Corticotropin-Releasing Factor Receptors: Inhibitors, Subtypes, Pharmacology, Localization, and Their Role in Central Nervous System Function

Corticotropin-releasing factor (CRF) plays a major role in coordinating the endocrine, autonomic, and behavioral response to stress through actions in the brain and in the periphery. The actions of CRF are mediated through high affinity cell surface receptors which respond to CRF via activation of adenylyl cyclase and subsequent increases in cyclic AMP (cAMP) production. For more than a decade, receptors for CRF have been studied in an attempt to elucidate their structure-function relationship and define their potential as sites of therapeutic intervention for a variety indications. The recent cloning of the CRFJ and CRF2 receptors has begun a new era of CRF receptor study which has enabled precise pharmacological analysis and localization studies which will inevitably become the basis for understanding the activity of CRF as a multifunctional hormone and neurotransmitter. As will be highlighted in this review, studies now show that CRF1 and CRF2 receptors differ dramatically in their structures, pharmacological profiles, anatomical localizations within the central nervous system (CNS) and periphery, and their regulation in response to a variety of physiological challenges. This has led not only to the generation of novel hypotheses regarding CRF function, but more importantly to the tangible goal of creating selective CRF-based therapeutics which can target specific aspects of CRF-controlled behavior and physiology. The discovery of several classes of small molecule CRF receptor antagonists will allow testing of the function of CRF-based therapeutics