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Molecular Pharmacology

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Rapid CommunicationMinireview—Special Issue in Memory of Avram Goldstein

Sex-Biased Stress Signaling: The Corticotropin-Releasing Factor Receptor as a Model

Rita J. Valentino, Debra Bangasser and Elisabeth J. Van Bockstaele
Molecular Pharmacology April 2013, 83 (4) 737-745; DOI: https://doi.org/10.1124/mol.112.083550
Rita J. Valentino
The Children’s Hospital of Philadelphia (R.J.V.), Temple University (D.B.), and Thomas Jefferson University School of Medicine (E.J.V.), Philadelphia, Pennsylvania
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Debra Bangasser
The Children’s Hospital of Philadelphia (R.J.V.), Temple University (D.B.), and Thomas Jefferson University School of Medicine (E.J.V.), Philadelphia, Pennsylvania
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Elisabeth J. Van Bockstaele
The Children’s Hospital of Philadelphia (R.J.V.), Temple University (D.B.), and Thomas Jefferson University School of Medicine (E.J.V.), Philadelphia, Pennsylvania
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Abstract

Sex differences in the prevalence or severity of many diseases and in the response to pharmacological agents are well recognized. Elucidating the biologic bases of these differences can advance our understanding of the pathophysiology of disease and facilitate the development of treatments. Despite the importance to medicine, this has been an area of limited research. Here, we review physiologic, cellular, and molecular findings supporting the idea that there are sex differences in receptor signaling and trafficking that can be determinants of pathology. The focus is on the receptor for corticotropin-releasing factor (CRF), the orchestrator of the stress response, which has been implicated in diverse stress-related diseases that show a female prevalence. Data are reviewed that show sex differences in the association of the CRF receptor (CRF1) with the Gs protein and β-arrestin 2 that would render females more responsive to acute stress and less able to adapt to chronic stress as a result of compromised CRF1 internalization. Because β-arrestin 2 serves to link CRF1 to Gs-independent signaling pathways, this sex-biased signaling is proposed to result in distinct cellular responses to stress that are translated to different physiologic and behavioral coping mechanisms and that can have different pathologic consequences. Because stress has been implicated in diverse medical and psychiatric diseases, these sex differences in CRF1 signaling could explain sex differences in a multitude of disorders. The possibility that analogous sex differences may occur with other G-protein-coupled receptors underscores the impact of this effect and is discussed.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Mental Health [Grants MH040008, MH092438].

  • dx.doi.org/10.1124/mol.112.083550.

  • Received November 8, 2012.
  • Accepted December 13, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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In this issue

Molecular Pharmacology: 83 (4)
Molecular Pharmacology
Vol. 83, Issue 4
1 Apr 2013
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Rapid CommunicationMinireview—Special Issue in Memory of Avram Goldstein

Sex-Biased Stress Signaling

Rita J. Valentino, Debra Bangasser and Elisabeth J. Van Bockstaele
Molecular Pharmacology April 1, 2013, 83 (4) 737-745; DOI: https://doi.org/10.1124/mol.112.083550

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Rapid CommunicationMinireview—Special Issue in Memory of Avram Goldstein

Sex-Biased Stress Signaling

Rita J. Valentino, Debra Bangasser and Elisabeth J. Van Bockstaele
Molecular Pharmacology April 1, 2013, 83 (4) 737-745; DOI: https://doi.org/10.1124/mol.112.083550
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  • Article
    • Abstract
    • Introduction
    • Corticotropin-Releasing Factor and Stress-Related Psychiatric Disorders
    • Corticotropin-Releasing Factor and the Locus Coeruleus-Norepinephrine System
    • Sex Differences in Corticotropin-Releasing Factor Regulation of the Locus Coeruleus
    • CRF1 Signaling and Trafficking
    • Sex Differences in Corticotropin-Releasing Factor Signaling
    • Sex Differences in CRF1 Receptor Trafficking
    • Sex Differences in the Consequences of CRF Overexpression
    • Sex-Biased CRF Signaling
    • Overview and Implications
    • Authorship Contributions
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