PERRIN, M.H.; LEE, K-F.; BALE, T.*; LEWIS, K.; VAUGHAN, J.; VALE, W.: Diverse Roles of Corticotropin Releasing Factor Receptors and Their Ligands

Corticotropin releasing factor, CRF, plays a major role in homeostasis by mediating the endocrine, autonomic, immune and behavioral responses to stress. The actions of CRF result from activation of its receptors, CRF-R1 and CRF-R2, which are encoded by distinct genes and belong to the family of 7-TMD receptors which includes those for GRF, secretin, calcitonin and PTH. The receptors couple to GTP-binding proteins and activate adenylate cyclase. CRF-R1 is widely expressed in the central nervous system and also in the pituitary, gonads, thymus and adrenals. One splice variant of CRF-R2 is expressed mainly in the central nervous system while the other variant is appears in the heart, skeletal muscle, epididymis and GI tract. The second mammalian CRF-related peptide, urocortin, Ucn is found in many brain areas and also in the heart, GI tract and immune system, regions of high expression of CRF-R2. Pharmacology of the CRF ligand family, including (fish) urotensin, (frog) sauvagine and (insect) diuretic hormone show that all the CRF ligands bind with similar high affinity to CRF-R1, but urocortin, urotensin and sauvagine are more potent than CRF for CRF-R2. Ucn is a potent anti-inflammatory agent, modulates vascular tone, displays cardiovascular effects, and acting centrally, reduces appetite and food intake. Transgenic mice lacking functional CRF-R1 display impaired stress responses, reduced anxiety and lack of acute anorectic effect of Ucn. In contrast, CRF-R2 knock-out mice show hypersensitivity to stress, anxiety-like behavior, reduced food intake following food deprivation and lack of Ucn-induced hypotension. The future holds promise for discovering new CRF ligands and receptors and further understanding of their manifold physiologic roles.