Urocortin

Urocortin is a protein that in humans is encoded by the UCN gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is involved in the mammalian stress response, and regulates aspects of appetite and stress response.[4][5][6]

UCN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2RMF, 3N96
Identifiers
Aliases	UCN, UI, UROC, urocortin
External IDs	OMIM: 600945 MGI: 1276123 HomoloGene: 2515 GeneCards: UCN
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p23.3 Start 27,307,400 bp[1] End 27,308,445 bp[1]
Gene ontology Molecular function • histone deacetylase inhibitor activity • hormone activity • GO:0001948 protein binding • neuropeptide hormone activity • G-protein coupled receptor binding • corticotropin-releasing hormone receptor 1 binding • corticotropin-releasing hormone receptor 2 binding • corticotropin-releasing hormone activity Cellular component • axon terminus • perikaryon • varicosity • axon • dendrite • neuronal cell body • extracellular region • extracellular Biological process • positive regulation of collagen biosynthetic process • G-protein coupled receptor signaling pathway • negative regulation of histone deacetylation • activation of protein kinase A activity • response to estradiol • positive regulation of protein phosphorylation • associative learning • startle response • gastric emptying • negative regulation of blood pressure • female pregnancy • negative regulation of gastric acid secretion • negative regulation of apoptotic process • response to glucocorticoid • sensory perception of sound • pancreatic juice secretion • response to oxidative stress • negative regulation of appetite • positive regulation of translation • negative regulation of gene expression • negative regulation of cell death • positive regulation of peptidyl-serine phosphorylation • positive regulation of DNA replication • aerobic respiration • positive regulation of calcium ion import • positive regulation of cell growth • positive regulation of vascular permeability • positive regulation of gene expression • drinking behavior • response to pain • positive regulation of cardiac muscle contraction • feeding behavior • positive regulation of interleukin-6 production • response to auditory stimulus • learning or memory • social organism behavior • regulation of synaptic transmission, glutamatergic • inflammatory response • neuropeptide signaling pathway • neuron projection development • negative regulation of necrotic cell death • positive regulation of behavioral fear response • negative regulation of cell size • positive regulation of transcription from RNA polymerase II promoter • negative regulation of neuron death • negative regulation of hormone secretion • positive regulation of blood vessel diameter • negative regulation of feeding behavior • regulation of receptor activity • positive regulation of cAMP-mediated signaling • positive regulation of corticotropin secretion • negative regulation of epinephrine secretion • positive regulation of cortisol secretion • negative regulation of glucagon secretion Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7349	22226
Ensembl	ENSG00000163794	n/a
UniProt	P55089	P81615
RefSeq (mRNA)	NM_003353	NM_021290 NM_001346010
RefSeq (protein)	NP_003344	NP_001332939 NP_067265
Location (UCSC)	Chr 2: 27.31 – 27.31 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Structure, localization, and interactions

Urocortin is a peptide composed of 40 amino acids. Urocortin is composed of a single alpha helix structure. The human UCN gene contains two exons, and the entirety of the coding region is contained within the second exon.[7] Urocortin is expressed widely in the central and peripheral nervous systems, with a pattern similar to that of CRF.[8] Areas of similarity between urocortin and CRF expression include the supraoptic nucleus and the hippocampus.[9][10] Urocortin is also expressed in areas distinct from CRF expression; these areas notably include the median eminence, the Edinger-Westphal nucleus, and the sphenoid nucleus.[10] Additionally, Urocortin is expressed in peripheral tissues such as the heart.[11]

Urocortin is known to interact both with the CRF type 1 and CRF type 2 receptors.[12][13][14] Furthermore, Urocortin is thought to be the primary ligand for the CRF type 2 receptor, as it has higher binding affinity for the CRF type 2 receptor than CRF.[12] Additionally, urocortin interacts with CRF Binding Protein in the mammalian brain.[15]

Stress response and social behavior

Urocortin is closely related to CRF, which mediates the mammalian stress response. Urocortin is consequently implicated in a number of stress responses, primarily relating to appetite and food intake. Administration of urocortin to the central nervous system of mice and rats has been shown to decrease appetite.[16] Additionally, central urocortin treatment increases anxiety-linked behaviors and increases motor activity in mice and rats.[16] These general anxiety-linked behaviors are likely induced through the CRF type 1 receptor, and the appetite behaviors are likely induced through the CRF type 2 receptor. The reduction in appetite from urocortin treatment could be a result of suppression of gastric emptying and/or hypoglycemia, which have been shown to result from urocortin treatment.[17] Urocortin expression is stimulated in response to osmotic stress; water deprivation in rats has been shown to induce urocortin expression in the supraoptic nucleus.[18]

Montane Voles and Meadow Voles are closely related species of voles which are regularly studied as a model for social and mating behavior. The distribution of urocortin-expressing neurons differs in meadow voles compared to montane voles, suggesting urocortin may also play a role in modulating social behavior in some species.[19]

Cardiovascular effects

Urocortin has been shown to induce increases in heart rate and coronary blood flow when applied peripherally.[11] These effects are likely mediated through the CRF type 2 receptor, as this receptor is found in the cardiac atria and ventricles.[20] Urocortin also functions to protect cardiovascular tissue from ischemic injury.[21] Urocortin's cardiovascular effects separate it from other members of the CRF family, and likely represent its primary biological function.

In non-mammals

Urocortin is not present in all non-mammals; the closet analogue in teleost fish is urotensin I.[22] However, in amphibian species such as Xenopus laevis, urocortin is expressed in tissues such as brain, pituitary, kidney, heart, and skin. Urocortin in Xenopus has been shown to increase cAMP accumulation and inhibit appetite[22]

References

1. GRCh38: Ensembl release 89: ENSG00000163794 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Zhao L, Donaldson CJ, Smith GW, Vale WW (May 1998). "The structures of the mouse and human urocortin genes (Ucn and UCN)". Genomics. 50 (1): 23–33. doi:10.1006/geno.1998.5292. PMID 9628819.
5. Tsarev OB (July 1977). "[Dynamics of matrix synthesis in molecular biophysics. II. Principle of insertability and the single-valued solution of feedback tasks]". Biofizika. 22 (2): 197–200. PMID 861256.
6. "Entrez Gene: UCN urocortin".
7. Zhao L, Donaldson CJ, Smith GW, Vale WW (May 1998). "The structures of the mouse and human urocortin genes (Ucn and UCN)". Genomics. 50 (1): 23–33. doi:10.1006/geno.1998.5292. PMID 9628819.
8. Furman BL (2007-01-01). "Urocortin". xPharm: The Comprehensive Pharmacology Reference. New York: Elsevier. pp. 1–2. doi:10.1016/B978-008055232-3.62835-1. ISBN 978-0-08-055232-3.
9. Smagin GN, Heinrichs SC, Dunn AJ (2001). "The role of CRH in behavioral responses to stress". Peptides. 22 (5): 713–24. CiteSeerX 10.1.1.337.3880. doi:10.1016/S0196-9781(01)00384-9. PMID 11337084.
10. Morin SM, Ling N, Liu XJ, Kahl SD, Gehlert DR (1999). "Differential distribution of urocortin- and corticotropin-releasing factor-like immunoreactivities in the rat brain". Neuroscience. 92 (1): 281–91. doi:10.1016/S0306-4522(98)00732-5. PMID 10392850.
11. Latchman DS (August 2002). "Urocortin". The International Journal of Biochemistry & Cell Biology. 34 (8): 907–10. doi:10.1016/S1357-2725(02)00011-0. PMID 12007627.
12. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C (November 1995). "Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor". Nature. 378 (6554): 287–92. Bibcode:1995Natur.378..287V. doi:10.1038/378287a0. PMID 7477349.
13. Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology. 36 (10): 1439–46. doi:10.1016/S0028-3908(97)00098-1. PMID 9423932.
14. Donaldson CJ, Sutton SW, Perrin MH, Corrigan AZ, Lewis KA, Rivier JE, Vaughan JM, Vale WW (May 1996). "Cloning and characterization of human urocortin". Endocrinology. 137 (5): 2167–70. doi:10.1210/en.137.5.2167. PMID 8612563.
15. Baigent SM, Lowry PJ (2000). "Urocortin is the principal ligand for the corticotrophin-releasing factor binding protein in the ovine brain with no evidence for a sauvagine-like peptide". Journal of Molecular Endocrinology. 24 (1): 53–63. doi:10.1677/jme.0.0240053. PMID 10656997.
16. Skelton KH, Owens MJ, Nemeroff CB (2000). "The neurobiology of urocortin". Regulatory Peptides. 93 (1–3): 85–92. doi:10.1016/S0167-0115(00)00180-4. PMID 11033056.
17. Stengel A, Taché Y (2014-01-01). "CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress". Frontiers in Neuroscience. 8: 52. doi:10.3389/fnins.2014.00052. PMC 3957495. PMID 24672423.
18. Hara Y, Ueta Y, Isse T, Kabashima N, Shibuya I, Hattori Y, Yamashita H (1997). "Increase of urocortin-like immunoreactivity in the rat supraoptic nucleus after dehydration but not food deprivation". Neuroscience Letters. 229 (1): 65–8. doi:10.1016/S0304-3940(97)00419-9. PMID 9224803.
19. Lim MM, Tsivkovskaia NO, Bai Y, Young LJ, Ryabinin AE (2006-01-01). "Distribution of corticotropin-releasing factor and urocortin 1 in the vole brain". Brain, Behavior and Evolution. 68 (4): 229–40. doi:10.1159/000094360. PMC 1828133. PMID 16816534.
20. Kishimoto T, Pearse RV, Lin CR, Rosenfeld MG (February 1995). "A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle". Proceedings of the National Academy of Sciences of the United States of America. 92 (4): 1108–12. Bibcode:1995PNAS...92.1108K. doi:10.1073/pnas.92.4.1108. PMC 42647. PMID 7755719.
21. Brar BK, Jonassen AK, Stephanou A, Santilli G, Railson J, Knight RA, Yellon DM, Latchman DS (March 2000). "Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway". The Journal of Biological Chemistry. 275 (12): 8508–14. doi:10.1074/jbc.275.12.8508. PMID 10722688.
22. Boorse GC, Crespi EJ, Dautzenberg FM, Denver RJ (November 2005). "Urocortins of the South African clawed frog, Xenopus laevis: conservation of structure and function in tetrapod evolution". Endocrinology. 146 (11): 4851–60. doi:10.1210/en.2005-0497. PMID 16037378.

Further reading

• Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M (March 2004). "Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ". FASEB Journal. 18 (3): 439–56. CiteSeerX 10.1.1.325.45. doi:10.1096/fj.03-0641rev. PMID 15003990.
• Huang Y, Yao XQ, Lau CW, Chan YC, Tsang SY, Chan FL (Mar 2004). "Urocortin and cardiovascular protection". Acta Pharmacol. Sin. 25 (3): 257–65. PMID 15000874.
• Takahashi, Kazuhiro (2004). "Translational medicine in fish-derived peptides: From fish endocrinology to human physiology and diseases". Endocrine Journal. 51 (1): 1–17. doi:10.1507/endocrj.51.1. PMID 15004403.
• Adachi T, Schamel WW, Kim KM, Watanabe T, Becker B, Nielsen PJ, Reth M (April 1996). "The specificity of association of the IgD molecule with the accessory proteins BAP31/BAP29 lies in the IgD transmembrane sequence". The EMBO Journal. 15 (7): 1534–41. doi:10.1002/j.1460-2075.1996.tb00497.x. PMC 450061. PMID 8612576.
• Iino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Totsune K, Takahashi K, Suzuki H, Nagura H, Yoshimi T (November 1997). "Urocortin expression in human pituitary gland and pituitary adenoma". The Journal of Clinical Endocrinology and Metabolism. 82 (11): 3842–50. doi:10.1210/jc.82.11.3842. PMID 9360550.
• Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology. 36 (10): 1439–46. doi:10.1016/S0028-3908(97)00098-1. PMID 9423932.
• Bamberger CM, Wald M, Bamberger AM, Ergün S, Beil FU, Schulte HM (February 1998). "Human lymphocytes produce urocortin, but not corticotropin-releasing hormone". The Journal of Clinical Endocrinology and Metabolism. 83 (2): 708–11. doi:10.1210/jc.83.2.708. PMID 9467598.
• Takahashi K, Totsune K, Sone M, Murakami O, Satoh F, Arihara Z, Sasano H, Iino K, Mouri T (1998). "Regional distribution of urocortin-like immunoreactivity and expression of urocortin mRNA in the human brain". Peptides. 19 (4): 643–7. doi:10.1016/S0196-9781(98)00012-6. PMID 9622018.
• Iino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Takahashi K, Suzuki H, Tezuka F, Yoshimi T, Nagura H (January 1999). "Urocortin expression in the human central nervous system". Clinical Endocrinology. 50 (1): 107–14. doi:10.1046/j.1365-2265.1999.00624.x. PMID 10341863.
• Watanabe F, Oki Y, Ozawa M, Masuzawa M, Iwabuchi M, Yoshimi T, Nishiguchi T, Iino K, Sasano H (1999). "Urocortin in human placenta and maternal plasma". Peptides. 20 (2): 205–9. doi:10.1016/S0196-9781(98)00175-2. PMID 10422876.
• Slominski A, Roloff B, Curry J, Dahiya M, Szczesniewski A, Wortsman J (February 2000). "The skin produces urocortin". The Journal of Clinical Endocrinology and Metabolism. 85 (2): 815–23. doi:10.1210/jc.85.2.815. PMID 10690896.
• Muramatsu Y, Fukushima K, Iino K, Totsune K, Takahashi K, Suzuki T, Hirasawa G, Takeyama J, Ito M, Nose M, Tashiro A, Hongo M, Oki Y, Nagura H, Sasano H (December 2000). "Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa". Peptides. 21 (12): 1799–809. doi:10.1016/S0196-9781(00)00335-1. PMID 11150640.
• Muramatsu Y, Sugino N, Suzuki T, Totsune K, Takahashi K, Tashiro A, Hongo M, Oki Y, Sasano H (March 2001). "Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries". The Journal of Clinical Endocrinology and Metabolism. 86 (3): 1362–9. doi:10.1210/jc.86.3.1362. PMID 11238533.
• Hsu SY, Hsueh AJ (May 2001). "Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor". Nature Medicine. 7 (5): 605–11. doi:10.1038/87936. PMID 11329063.
• Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW (June 2001). "Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor". Proceedings of the National Academy of Sciences of the United States of America. 98 (13): 7570–5. Bibcode:2001PNAS...98.7570L. doi:10.1073/pnas.121165198. PMC 34709. PMID 11416224.
• Kimura Y, Takahashi K, Totsune K, Muramatsu Y, Kaneko C, Darnel AD, Suzuki T, Ebina M, Nukiwa T, Sasano H (January 2002). "Expression of urocortin and corticotropin-releasing factor receptor subtypes in the human heart". The Journal of Clinical Endocrinology and Metabolism. 87 (1): 340–6. doi:10.1210/jc.87.1.340. PMID 11788672.
• Florio P, Arcuri F, Ciarmela P, Runci Y, Romagnoli R, Cintorino M, Di Blasio AM, Petraglia F (May 2002). "Identification of urocortin mRNA and peptide in the human endometrium". The Journal of Endocrinology. 173 (2): R9–14. doi:10.1677/joe.0.173R009. PMID 12010647.
• Arcuri F, Cintorino M, Florio P, Floccari F, Pergola L, Romagnoli R, Petraglia F, Tosi P, Teresa Del Vecchio M (August 2002). "Expression of urocortin mRNA and peptide in the human prostate and in prostatic adenocarcinoma". The Prostate. 52 (3): 167–72. doi:10.1002/pros.10094. PMID 12111693.
• Ikeda K, Tojo K, Oki Y, Nakao K (September 2002). "Urocortin has cell-proliferative effects on cardiac non-myocytes". Life Sciences. 71 (16): 1929–38. doi:10.1016/S0024-3205(02)01945-8. PMID 12175707.

External links

• Overview of all the structural information available in the PDB for UniProt: P55089 (Urocortin) at the PDBe-KB.