Role of CRF receptor signaling in stress vulnerability, anxiety, and depression.
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.
Hauger
Richard L
RL
Psychiatry Service, VA Healthcare System, University of California, San Diego, La Jolla, California, USA. rhauger@ucsd.edu
Risbrough
Victoria
V
Oakley
Robert H
RH
Olivares-Reyes
J Alberto
JA
Dautzenberg
Frank M
FM
D001007:Anxiety / Q000503:physiopathology*; D001008:Anxiety Disorders / Q000188:drug therapy / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008954:Models, Biological; D010913:Pituitary-Adrenal System / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism*
D018019:Receptors, Corticotropin-Releasing Hormone