Corticotropin-Releasing Factor. Fig. 1. The hypothalamic-pituitary-adrenal axis. External stressors cause initiation of the HPA axis by first stimulating CRF neurons in the hypothalamus. Negative feedback inhibition loops return the system toward homeostasis (Adapted by permission from Krishnan and Nestler 2003).

and hippocampus where it binds to the ► glucocorticoid receptor (GR), a nuclear receptor transcription factor. Upon binding, the GR dissociates from a chaperone complex, which keeps it in an inactive state, and homodi-merizes with another cortisol-bound GR. The homodimer translocates into the nucleus and binds to specific glucocor-ticoid response elements to cause the transcriptional regulation of CRF and POMC related genes, as well as many others, decreasing CRF and POMC production and release.


Unbound CRF is sequestered by a rather unique CRF-binding protein (CRF-BP), a 37 kDa protein characterized by Orth and Mount in 1987. CRF-BP and the CRF receptors bind CRF with similar affinity (0.2 nM). The protein also binds CRF fragments from residues 6-33 (designated as CRF 6-33) and residues 9-33 (CRF 9-33) with high affinity while the receptors bind these fragments with a lower affinity, supporting a role of the binding protein in modulating CRF ► bioavailability. Additionally, 40-60% of brain CRF is bound to CRF-BP, further supporting a role for this protein in CRF bioavailability. CRF-BP also binds peptides in the same family as CRF such as urocortin, sauvagine, and urotensin. In the brain, CRF-BP localization coincides with CRF and the CRF receptors in the ► amygdala and pituitary but is also distributed in the cerebral cortex and brain stem. Peripheral CRF-BP is highly expressed in only the human and primate placenta and to a lesser extent in the liver. These studies contribute to the theory that CRF-BP regulates CRF levels and acts as a reservoir for CRF when needed (Kemp et al. 1998). During the end of pregnancy, CRF-BP levels fall as pla-cental CRF rises further implicating the protein as a CRF regulator. Novel treatments for mood and ► anxiety disorders (vide infra) may involve drugs targeting the CRF-BP in order to modulate free CRF concentrations without fully blocking the receptor as an antagonist might.

The endogenous enzyme(s) responsible for the degradation of CRF are unknown. However, experiments using purified endogenous ectopeptidases show that CRF is cleaved into smaller fragments. These fragments have reduced activity at CRF receptors.

Mechanism of Action

CRF binds exclusively to CRF1 and CRF2 receptors to produce its intracellular effects. Both CRF receptor ► subtypes are part of the Class B family of GPCRs, which also includes the calcitonin receptors and the parathyroid hormone receptor (De Souza 1995). Class B

receptors contain an N-terminal extracellular ligand binding site (ECD), a seven transmembrane/juxtamembrane domain (JD), and a C-terminal binding site for the G protein (guanine nucleotide exchange protein). CRF binding has been proposed to proceed according to a "Two Domain Model'' in which the C-terminus of CRF binds the N-terminus of the receptor (Fig. 2). This initial binding increases the affinity of the N-terminus of CRF for the J-domain of the CRF receptor. The N-terminus of the newly formed a-helical CRF binds the J-domain and initiates the activation of the CRF receptor, which can in turn activate adenylate cyclase via G-protein mediated signal transduction (Hoare 2005). This model explains some of the discrepancies in the loss of binding affinity observed in CRF fragments because the fragments may only be binding to one domain or blocking the binding pocket.

CRF1 and CRF2 receptor subtypes display 71% amino acid sequence homology to one another but mediate very different actions. CRF1 receptors are implicated in the stress response while CRF2 receptors are associated with feeding behaviors and, arguably, stress-coping behaviors. CRF1 receptors are highly expressed in the anterior pituitary and mediate the pituitary-adrenal axis response to stress. It is also diversely expressed in the cerebral cortex, hippocampus, amygdala, cerebellum, and hypothalamus. Peripheral CRF1 receptors are localized within the adrenal glands and the GI tract as well as the testis, ovaries, and immune system where they serve a variety of para-crine roles.

There are three separate ► isoforms of CRF2 receptor delineated as CRF2A, CRF2B, and CRF2C. These are produced from post-transcriptional mRNA processing of the same gene leading to splice variants, which produce different forms of the N-terminus and a single amino acid change at position 41. The exact importance of these changes is not clearly understood. However, binding studies have shown that the isoforms display slight changes in affinity for certain peptides in the CRF family (Dautzenberg and Hauger 2002). CRF2A receptors are localized primarily in the lateral septum, raphe nucleus, and ► BNST. Unlike rodents, there is significant CRF2A receptor density within primate cortex. Peptides that are CRF2A selective antagonists have been shown to have some anxiolytic effects following stress conditions although transgenic studies in mice show that CRF2A receptors may be involved in coping responses following stress. CRF2B receptors are localized within ventricles and arterioles of the cerebro-vasculature. There are detectable levels of mRNA expression in cardiac and skeletal muscles. Human CRF2C

Corticotropin-Releasing Factor. Fig. 2. CRF receptor binding and activation. Binding of CRF and/or small molecule antagonist to CRF receptor. Non-peptide small molecule antagonist (M) can bind regardless of ligand but if bound, M will block binding of CRF N-terminus resulting in noncompetitive antagonism (Adapted by permission from Grigoriadis et al. 2009).

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Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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