25 Ucn 3 has a wider distribution in the brain and is localized in the perifornical area of the hypothalamus, BNST, lateral septum (LS), and amygdala.28 The widespread anatomical distribution of CRF and the urocortins correlates well with the diverse array of physiological 10058-F4 functions associated with this peptide family CRF receptors The physiological actions of the CRF

family of peptides are mediated through two distinct receptor Inhibitors,research,lifescience,medical subtypes belonging to the class B family of G-protein coupled receptors.29 The CRF type 1 receptor (CRFR1) gene encodes one functional variant (α) in humans and rodents along with several nonfunctional splice variants.30-32 The CRF type 2 receptor (CRFR2) has three functional splice variants in human (α, β, and γ) and two in rodents (α and β) resulting from

the use of alternate Inhibitors,research,lifescience,medical 5′ starting exons.33,34 CRFR1 is expressed at high levels in the brain and pituitary and low levels in peripheral tissues. The highest levels of CRFR1 expression are found in the anterior pituitary, olfactory bulb, cerebral cortex, hippocampus, and cerebellum. In peripheral tissues, low levels of CRFR1 Inhibitors,research,lifescience,medical are found in the adrenal gland, testis, and ovary.35,36 In contrast, CRFR2 is highly expressed in peripheral tissues and localized in a limited number of nuclei in the brain.37 In rodents, the CRF type 2α splice variant is preferentially expressed in the mammalian brain and is localized in the lateral septum, BNST, ventral medial hypothalamus, and mesencephalic raphe nuclei.36 Inhibitors,research,lifescience,medical The CRF type 2β variant is expressed in the periphery and is concentrated in the heart, skeletal muscle, skin, and the gastrointestinal tract.29,38,39 Radioligand binding and functional assays have revealed that CRFR1 and CRFR2 have different pharmacological profiles. CRF binds to the CRFR1 with higher affinity Inhibitors,research,lifescience,medical than to CRFR2.29,33 Ucnl has high affinity for both CRFR1 and CRFR2 and is more potent than CRF on CRFR2.24,33 Ucn 2 and Ucn 3 are Farnesyltransferase highly

selective for CRFR2 and exhibit low affinities for CRFR1. In addition, Ucn 2 and Ucn 3 minimally induce cyclic adenosine monophosphate (cAMP) production in cells expressing either endogenous or transfected CRFRl.25-27 The neuroendocrine properties of CRF are mediated through CRFRl in the anterior pituitary. Binding of CRF to the type 1 receptor results in the stimulation of adenylate cyclase and a subsequent activation of cAMP pathway events that culminate with the release of ACTH from pituitary corticotropes.29,39,40 The integral role of CRFRl in the regulation of ACTH release was confirmed by the phenotype of CRFRl -deficient mice. Mice deficient for CRFRl have a severely attenuated HPA response to stress and display decreased anxietylike behaviors.