Letter | Published:

Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2

Nature Genetics volume 24, pages 415419 (2000) | Download Citation

Subjects

Abstract

Corticotropin-releasing hormone1,2 (Crh), a 41-residue polypeptide, activates two G-protein–coupled receptors, Crhr1 (refs 3,​4,​5) and Crhr2 (refs 6,​7,​8,​9), causing (among other transductional events) phosphorylation of the transcription factor Creb (ref. 10). The physiologic role of these receptors is only partially understood. Here we report that male, but not female, Crhr2-deficient mice exhibit enhanced anxious behaviour in several tests of anxiety in contrast to mice lacking Crhr1 (refs 11,12). The enhanced anxiety of Crhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific brain regions involved in emotional and autonomic function, as monitored by a reduction of Creb phosphorylation in male, but not female, Crhr2−/− mice. We propose that Crhr2 predominantly mediates a central anxiolytic response, opposing the general anxiogenic effect of Crh mediated by Crhr1. Neither male nor female Crhr2-deficient mice show alterations of baseline feeding behaviour. Both respond with increased edema formation in response to thermal exposure, however, indicating that in contrast to its central role in anxiety, the peripheral role of Crhr2 in vascular permeability is independent of gender.

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.

    , , & Primary structure of corticotropin-releasing factor from ovine hypothalamus. Proc. Natl Acad. Sci. USA 78, 6517–6521 (1981).

  2. 2.

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

  3. 3.

    , , & Identification of a seven transmembrane helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain. Neuron 11, 1187–1195 (1993).

  4. 4.

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

  5. 5.

    et al. Primary structure and functional expression of mouse pituitary and human brain corticotrophin releasing factor receptors. FEBS Lett. 335, 1–5 (1993).

  6. 6.

    , , & A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle. Proc. Natl Acad. Sci. USA 92, 1108–1112 (1995).

  7. 7.

    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).

  8. 8.

    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).

  9. 9.

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

  10. 10.

    , , , & Corticotropin-releasing factor type 1 and type 2α receptors regulate phosphorylation of calcium/cyclic adenosine 3′,5′-monophosphate response element-binding protein and activation of p42/p44 mitogen-activated protein kinase. Endocrinology 140, 1525–1536 (1999).

  11. 11.

    et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nature Genet. 19, 162–166 (1998).

  12. 12.

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

  13. 13.

    , & 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).

  14. 14.

    & The hippocampus and amygdala mediate the locomotor stimulating effects of corticotropin-releasing factor in mice. Behav. Neural Biol. 51, 412–423 (1989).

  15. 15.

    , , , & Structural requirements for peptidic antagonists of the corticotropin-releasing factor receptor (CRFR): development of CRFR2β-selective antisauvagine-30. Proc. Natl Acad. Sci. USA 95, 15264–15269 (1998).

  16. 16.

    , , , & Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J. Neurosci. 14, 2579–2584 (1994).

  17. 17.

    , , , & CRF antagonist reverses the ‘anxiogenic’ response to ethanol withdrawal in the rat. Psychopharmacology 103, 227–232 (1991).

  18. 18.

    , & Fluctuations in responses to diazepam during the oestrus cycle in the mouse. Pharmacol. Biochem. Behav. 41, 719–725 (1992).

  19. 19.

    , , , & The anxiolytics CI-988 and chlordiazepoxide fail to reduce immediate early gene mRNA stimulation following exposure to the rat elevated X-maze. Eur. J. Pharmacol. 312, 153–161 (1996).

  20. 20.

    , & Relationship between FOS production and classical fear conditioning: effects of novelty, latent inhibition and unconditioned stimulus preexposure. J. Neurosci. 18, 7452–7461 (1998).

  21. 21.

    Corticotropin-releasing factor: endocrine and autonomic integration of responses to stress. Trends Pharmacol. Sci. 10, 189–193 (1989).

  22. 22.

    , & Urocortin, a corticotropin-releasing factor-related mammalian peptide, inhibits edema due to thermal injury in rats. Eur. J. Pharmacol. 303, 213–216 (1996).

  23. 23.

    Reflex-ontogeny and behavioural development of the mouse. Animal Behav. 13, 234–264 (1965).

  24. 24.

    The oestrus cycle in the mouse. Am. J. Anat. 30, 297–371, 1922.

  25. 25.

    The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92, 180–185 (1987).

  26. 26.

    & Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol. Biochem. Behav. 52, 297–303 (1995).

  27. 27.

    , , & Corticotropin-releasing factor modulates defensive-withrawal and exploratory behavior in rats. Behav. Neurosci. 103, 645–654.

  28. 28.

    , , & Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J. Neurosci. 15, 5016–5025 (1999).

  29. 29.

    & Correlation of neuroendocrine and anti-edema activities of alanine-corticotropin-releasing factor analogs. Eur. J. Pharmacol. 263, 319–321 (1994).

Download references

Acknowledgements

We thank M. Ayers, M. Fisher, C. Todorovic, K. Eckart, T. Liepold and A. Burgdorf for discussions and assistance. O.H. is supported by the Swedish Brain Foundation. M.G.R. is an investigator with the Howard Hughes Medical Institute. This work is supported by NIH grants to M.G.R. and MPG funds to J.S.

Author information

Author notes

    • Toshimitsu Kishimoto

    Present address: Yoshitomi Pharmaceutical Ind. Ltd, Oosaka Laboratories, 2-25-1 Shodai-Ootan, Hirakata City, Oosaka, Japan

    • Toshimitsu Kishimoto
    •  & Jelena Radulovic

    These authors contributed equally to this work.

Affiliations

  1. Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, California, USA

    • Toshimitsu Kishimoto
    • , Chijen R. Lin
    • , Farideh Hooshmand
    • , Ola Hermanson
    •  & Michael G. Rosenfeld
  2. Max Planck Institute for Experimental Medicine, Department for Molecular Neuroendocrinology, Goettingen, Germany

    • Jelena Radulovic
    • , Marko Radulovic
    • , Christina Schrick
    •  & Joachim Spiess

Authors

  1. Search for Toshimitsu Kishimoto in:

  2. Search for Jelena Radulovic in:

  3. Search for Marko Radulovic in:

  4. Search for Chijen R. Lin in:

  5. Search for Christina Schrick in:

  6. Search for Farideh Hooshmand in:

  7. Search for Ola Hermanson in:

  8. Search for Michael G. Rosenfeld in:

  9. Search for Joachim Spiess in:

Corresponding authors

Correspondence to Marko Radulovic or Michael G. Rosenfeld or Joachim Spiess.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/74271

Further reading