Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Wiley full text link Wiley Free PMC article
Full text links

Actions

Review
.2009 Oct:1179:120-43.
doi: 10.1111/j.1749-6632.2009.05011.x.

Role of CRF receptor signaling in stress vulnerability, anxiety, and depression

Affiliations
Review

Role of CRF receptor signaling in stress vulnerability, anxiety, and depression

Richard L Hauger et al. Ann N Y Acad Sci.2009 Oct.

Abstract

Markers of hyperactive central corticotropin releasing factor (CRF) systems and CRF-related single nucleotide polymorphisms (SNPs) have been identified in patients with anxiety and depressive disorders. Designing more effective antagonists may now be guided by data showing that small molecules bind to transmembrane domains. Specifically, CRF(1) receptor antagonists have been developed as novel anxiolytic and antidepressant treatments. Because CRF(1) receptors become rapidly desensitized by G protein-coupled receptor kinase (GRK) and beta-arrestin mechanisms in the presence of high agonist concentrations, neuronal hypersecretion of synaptic CRF alone may be insufficient to account for excessive central CRF neurotransmission in stress-induced affective pathophysiology. In addition to desensitizing receptor function, GRK phosphorylation and beta-arrestin binding can shift a G protein-coupled receptor (GPCR) to signal selectively via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) or Akt pathways independent of G proteins. Also, Epac-dependent CRF(1) receptor signaling via the ERK-MAPK pathway has been found to potentiate brain-derived neurotrophic factor (BDNF)-stimulated TrkB signaling. Thus, genetic or acquired abnormalities in GRK and beta-arrestin function may be involved in the pathophysiology of stress-induced anxiety and depression.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Effect of agonists and antagonists on receptor conformations and G protein–coupled signal transduction. Homologous desensitization rapidly regulates signaling after classical agonists activate GPCRs. Antagonists inhibit Gsα coupling and β-arrestin recruitment. Certain agonists selectively stimulate β-arrestin-biased signal transduction. (In color inAnnals online.)
Figure 2
Figure 2
Intracellular sequences of the human CRF1 receptor. The full-length wild-type human CRF1 receptor is a 415 amino acid–long protein. Serines and threonines are highlighted in pink as potential sites for GRK or PKC phosphorylation. Important motifs in the C terminus include a potential arrestin binding site (T399S400P401T402) and a class I PDZ binding domain (S412T413A414V415) that may regulate CRF1 receptor interactions with signaling proteins. Agonist-induced phosphorylation of C-terminal motifs is required for translocation of β-arrestin2 to the membrane and hierarchical phosphorylation of the IC3’s STTSET motif. Arrestin recruitment may also be promoted by the basic His214 and the adjacent hydrophobic sequence (A216I217V218L219). (In color inAnnals online.)
Figure 3
Figure 3
Recruitment of β-arrestins by the agonist-activated CRF1 receptor. Confocal images depict the translocation of cytosolic β-arrestin1-GFP (A) or β-arrestin2-GFP (B) to membrane CRF1 receptors recombinantly expressed in HEK293 cells. A slower redistribution of β-arrestin1 to the cell surface occurred after (2-, 5-, 20-min) treatment with 200 nM CRF while a dramatically more rapid and robust recruitment of β-arrestin2 developed in cells after (20 sec, 40 sec, 20 min) treatment with 200 nM CRF.
Figure 4
Figure 4
Intracellular sequences of the human CRF2(a) receptor. The full-length wild-type CRF2(a) receptor protein is 411 amino acids in length. Potential sites for GRK or PKC phosphorylation, or arrestin recruitment are highlighted in pink. The CRF2(a) receptor C-terminal tip does not contain a PDZ domain. (In color inAnnals online.)
Figure 5
Figure 5
Major intracellular signal transduction pathways for CRF1 and CRF2 receptors. While the dominant mode of signaling for both CRF receptors signaling is Gs-coupled AC-PKA cascade, they may also signal via the PLC-PKC and ERK-MAPK cascades. CRF receptor AC-PKA signaling is stringently regulated by GRK- and arrestin-mediated homologous desensitization. Although the mechanisms regulating CRF receptor ERK-MAPK signaling are not yet fully understood, this pathway may potentiate BDNF-stimulated TrkB receptor function. (In color inAnnals online.)
See this image and copyright information in PMC

References

    1. Bale TL, Vale WW. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu. Rev. Toxicol. 2004;44:525–557. - PubMed
    1. Bonne O, Grillon C, Vythilingam M, et al. Adaptive and maladaptive psychobiological responses to severe psychological stress. Neurosci. Biobehav. Rev. 2004;28:65–94. - PubMed
    1. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 2007;87:873–904. - PubMed
    1. Leonardo ED, Hen R. Genetics of affective and anxiety disorders. Annu. Rev. Psychol. 2006;57:117–137. - PubMed
    1. Heim C, Newport DJ, Mietzko T, et al. The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology. 2008;33:693–710. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full text links
Wiley full text link Wiley Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp