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Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor

Abstract

Adaptive stress responses mediated by the endocrine, autonomic, cardiovascular and immune systems are essential for the survival of the individual. Initial stress-induced responses provide a vital short-term metabolic lift, but prolonged or inappropriate exposure to stress can compromise homeostasis thereby leading to disease. This 'fight-or-flight' response is characterized by the activation of the corticotropin-releasing hormone (CRH)–adrenocorticotropin–glucocorticoid axis, mediated by the type 1 CRH receptor. In contrast, the type 2 CRH receptor mediates the stress-coping responses during the recovery phase of stress. We identified human stresscopin (SCP) and stresscopin-related peptide (SRP) as specific ligands for the type 2 CRH receptor. The genes encoding these peptides were expressed in diverse peripheral tissues as well as in the central nervous system. Treatment with SCP or SRP suppressed food intake, delayed gastric emptying and decreased heat-induced edema. Thus SCP and SRP might represent endogenous ligands for maintaining homeostasis after stress, and could allow the design of drugs to ameliorate stress-related diseases.

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Figure 1: Sequences and evolution of SCP and related polypeptides.
Figure 2: Expression of SCP and SRP transcripts in human tissues.
Figure 3: Immunohistochemical localization of SCP and SRP in mouse tissues.
Figure 4: Human SCP and SRP preferentially activate CRHR2.
Figure 5: Selective activation of CRHR2 by N-terminal variants of SRP and ligand-receptor interactions between CRHR2 and CRH family members.
Figure 6: Pharmacological actions of stresscopin peptides.

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References

  1. Seyle, H. Stress and disease. Science 122, 625–631 (1955).

    Article  Google Scholar 

  2. Spiess, J., Rivier, J., Rivier, C. & Vale, W. Primary structure of corticotropin-releasing factor from ovine hypothalamus. Proc. Natl. Acad. Sci. USA 78, 6517–6521 (1981).

    Article  CAS  Google Scholar 

  3. Chen, R., Lewis, K.A., Perrin, M.H. & Vale, W.W. Expression cloning of a human corticotropin-releasing-factor receptor. Proc. Natl. Acad. Sci. USA 90, 8967–8971 (1993).

    Article  CAS  Google Scholar 

  4. Perrin, M.H. & Vale, W.W. Corticotropin releasing factor receptors and their ligand family. Ann. NY Acad. Sci. 885, 312–328 (1999).

    Article  CAS  Google Scholar 

  5. Weninger, S.C. et al. Stress-induced behaviors require the corticotropin-releasing hormone (CRH) receptor, but not CRH. Proc. Natl. Acad. Sci. USA 96, 8283–8288 (1999).

    Article  CAS  Google Scholar 

  6. Vaughan, J. et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 378, 287–292 (1995).

    Article  CAS  Google Scholar 

  7. Smith, G.W. et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20, 1093–1102 (1998).

    Article  CAS  Google Scholar 

  8. Timpl, P. et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor. Nature Genet. 19, 162–166 (1998).

    Article  CAS  Google Scholar 

  9. Bale, T.L. et al. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nature Genet. 24, 410–414 (2000).

    Article  CAS  Google Scholar 

  10. Kishimoto, T. et al. Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nature Genet. 24, 415–419 (2000).

    Article  CAS  Google Scholar 

  11. Coste, S.C. et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nature Genet. 24, 403–409 (2000).

    Article  CAS  Google Scholar 

  12. Brar, B.K. et al. Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. J. Biol. Chem. 275, 8508–8514 (2000).

    Article  CAS  Google Scholar 

  13. Bittencourt, J.C. et al. Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors. J. Comp. Neurol. 415, 285–312 (1999).

    Article  CAS  Google Scholar 

  14. Lau, S.H., Rivier, J., Vale, W., Kaiser, E.T. & Kezdy, F.J. Surface properties of an amphiphilic peptide hormone and of its analog: corticotropin-releasing factor and sauvagine. Proc. Natl. Acad. Sci. USA 80, 7070–7074 (1983).

    Article  CAS  Google Scholar 

  15. Reyes, T.M. et al. Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc. Natl. Acad. Sci. USA 98, 2843–2848. (2001).

    Article  CAS  Google Scholar 

  16. Brunner, B. et al. Molecular cloning and characterization of the Fugu rubripes MEST/COPG2 imprinting cluster and chromosomal localization in Fugu and Tetraodon nigroviridis. Chromosome Res. 8, 465–476 (2000).

    Article  CAS  Google Scholar 

  17. Perrin, M. et al. Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc. Natl. Acad. Sci. USA 92, 2969–2973 (1995).

    Article  CAS  Google Scholar 

  18. Lovenberg, T.W. et al. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc. Natl. Acad. Sci. USA 92, 836–840 (1995).

    Article  CAS  Google Scholar 

  19. Hauger, R.L., Dautzenberg, F.M., Flaccus, A., Liepold, T. & Spiess, J. Regulation of corticotropin-releasing factor receptor function in human Y-79 retinoblastoma cells: rapid and reversible homologous desensitization but prolonged recovery. J. Neurochem. 68, 2308–2316 (1997).

    Article  CAS  Google Scholar 

  20. Kageyama, K., Gaudriault, G.E., Bradbury, M.J. & Vale, W.W. Regulation of corticotropin-releasing factor receptor type 2 beta messenger ribonucleic acid in the rat cardiovascular system by urocortin, glucocorticoids, and cytokines. Endocrinology 141, 2285–2293 (2000).

    Article  CAS  Google Scholar 

  21. Turnbull, A.V., Vale, W. & Rivier, C. Urocortin, a corticotropin-releasing factor-related mammalian peptide, inhibits edema due to thermal injury in rats. Eur. J. Pharmacol. 303, 213–216 (1996).

    Article  CAS  Google Scholar 

  22. Heinrichs, S.C. & Richard, D. The role of corticotropin-releasing factor and urocortin in the modulation of ingestive behavior. Neuropeptides 33, 350–359 (1999).

    Article  CAS  Google Scholar 

  23. Nozu, T., Martinez, V., Rivier, J. & Tache, Y. Peripheral urocortin delays gastric emptying: role of CRF receptor 2. Am. J. Physiol. 276, G867–874 (1999).

    CAS  PubMed  Google Scholar 

  24. Asakawa, A. et al. Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice. Gastroenterology 116, 1287–1292 (1999).

    Article  CAS  Google Scholar 

  25. Chrousos, G.P. Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann. NY Acad. Sci. 851, 311–335 (1998).

    Article  CAS  Google Scholar 

  26. Selye, H. The general adaptation syndrome and the diseases of adaptation. J. Clin. Endocrinol. 6, 117–230 (1946).

    Article  CAS  Google Scholar 

  27. Hsu, S.Y. Cloning of two novel mammalian paralogs of relaxin/insulin family proteins and their expression in testis and kidney. Mol. Endocrinol. 13, 2163–2174. (1999).

    Article  CAS  Google Scholar 

  28. Hsueh, A.J., Erickson, G.F. & Yen, S.S. Sensitisation of pituitary cells to luteinising hormone releasing hormone by clomiphene citrate in vitro. Nature 273, 57–59 (1978).

    Article  CAS  Google Scholar 

  29. Hsu, S.Y., Liang, S.G. & Hsueh, A.J. Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol. Endocrinol. 12, 1830–1845 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. Klein, C. Spencer and A. Sanchez for technical and editorial assistance; and A. Payne and B. Kobilka for comments on the manuscript.

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Correspondence to Sheau Yu Hsu.

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Hsu, S., Hsueh, A. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 7, 605–611 (2001). https://doi.org/10.1038/87936

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