Urocortin Explained

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.^{[1] [2] [3]}

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.^[1] Urocortin is expressed widely in the central and peripheral nervous systems, with a pattern similar to that of CRF.^[4] Areas of similarity between urocortin and CRF expression include the supraoptic nucleus and the hippocampus.^{[5] [6]} 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. Additionally, Urocortin is expressed in peripheral tissues such as the heart.^[7]

Urocortin is known to interact both with the CRF type 1 and CRF type 2 receptors.^{[8] [9] [10]} 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. Additionally, urocortin interacts with CRF Binding Protein in the mammalian brain.^[11]

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.^[12] Additionally, central urocortin treatment increases anxiety-linked behaviors and increases motor activity in mice and rats. 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.^[13] Urocortin expression is stimulated in response to osmotic stress; water deprivation in rats has been shown to induce urocortin expression in the supraoptic nucleus.^[14]

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.^[15]

Cardiovascular effects

Urocortin has been shown to induce increases in heart rate and coronary blood flow when applied peripherally. These effects are likely mediated through the CRF type 2 receptor, as this receptor is found in the cardiac atria and ventricles.^[16] Urocortin also functions to protect cardiovascular tissue from ischemic injury.^[17] 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.^[18] 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

Further reading

• Inui A, Asakawa A, Bowers CY, Mantovani G, Laviano A, Meguid MM, Fujimiya M . Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ . FASEB Journal . 18 . 3 . 439–56 . March 2004 . 15003990 . 10.1096/fj.03-0641rev . free . 10.1.1.325.45 . 15642270 .
• 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 . 15000874 .
• Takahashi, Kazuhiro . 2004 . Translational medicine in fish-derived peptides: From fish endocrinology to human physiology and diseases . Endocrine Journal. 51 . 1. 1–17 . 10.1507/endocrj.51.1. 15004403 . free .
• Adachi T, Schamel WW, Kim KM, Watanabe T, Becker B, Nielsen PJ, Reth M . 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 . April 1996 . 8612576 . 450061 . 10.1002/j.1460-2075.1996.tb00497.x.
• Iino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Totsune K, Takahashi K, Suzuki H, Nagura H, Yoshimi T . Urocortin expression in human pituitary gland and pituitary adenoma . The Journal of Clinical Endocrinology and Metabolism . 82 . 11 . 3842–50 . November 1997 . 9360550 . 10.1210/jc.82.11.3842 . free . 10271/1571 . free .
• Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ . Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin . Neuropharmacology . 36 . 10 . 1439–46 . October 1997 . 9423932 . 10.1016/S0028-3908(97)00098-1 . 6235036 .
• Bamberger CM, Wald M, Bamberger AM, Ergün S, Beil FU, Schulte HM . Human lymphocytes produce urocortin, but not corticotropin-releasing hormone . The Journal of Clinical Endocrinology and Metabolism . 83 . 2 . 708–11 . February 1998 . 9467598 . 10.1210/jcem.83.2.4693 . free .
• Takahashi K, Totsune K, Sone M, Murakami O, Satoh F, Arihara Z, Sasano H, Iino K, Mouri T . Regional distribution of urocortin-like immunoreactivity and expression of urocortin mRNA in the human brain . Peptides . 19 . 4 . 643–7 . 1998 . 9622018 . 10.1016/S0196-9781(98)00012-6 . 45625371 .
• Iino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Takahashi K, Suzuki H, Tezuka F, Yoshimi T, Nagura H . Urocortin expression in the human central nervous system . Clinical Endocrinology . 50 . 1 . 107–14 . January 1999 . 10341863 . 10.1046/j.1365-2265.1999.00624.x . 29828148 .
• Watanabe F, Oki Y, Ozawa M, Masuzawa M, Iwabuchi M, Yoshimi T, Nishiguchi T, Iino K, Sasano H . Urocortin in human placenta and maternal plasma . Peptides . 20 . 2 . 205–9 . 1999 . 10422876 . 10.1016/S0196-9781(98)00175-2 . 40604220 .
• Slominski A, Roloff B, Curry J, Dahiya M, Szczesniewski A, Wortsman J . The skin produces urocortin . The Journal of Clinical Endocrinology and Metabolism . 85 . 2 . 815–23 . February 2000 . 10.1210/jcem.85.2.6381 . 10690896 . free .
• 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 . Urocortin and corticotropin-releasing factor receptor expression in the human colonic mucosa . Peptides . 21 . 12 . 1799–809 . December 2000 . 11150640 . 10.1016/S0196-9781(00)00335-1 . 561707 .
• Muramatsu Y, Sugino N, Suzuki T, Totsune K, Takahashi K, Tashiro A, Hongo M, Oki Y, Sasano H . Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries . The Journal of Clinical Endocrinology and Metabolism . 86 . 3 . 1362–9 . March 2001 . 10.1210/jcem.86.3.7299 . 11238533 . free .
• Hsu SY, Hsueh AJ . Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor . Nature Medicine . 7 . 5 . 605–11 . May 2001 . 11329063 . 10.1038/87936 . 22916906 .
• 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 . 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 . June 2001 . 11416224 . 34709 . 10.1073/pnas.121165198 . 2001PNAS...98.7570L . free .
• Kimura Y, Takahashi K, Totsune K, Muramatsu Y, Kaneko C, Darnel AD, Suzuki T, Ebina M, Nukiwa T, Sasano H . Expression of urocortin and corticotropin-releasing factor receptor subtypes in the human heart . The Journal of Clinical Endocrinology and Metabolism . 87 . 1 . 340–6 . January 2002 . 11788672 . 10.1210/jcem.87.1.8160 . free .
• Florio P, Arcuri F, Ciarmela P, Runci Y, Romagnoli R, Cintorino M, Di Blasio AM, Petraglia F . Identification of urocortin mRNA and peptide in the human endometrium . The Journal of Endocrinology . 173 . 2 . R9–14 . May 2002 . 12010647 . 10.1677/joe.0.173R009 . free .
• Arcuri F, Cintorino M, Florio P, Floccari F, Pergola L, Romagnoli R, Petraglia F, Tosi P, Teresa Del Vecchio M . Expression of urocortin mRNA and peptide in the human prostate and in prostatic adenocarcinoma . The Prostate . 52 . 3 . 167–72 . August 2002 . 12111693 . 10.1002/pros.10094 . 29785784 .
• Ikeda K, Tojo K, Oki Y, Nakao K . Urocortin has cell-proliferative effects on cardiac non-myocytes . Life Sciences . 71 . 16 . 1929–38 . September 2002 . 12175707 . 10.1016/S0024-3205(02)01945-8 .

Notes and References

1. Zhao L, Donaldson CJ, Smith GW, Vale WW . The structures of the mouse and human urocortin genes (Ucn and UCN) . Genomics . 50 . 1 . 23–33 . May 1998 . 9628819 . 10.1006/geno.1998.5292 .
2. Tsarev OB . [Dynamics of matrix synthesis in molecular biophysics. II. Principle of insertability and the single-valued solution of feedback tasks] . Biofizika . 22 . 2 . 197–200 . July 1977 . 861256 .
3. Web site: Entrez Gene: UCN urocortin.
4. Book: Furman, Brian L. . 10.1016/B978-008055232-3.62835-1 . XPharm: The Comprehensive Pharmacology Reference . vanc . 2007-01-01 . Elsevier . 978-0-08-055232-3 . New York . 1–2 . Urocortin .
5. Smagin GN, Heinrichs SC, Dunn AJ . The role of CRH in behavioral responses to stress . Peptides . 22 . 5 . 713–24 . 2001 . 11337084 . 10.1016/S0196-9781(01)00384-9 . 10.1.1.337.3880 . 15756279 .
6. Morin SM, Ling N, Liu XJ, Kahl SD, Gehlert DR . Differential distribution of urocortin- and corticotropin-releasing factor-like immunoreactivities in the rat brain . Neuroscience . 92 . 1 . 281–91 . 1999 . 10392850 . 10.1016/S0306-4522(98)00732-5 . 33000632 .
7. Latchman DS . Urocortin . The International Journal of Biochemistry & Cell Biology . 34 . 8 . 907–10 . August 2002 . 12007627 . 10.1016/S1357-2725(02)00011-0 .
8. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, Rivier C . Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor . Nature . 378 . 6554 . 287–92 . November 1995 . 7477349 . 10.1038/378287a0 . 1995Natur.378..287V . 4373077 .
9. Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ . Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin . Neuropharmacology . 36 . 10 . 1439–46 . October 1997 . 9423932 . 10.1016/S0028-3908(97)00098-1 . 6235036 .
10. Donaldson CJ, Sutton SW, Perrin MH, Corrigan AZ, Lewis KA, Rivier JE, Vaughan JM, Vale WW . Cloning and characterization of human urocortin . Endocrinology . 137 . 5 . 2167–70 . May 1996 . 8612563 . 10.1210/endo.137.5.8612563 . free .
11. Baigent SM, Lowry PJ . 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 . 2000 . 10656997 . 10.1677/jme.0.0240053 . free .
12. Skelton KH, Owens MJ, Nemeroff CB . The neurobiology of urocortin . Regulatory Peptides . 93 . 1–3 . 85–92 . 2000 . 11033056 . 10.1016/S0167-0115(00)00180-4 . 34797789 .
13. Stengel A, Taché Y . CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress . Frontiers in Neuroscience . 8 . 52 . 2014-01-01 . 24672423 . 3957495 . 10.3389/fnins.2014.00052 . free .
14. Hara Y, Ueta Y, Isse T, Kabashima N, Shibuya I, Hattori Y, Yamashita H . Increase of urocortin-like immunoreactivity in the rat supraoptic nucleus after dehydration but not food deprivation . Neuroscience Letters . 229 . 1 . 65–8 . 1997 . 9224803 . 10.1016/S0304-3940(97)00419-9 . 6006767 .
15. Lim MM, Tsivkovskaia NO, Bai Y, Young LJ, Ryabinin AE . Distribution of corticotropin-releasing factor and urocortin 1 in the vole brain . Brain, Behavior and Evolution . 68 . 4 . 229–40 . 2006-01-01 . 16816534 . 1828133 . 10.1159/000094360 .
16. Kishimoto T, Pearse RV, Lin CR, Rosenfeld MG . 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 . February 1995 . 7755719 . 42647 . 10.1073/pnas.92.4.1108 . 1995PNAS...92.1108K . free .
17. Brar BK, Jonassen AK, Stephanou A, Santilli G, Railson J, Knight RA, Yellon DM, Latchman DS . Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway . The Journal of Biological Chemistry . 275 . 12 . 8508–14 . March 2000 . 10722688 . 10.1074/jbc.275.12.8508 . free .
18. Boorse GC, Crespi EJ, Dautzenberg FM, Denver RJ . Urocortins of the South African clawed frog, Xenopus laevis: conservation of structure and function in tetrapod evolution . Endocrinology . 146 . 11 . 4851–60 . November 2005 . 16037378 . 10.1210/en.2005-0497 . free .