Chapter 2.2 Molecular regulation of the CRF system

Abstract

Abstract: The corticotropin-releasing factor (CRF) system, including the urocortin peptides, is a key regulator of how the body responds to stress. A large amount of preclinical data in rodents and nonhuman primates implicates the CRF system in mediating the various physiological and psychological responses to stress. Importantly, alterations in the CRF system are associated with depression and anxiety disorders in humans. The goal of this chapter is to review what is known about the molecular mechanisms that regulate the activity of the CRF system. The role of the CRF system in stress-induced psychopathology is initially reviewed. Stress-induced molecular changes that are associated with activation of the CRF system are then described, along with the effects of manipulations that mimic or block the effects of stress. CRF receptor regulation is outlined in detail including an overview of recent data implicating the role of G-protein receptor kinase 3 in the phosphorylation and desensitization of the CRF 1 receptor. The limited data on the regulation of the CRF 2 receptors is also described. Finally, preliminary data from the use of microarrays and gene chips aimed at identifying stress-induced changes in gene expression that are CRF receptor dependent or independent will be described. A detailed understanding of the molecular mechanisms that mediate the stress-induced changes in the CRF system will enable identification of novel targets for the treatment and prevention of stress-related disorders.