SEASHOLTZ, A.F.: Corticotropin-Releasing Hormone-Binding Protein: In vivo Roles in the Pituitary and CNS

Corticotropin-releasing hormone (CRH) is widely recognized as the key physiological regulator of the mammalian stress response.� Within the HPA axis, CRH is the principal hypothalamic hormone controlling pituitary ACTH synthesis and release. At other sites in the central nervous system (CNS), CRH is thought to act as a neurotransmitter to mediate behavioral and autonomic responses to stress, including stress-induced anxiogenic behavior. The recent characterization of the urocortin peptides, new CRH-like mammalian ligands, adds to the complexity of the CRH system.� Both CRH and urocortin mediate their endocrine and/or synaptic effects via two classes of CRH receptors.� Similarly, both CRH and urocortin bind to CRH-binding protein (CRH-BP).� This secreted binding protein binds CRH and urocortin with an affinity equal to or greater than that of the receptors. CRH-BP expression has been detected in a variety of brain regions and in pituitary corticotropes, colocalizing with numerous sites of CRH synthesis or release. These data suggest that the CRH-BP may be an important modulator of endocrine and synaptic actions of CRH and other CRH-like ligands.�A variety of in vitro and in vivo studies have shown that CRH-BP expression is regulated not only by adrenal and gonadal steroids, but also by CRH. To further elucidate the physiological role of the CRH-BP, mouse models of CRH-BP overexpression and deficiency were developed.�These animal models show numerous physiological changes in the HPA axis.� CRH-BP-deficient mice also exhibit increased anxiety-like behavior and decreased weight gain, consistent with the anxiogenic and anorectic effects of elevated CRH and/or urocortin.�Together, these studies demonstrate an important role for the CRH-BP in regulating levels of “free” CRH and urocortin in the pituitary and central nervous system.