Peptidomics refers to a comprehensive study of peptides that are naturally cleaved from larger proteins by endogenous proteases. Of all naturally occurring peptides, bioactive peptides such as peptide hormones and neuropeptides have received the most attention in life sciences, since they function as intercellular signaling molecules to regulate physiological processes. While an increasing number of endogenous peptides are identified by peptidomics, sequence information alone does not tell us which peptides are bioactive. To facilitate the discovery of bioactive peptides, we focused on C-terminal amidation, a post-translational modification shared by many known bioactive peptides. We peptidomically analyzed peptides released by a human cell line and identified two novel amidated peptides, designated neuroendocrine regulatory peptide (NERP)-1 and NERP-2(1). NERPs are derived from the neurosecretory protein VGF that was originally thought to associate with neuronal differentiation (2,3). The endogenous presence of NERPs in rat brain was confirmed by mass spectrometric characterization of immunoreactive substances. Since immunoreactive NERPs were present in the rat hypothalamic neurons producing the antidiuretic hormone vasopressin, we investigated biological functions of NERPs in the context of vasopressin physiology and obtained evidence that they are suppressors of vasopressin release. It should be noted that NERPs would evade proteomic analysis because they harbor several basic amino acid residues. To the best of our knowledge, NERPs are the first mammalian bioactive peptides discovered by peptidomic studies. Overall, this study illustrates one solution to identify novel bioactive peptides in "omic" studies. References: 1) Yamaguchi, H., Sasaki, K. et al. J. Biol. Chem. 282, 26354-60 (2007). 2) Levi, A., Eldridge, J.D. & Patterson, B.M. Science 229, 393-5 (1985). 3) Nagasaki, K., Sasaki, K. et al. Neurosci. Lett. 267, 177-80 (1999).
