Endocrine Abstracts (2004) 7 S3

Corticotropin releasing factor (CRF) family of ligands and their receptors

W Vale, T Bale, C Li, T Reyes, M Perrin, P Jamieson, A Chen, B Brar, J Vaghan & J Rivier

The Salk Institute, Univ. of California, San Diego and Scripps Research Institute, La Jolla, CA.

CRF mediates numerous complementary stress-related endocrine (HPA), autonomic and behavioral responses. CRF antagonists block many stress-induced responses in experimental animals. Furthermore, perturbations of the CRF system or HPA have been reported in human affective disorders. CRF acts through two Class B G protein coupled receptors derived from two genes, which have alternative splice variants and distinct expression patterns. Mice null for CRF-R1 exhibit reduced basal and stress-induced HPA activity and diminished behavioral responses to anxiogenic stimuli. Mice null for CRF-R2 exhibit endocrine and behavioral hyper-responsiveness to stressors, revealing potential anxiolytic roles for CRF-R2 and cognate ligands. However, the responses to administration of R2 agonists and antagonists into specific brain regions reveal anxiogenic-like roles for CRF-R2 as well. Urocortin (Ucn) was identified in rat brain and human genome as a potential ligand for CRF-R2 and found to have high affinity for and potent actions on both CRF-R1 and CRF-R2. The coincidence of Ucn-like immunoreactive fibers with some but not all sites of CRF-R2 expression supported the hypothesis that urocortin is an endogenous ligand for a subset of CRF-R2; however, this also raised the possibility of the existence of additional ligands. Our group and Hsu and Hsueh have identified two new human genes, Ucn II and Ucn III (stresscopin). Additionally, we cloned the mouse orthologues of Ucn II and Ucn III. Peptides deduced from the Ucn II and Ucn III precursors are highly selective for CRF-R2, inhibiting appetite, delaying gastric emptying, decreasing peripheral resistance and stimulating cardiac output and elasticity. In the rodent, Ucn, Ucn II and III mRNA's and peptides display unique CNS and peripheral distributions. Specifying the contributions of the various members of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage affective and other disorders.

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