Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor

The corticotropin-releasing factor (CRF) family of neuropeptides includes t he mammalian peptides CRF, urocortin, and urocortin II, as well as piscine urotensin I and frog sauvagine. The mammalian peptides signal through two G protein-coupled receptor types to modulate endocrine, autonomic, and behav ioral responses to stress, as well as a range of peripheral (cardiovascular , gastrointestinal, and immune) activities. The three previously known liga nds are differentially distributed anatomically and have distinct specifici ties for the two major receptor types. Here we describe the characterizatio n of an additional CRF-related peptide, urocortin III. in the human and mou se. In searching the public human genome databases we found a partial expre ssed sequence tagged (EST) clone with significant sequence identity to mamm alian and fish urocortin-related peptides. By using primers based on the hu man EST sequence, a full-length human clone was isolated from genomic DNA t hat encodes a protein that includes a predicted putative 38-aa peptide stru cturally related to other known family members. With a human probe, we then cloned the mouse ortholog from a genomic library. Human and mouse urocorti n III share 90% identity in the 38-aa putative mature peptide. In the pepti de coding region, both human and mouse urocortin III are 76% identical to p ufferfish urocortin-related peptide and more distantly related to urocortin II, CRF, and urocortin from other mammalian species. Mouse urocortin III m RNA expression is found in areas of the brain including the hypothalamus, a mygdala, and brainstem, but is not evident in the cerebellum, pituitary, or cerebral cortex: it is also expressed peripherally in small intestine and skin. Urocortin III is selective for type 2 CRF receptors and thus represen ts another potential endogenous ligand for these receptors.