Letter | Published:

Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2

Nature Genetics volume 24, pages 403409 (2000) | Download Citation

Subjects

Abstract

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine1 and behavioural responses to stress2, and the related hormone urocortin3 (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2 (refs 4,5). These receptors may exhibit distinct functions due to unique tissue distribution6 and pharmacology4,5. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses7,8. Here we generate Crhr2−/− mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2−/− mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2−/− mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2–/– mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2−/− mice following Ucn, but Crhr2−/− mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2−/− mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2−/− mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and β-endorphin. Science 213, 1394–1397 (1981).

  2. 2.

    , , , & Corticotropin-releasing factor produces fear-enhancing behavioral activation in rats. J. Neurosci. 10, 176–183 (1982).

  3. 3.

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

  4. 4.

    et al. Identification of a novel murine receptor for corticotropin-releasing hormone expressed in the heart. Mol. Endocrinol. 9, 637–645 (1995).

  5. 5.

    , , & Expression cloning of a human corticotropin-releasing-factor receptor. Proc. Natl Acad. Sci. USA 90, 8967–8971 (1993).

  6. 6.

    , & Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. J. Neurosci. 15, 6340–6350 (1995).

  7. 7.

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

  8. 8.

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

  9. 9.

    , , , & Corticotropin-releasing hormone receptor expression and functional coupling in neonatal cardiac myocytes and AT-1 cells. Endocrinology 137, 3631–3639 (1996).

  10. 10.

    , , , & Corticotropin-releasing factor activates c-fos, NGFI-B, and corticotropin-releasing factor gene expression within the paraventricular nucleus of the rat hypothalamus. Mol. Endo. 7, 1357–1367 (1993).

  11. 11.

    , , & Ultrashort-loop positive feedback of corticotropin (ACTH)-releasing factor to enhance ACTH release in stress. Proc. Natl Acad. Sci. USA 82, 3528–3531 (1985).

  12. 12.

    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).

  13. 13.

    , , , & Differential behavioral effects of chronic infusion of CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain. J. Psychiatr. Res. 33, 153–163 (1999).

  14. 14.

    , & Ethology and neurobiology of grooming behavior. Physiol. Rev. 72, 825–852 (1992).

  15. 15.

    Stress, adaptation and disease: allostasis and allostatic load. Ann. NY Acad. Sci. 840, 33–44 (1998).

  16. 16.

    et al. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 273, 1561–1564 (1996).

  17. 17.

    , , , & Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats. Am. J. Physiol. 255, E255–E259 (1988).

  18. 18.

    , & & Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383 (1998).

  19. 19.

    & Differentiated hemodynamic responses to central versus peripheral administration of corticotropin-releasing factor in conscious rats. J. Auton. Nerv. Syst. 35, 43–52 (1991).

  20. 20.

    et al. Expression and protective effects of urocortin in cardiac myocytes. Neuropeptides 32, 167–171 (1998).

  21. 21.

    et al. Dilatory and inotropic effects of corticotropin-releasing factor (CRF) on the isolated heart. Horm. Metab. Res. 24, 56–59 (1992).

  22. 22.

    , , , & Cardiac inotropic actions of urocortin in conscious sheep. Am. J. Physiol. 272, H2115–H2122 (1997).

  23. 23.

    et al. Evalulation of ventricular and arterial hemodynamics in anesthetized closed-chest mice. J. Am. Soc. Echocardiogr. 10, 915–925 (1997).

  24. 24.

    & Cardiovascular and respiratory actions of desflurane: is desflurane different from isoflurane? Anesth. Analg. 75 (suppl.), S17–29 (1992).

  25. 25.

    , , & β-Adrenergic regulation of contractility and protein phosphorylation in spontaneously beating isolated rat myocardial cells. J. Biochem. 102, 211–224 (1987).

  26. 26.

    & The Mouse Brain in Stereotaxic Coordinates (Academic Press, San Diego, 1997).

  27. 27.

    , & Hormonal regulation of glutamate receptor gene expression in the anteroventral periventricular nucleus of the hypothalamus. J. Neurosci. 19, 3213–3222 (1999).

  28. 28.

    et al. Lysis of adult ventricular myocytes by cells infiltrating rejecting murine cardiac allografts. Circulation 93, 111–119 (1996).

  29. 29.

    et al. Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J. Biol. Chem. 268, 11617–11621 (1993).

Download references

Acknowledgements

We thank K. Lee and A. Contarino for discussing relevant and unpublished data; and J. Auld, W. Yeung and Q. Yue for assistance. This work was supported by National Institute of Health grants HL55512 (M.P.S.-P.), HL45043 (A.R.H.), HD30236 (M.J.L.), 2T32EY07123 (K.A.H.), AI14985 (M.B.R.) and an American Heart Association Fellowship (S.C.C.).

Author information

Author notes

    • Sarah C. Coste
    •  & Robert A. Kesterson

    These authors contributed equally to this work.

Affiliations

  1. Departments of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, Oregon, USA

    • Sarah C. Coste
    • , Kurt A. Heldwein
    • , Susan L. Stevens
    • , Amanda D. Heard
    • , Jacob H. Hollis
    • , Susan E. Murray
    • , Jennifer K. Hill
    • , Marvin B. Rittenberg
    •  & Mary P. Stenzel-Poore
  2. Departments of Medicine, Oregon Health Sciences University, Portland, Oregon, USA

    • George A. Pantely
  3. Departments of Obstetrics and Physiology, Oregon Health Sciences University, Portland, Oregon, USA

    • Alan R. Hohimer
  4. Departments of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon, USA

    • Daniel C. Hatton
    • , Tamara J. Phillips
    •  & Deborah A. Finn
  5. Departments of Pathology, Oregon Health Sciences University, Portland, Oregon, USA

    • Peter Stenzel
  6. Departments of Vollum Institute, Oregon Health Sciences University, Portland, Oregon, USA

    • Malcolm J. Low
  7. Departments of Congenital Heart Research Center, Oregon Health Sciences University, Portland, Oregon, USA

    • George A. Pantely
    • , Alan R. Hohimer
    • , Daniel C. Hatton
    • , Peter Stenzel
    •  & Mary P. Stenzel-Poore
  8. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    • Robert A. Kesterson
  9. Department of Veterans Affairs Medical Center, Portland, Oregon, USA

    • Tamara J. Phillips

Authors

  1. Search for Sarah C. Coste in:

  2. Search for Robert A. Kesterson in:

  3. Search for Kurt A. Heldwein in:

  4. Search for Susan L. Stevens in:

  5. Search for Amanda D. Heard in:

  6. Search for Jacob H. Hollis in:

  7. Search for Susan E. Murray in:

  8. Search for Jennifer K. Hill in:

  9. Search for George A. Pantely in:

  10. Search for Alan R. Hohimer in:

  11. Search for Daniel C. Hatton in:

  12. Search for Tamara J. Phillips in:

  13. Search for Deborah A. Finn in:

  14. Search for Malcolm J. Low in:

  15. Search for Marvin B. Rittenberg in:

  16. Search for Peter Stenzel in:

  17. Search for Mary P. Stenzel-Poore in:

Corresponding author

Correspondence to Mary P. Stenzel-Poore.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/74255

Further reading