Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor

Abstract

CORTICOTROPIN-RELEASING factor (CRF), a peptide first isolated from mammalian brain1, is critical in the regulation of the pituitary–adrenal axis, and in complementary stress-related endocrine, autonomic and behavioural responses2. Fish urotensin I and amphibian sauvagine were considered to be homologues3 of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes4,5. We have characterized another mammalian member of the CRF family and have localized its urotensin-like immunoreactivity to, and cloned related complementary DNAs from, a discrete rat midbrain region. The deduced protein encodes a peptide that we name urocortin, which is related to urotensin (63% sequence identity) and CRF (45% sequence identity). Synthetic urocortin evokes secretion of adrenocortico-tropic hormone (ACTH) both in vitro and in vivo and binds and activates transfected type-1 CRF receptors6–9, the subtype expressed by pituitary corticotropes. The coincidence of urotensin-like immunoreactivity with type-2 CRF receptors10–13 in brain, and our observation that urocortin is more potent than CRF at binding and activating type-2 CRF receptors, as well as at inducing c-Fos (an index of cellular activation) in regions enriched in type-2 CRF receptors, indicate that this new peptide could be an endogenous ligand for type-2 CRF receptors.