardiovascular
Short term effects of the activation of the urotensin II receptor is the burst intercellular calcium in the aorta which causes vasoconstriction of the vessel. There is also evidence that there are long term effects of the activation of the urotensin II receptor which could play a role in cardiomyocytic hypertrophy.[11]
Gene
Human urotensin II receptor is located on chromosome 17q25 as an intronless gene. There are no known subtypes of the receptor but the possibility cannot be discounted. It has similar domain sequences to the somatostatin receptor, and in lab conditions can be activated by somatostatin.[12]
Clinical significance
Mutations
There is one single-nucleotide polymorphism that is known to occur in humans regarding the urotensin II receptor. R1483.50 is instead H1483.50 which effects how the cell responds when the urotensin II receptor is activated. The receptor cannot activate the PKC but it can still activate the ERK1/2 pathway although it is a little bit slower.
There have been studies done on specific amino acids on the urotensin II receptor especially the ones that are homologous to the other members of the rhodopsin family. These include, D972.50, E1473.49, and Y1493.50. In all cases the amino acids were converted to alanine and their effects were observed. The mutated D972.50 receptor could not activate PKC nor could it activate the ERK1/2 pathway. This meant that it affected the activation of both pathways and plays a critical role. The other two amino acids which were mutated E1473.49 and Y1493.50 still activated both PKC and ERK1/2 suggesting that they did not play a critical role in the activation of the pathway.[13]
References
^ abcGRCh38: Ensembl release 89: ENSG00000181408 – Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000039321 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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". The Journal of Pharmacology and Experimental Therapeutics. 311 (1): 204–12. doi:10.1124/jpet.104.068320. PMID 15146030. S2CID 2011410.
^Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, et al. (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.
^Gartlon J, Parker F, Harrison DC, Douglas SA, Ashmeade TE, Riley GJ, Hughes ZA, Taylor SG, Munton RP, Hagan JJ, Hunter JA, Jones DN (2001). "Central effects of urotensin-II following ICV administration in rats". Psychopharmacology. 155 (4): 426–33. doi:10.1007/s002130100715. PMID 11441433. S2CID 22774771.
^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. doi:10.1016/s0006-8993(01)03208-5. PMID 11743979. S2CID 29248060.
^Watson AM, Lambert GW, Smith KJ, May CN (2003). "Urotensin II acts centrally to increase epinephrine and ACTH release and cause potent inotropic and chronotropic actions". Hypertension. 42 (3): 373–9. doi:10.1161/01.HYP.0000084633.85427.E6. PMID 12885791.
^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. S2CID 83184639.
^Saetrum Opgaard O, Nothacker H, Ehlert FJ, Krause DN (2000). "Human urotensin II mediates vasoconstriction via an increase in inositol phosphates". European Journal of Pharmacology. 406 (2): 265–71. doi:10.1016/s0014-2999(00)00672-5. PMID 11020490.
^Nothacker HP, Wang Z, McNeill AM, Saito Y, Merten S, O'Dowd B, Duckles SP, Civelli O (1999). "Identification of the natural ligand of an orphan G-protein-coupled receptor involved in the regulation of vasoconstriction". Nature Cell Biology. 1 (6): 383–5. doi:10.1038/14081. PMID 10559967. S2CID 41304445.
^Proulx CD, Holleran BJ, Boucard AA, Escher E, Guillemette G, Leduc R (2008). "Mutational analysis of the conserved Asp2.50 and ERY motif reveals signaling bias of the urotensin II receptor". Molecular Pharmacology. 74 (3): 552–61. doi:10.1124/mol.108.045054. PMID 18509066. S2CID 9019351.
Further reading
Marchese A, Heiber M, Nguyen T, Heng HH, Saldivia VR, Cheng R, Murphy PM, Tsui LC, Shi X, Gregor P (Sep 1995). "Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors". Genomics. 29 (2): 335–44. doi:10.1006/geno.1995.9996. PMID 8666380.
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.
Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams DL, et al. (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.
Protopopov A, Kashuba V, Podowski R, Gizatullin R, Sonnhammer E, Wahlestedt C, Zabarovsky ER (2000). "Assignment of the GPR14 gene coding for the G-protein-coupled receptor 14 to human chromosome 17q25.3 by fluorescent in situ hybridization". Cytogenetics and Cell Genetics. 88 (3–4): 312–3. doi:10.1159/000015516. PMID 10828617. S2CID 39854406.
Maguire JJ, Kuc RE, Davenport AP (Oct 2000). "Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1". British Journal of Pharmacology. 131 (3): 441–6. doi:10.1038/sj.bjp.0703601. PMC 1572358. PMID 11015293.
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". Biochemical and Biophysical Research Communications. 310 (3): 860–8. doi:10.1016/j.bbrc.2003.09.102. PMID 14550283.
Birker-Robaczewska M, Boukhadra C, Studer R, Mueller C, Binkert C, Nayler O (2004). "The expression of urotensin II receptor (U2R) is up-regulated by interferon-gamma". Journal of Receptor and Signal Transduction Research. 23 (4): 289–305. doi:10.1081/RRS-120026972. PMID 14753294. S2CID 8558448.
Bousette N, Patel L, Douglas SA, Ohlstein EH, Giaid A (Sep 2004). "Increased expression of urotensin II and its cognate receptor GPR14 in atherosclerotic lesions of the human aorta". Atherosclerosis. 176 (1): 117–23. doi:10.1016/j.atherosclerosis.2004.03.023. PMID 15306183.
Suzuki S, Wenyi Z, Hirai M, Hinokio Y, Suzuki C, Yamada T, Yoshizumi S, Suzuki M, Tanizawa Y, Matsutani A, Oka Y (Oct 2004). "Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese". Peptides. 25 (10): 1803–8. doi:10.1016/j.peptides.2004.03.030. PMID 15476949. S2CID 11783160.
Qi JS, Minor LK, Smith C, Hu B, Yang J, Andrade-Gordon P, Damiano B (Apr 2005). "Characterization of functional urotensin II receptors in human skeletal muscle myoblasts: comparison with angiotensin II receptors". Peptides. 26 (4): 683–90. doi:10.1016/j.peptides.2004.11.018. PMID 15752584. S2CID 1244919.
Lehner U, Velić A, Schroter R, Schlatter E, Sindić A (2007). "Ligands and signaling of the G-protein-coupled receptor GPR14, expressed in human kidney cells". Cellular Physiology and Biochemistry. 20 (1–4): 181–92. doi:10.1159/000104165. PMID 17595527.
Segain JP, Rolli-Derkinderen M, Gervois N, Raingeard de la Blétière D, Loirand G, Pacaud P (Jul 2007). "Urotensin II is a new chemotactic factor for UT receptor-expressing monocytes". Journal of Immunology. 179 (2): 901–9. doi:10.4049/jimmunol.179.2.901. PMID 17617581.
Lehmann F, Pettersen A, Currier EA, Sherbukhin V, Olsson R, Hacksell U, Luthman K (Apr 2006). "Novel potent and efficacious nonpeptidic urotensin II receptor agonists". Journal of Medicinal Chemistry. 49 (7): 2232–40. doi:10.1021/jm051121i. PMID 16570919.
External links
"Urotensin Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-09.
