Chapter 3. Heterogeneity of Corticotropin Releasing Factor Receptors: Multiple Targets for the Treatment of CNS and Inflammatory Disorders

Abstract

Publisher Summary This chapter describes some of the recent studies on a variety of corticotropin-releasing factor (CRF) related targets, including three functionally distinct receptor subtypes and the CRF-binding protein (CRF-BP). The characteristics of the CRF receptors, including their sequence homologies, pharmacological profiles, and second messenger activities, are described in the chapter. In addition, the differential localization of messenger RNA (mRNA) for CRF receptors and CRF-BP is discussed in the chapter. As clinical data suggest that CRF may be implicated in psychiatric, neurologic, and immunological disorders, the chapter includes a brief description of the role of CRF, its receptors, and its binding protein in the etiology and pathophysiology of these diseases. Finally, the chapter provides an update on small molecule, nonpeptide CRF receptor antagonists. CRF, a 41-residue peptide, plays a crucial role in integrating the body's overall response to stress. The actions of CRF in the brain and in the periphery are mediated through multiple binding sites. There is heterogeneity of CRF binding sites with respect to sequence, pharmacology, and tissue distribution. There are three receptors; CRF1, CRF2α, and CRF2β, which encode 411, 415, and 431 amino acid proteins, respectively, comprising seven putative membrane-spanning domains characteristic of the G s -coupled receptors. All three receptors transduce a signal that involved stimulation of cyclic adenosine monophosphate (cAMP) production. CRF receptor antagonists may represent novel agents for the treatment of disorders associated with the elevated levels of CRF. The recent identification of high-affinity nonpeptide CRF receptor antagonists is expected to allow for rapid progress in drug development of the CRF receptor antagonists. In addition to the receptors, the actions of CRF in brain and in the periphery can also be modulated by a binding protein of 322 amino acids. While the precise function of the CRF-BP remains to be determined, it appears to play a role in binding and functionally inactivating CRF, and CRF-BP ligand inhibitors may represent a potential mechanism for increasing the endogenous CRF levels.