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Diversity of Neuropeptide Cell-Cell Signaling Molecules Generated by Proteolytic Processing Revealed by Neuropeptidomics Mass Spectrometry

  • Vivian Hook
  • Christopher B. Lietz
  • Sonia Podvin
  • Tomas Cajka
  • Oliver Fiehn
Focus: 29th Sanibel Conference, Peptidomics: Bridging the Gap Between Proteomics and Metabolomics by MS: Account & Perspective

Abstract

Neuropeptides are short peptides in the range of 3–40 residues that are secreted for cell-cell communication in neuroendocrine systems. In the nervous system, neuropeptides comprise the largest group of neurotransmitters. In the endocrine system, neuropeptides function as peptide hormones to coordinate intercellular signaling among target physiological systems. The diversity of neuropeptide functions is defined by their distinct primary sequences, peptide lengths, proteolytic processing of pro-neuropeptide precursors, and covalent modifications. Global, untargeted neuropeptidomics mass spectrometry is advantageous for defining the structural features of the thousands to tens of thousands of neuropeptides present in biological systems. Defining neuropeptide structures is the basis for defining the proteolytic processing pathways that convert pro-neuropeptides into active peptides. Neuropeptidomics has revealed that processing of pro-neuropeptides occurs at paired basic residues sites, and at non-basic residue sites. Processing results in neuropeptides with known functions and generates novel peptides representing intervening peptide domains flanked by dibasic residue processing sites, identified by neuropeptidomics. While very short peptide products of 2–4 residues are predicted from pro-neuropeptide dibasic processing sites, such peptides have not been readily identified; therefore, it will be logical to utilize metabolomics to identify very short peptides with neuropeptidomics in future studies. Proteolytic processing is accompanied by covalent post-translational modifications (PTMs) of neuropeptides comprising C-terminal amidation, N-terminal pyroglutamate, disulfide bonds, phosphorylation, sulfation, acetylation, glycosylation, and others. Neuropeptidomics can define PTM features of neuropeptides. In summary, neuropeptidomics for untargeted, global analyses of neuropeptides is essential for elucidation of proteases that generate diverse neuropeptides for cell-cell signaling.

Graphical Abstract

Keywords

Neuropeptides Proteases Mass spectrometry Peptidomics Cathepsin Pro-protein convertase Enkephalin NPY Regulation Neurotransmission Nervous system Endocrine 

Notes

Funding Information

This work was supported by grants from the National Institutes of Health (NIH) to V. Hook (R01 NS094597, R01NS094597-S1) and to O. Fiehn (U24DK097154). C. Lietz was supported by NIH T32MH019934 (awarded to Professor Dilip Jeste, Univ. of Calif., San Diego).

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Copyright information

© American Society for Mass Spectrometry 2018

Authors and Affiliations

  1. 1.Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of California San DiegoLa JollaUSA
  2. 2.Department of Neurosciences, School of MedicineUniversity of California San DiegoLa JollaUSA
  3. 3.West Coast Metabolomics Center, UC Davis Genome CenterUniversity of California DavisDavisUSA

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