Neuropeptides that evolved early in metazoan evolution may possess much larger networks of paralogous genes than later evolving peptides due to the increased exposure to gene and genomic duplication events. The corticotropin-releasing factor family of peptides, which also include invertebrate CRF-like peptides, are a candidate group that appear to have an early origin. We have attempted to find additional paralogous genes to the CRF family by doing a low-stringency screen of a rainbow trout hypothalamic cDNA library using a hamster urocortin probe. A clone was identified that represented the rainbow trout ortholog of teneurin-3. The C-terminal region of the last exon teneurin transmembrane protein gene possesses a neuropeptide-like sequence with a primary structure similarity to the corticotropin-releasing factor family of peptides. We have called this sequence teneurin C-terminal associated peptide (TCAP). The predicted peptide is 40 residues long and possesses an expected pyroglutamyl residue in the first position and an amidated carboxy terminus. A synthetic version of the rainbow trout (rt) TCAP-3 is potent at increasing the concentration of cAMP and stimulating proliferation in a neuronal cell line. The synthetic peptide can also either increase or decrease the expression of the teneurin-1 gene, depending upon its concentration. The teneurin/TCAP system may represent a novel and highly conserved regulatory signalling system in the vertebrate brain.