Premium
Role of CRF Receptor Signaling in Stress Vulnerability, Anxiety, and Depression
Author(s) -
Hauger Richard L.,
Risbrough Victoria,
Oakley Robert H.,
OlivaresReyes J. Alberto,
Dautzenberg Frank M.
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.05011.x
Subject(s) - tropomyosin receptor kinase b , mapk/erk pathway , signal transduction , endocrinology , neurotrophic factors , receptor , g protein coupled receptor , arrestin , medicine , protein kinase a , microbiology and biotechnology , biology , neuroscience , kinase
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 β‐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 β‐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 β‐arrestin function may be involved in the pathophysiology of stress‐induced anxiety and depression.