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Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology

Molecular Psychiatry volume 15, pages 896–904 (2010)Cite this article

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Abstract

Although the higher incidence of stress-related psychiatric disorders in females is well documented, its basis is unknown. Here, we show that the receptor for corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, signals and is trafficked differently in female rats in a manner that could result in a greater response and decreased adaptation to stressors. Most cellular responses to CRF in the brain are mediated by CRF receptor (CRFr) association with the GTP-binding protein, Gs. Receptor immunoprecipitation studies revealed enhanced CRFr-Gs coupling in cortical tissue of unstressed female rats. Previous stressor exposure abolished this sex difference by increasing CRFr-Gs coupling selectively in males. These molecular results mirrored the effects of sex and stress on sensitivity of locus ceruleus (LC)-norepinephrine neurons to CRF. Differences in CRFr trafficking were also identified that could compromise stress adaptation in females. Specifically, stress-induced CRFr association with β-arrestin2, an integral step in receptor internalization, occurred only in male rats. Immunoelectron microscopy confirmed that stress elicited CRFr internalization in LC neurons of male rats exclusively, consistent with reported electrophysiological evidence for stress-induced desensitization to CRF in males. Together, these studies identified two aspects of CRFr function, increased cellular signaling and compromised internalization, which render CRF-receptive neurons of females more sensitive to low levels of CRF and less adaptable to high levels of CRF. CRFr dysfunction in females may underlie their increased vulnerability to develop stress-related pathology, particularly that related to increased activity of the LC-norepinephrine system, such as depression or post-traumatic stress disorder.

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Acknowledgements

This work was supported by USPHS Grant MH40008 to RJV, and MH014654 and MH084423 to DAB.

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Authors and Affiliations

  1. Department of Anesthesiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    D A Bangasser, A Curtis, T T Bethea & R J Valentino

  2. Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, PA, USA

    B A S Reyes & E J Van Bockstaele

  3. Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    I Parastatidis & H Ischiropoulos

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  1. D A Bangasser
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  2. A Curtis
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  3. B A S Reyes
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Correspondence to D A Bangasser.

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Bangasser, D., Curtis, A., Reyes, B. et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol Psychiatry 15, 896–904 (2010). https://doi.org/10.1038/mp.2010.66

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Keywords

  • stress
  • locus ceruleus
  • norepinephrine
  • corticotropin-releasing hormone
  • depression
  • post-traumatic stress disorder

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