NEUROBIOLOGY OF CORTICOTROPIN-RELEASING FACTOR (CRF) RECEPTORS AND CRF-BINDING-PROTEIN - IMPLICATIONS FOR THE TREATMENT OF CNS DISORDERS

The actions of CRF in the brain and in the periphery are mediated thro ugh multiple binding sites. There are three receptors, CRF(1), CRF(2 a lpha) and CRF(2 beta), which encode 411, 415 and 431 amino acid protei ns and transduce signals via the stimulation of intracellular cAMP pro duction. The recent identification of high-affinity non-peptide CRF re ceptor antagonists should allow for rapid progress in drug development of CRF receptor antagonists. In addition to the receptors, the action s of CRF in brain and in the periphery can also be modulated by a bind ing protein of 322 amino acids. Ligands of CRF-BP, such as CRF (6-33) can elevate brain levels of 'free' CRF and improve learning and memory without stress-like side effects of CRF receptor agonists. Urocortin, a mammalian CRF-related peptide with close sequence homology to fish urotensin, interacts with CRF(1), CRF(2) receptors and with CRF-BP. Th ese data indicate that CRF receptor antagonists may be useful for the treatment of the disease states where CRF is elevated such as anxiety and depression, anorexia nervosa and stroke and that ligand inhibitors of CRF-BP may be used to elevate brain levels of 'free' urocortin and other CRF-related peptides.