title: Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 (DPP4) in blood circulation.
abstract: BACKGROUND
  Dipeptidyl peptidase 4 (DPP4; EC 3.4.14.5; CD26) is a membrane-bound or shedded serine protease that hydrolyzes dipeptides from the N-terminus of peptides with either proline or alanine at the penultimate position. Substrates of DPP4 include several stress-related neuropeptides implicated in anxiety, depression and schizophrenia. A decline of DPP4-like activity has been reported in sera from depressed patient, but not fully characterized regarding DPP4-like enzymes, therapeutic interventions and protein.
  
  
  METHODS
  Sera from 16 melancholic- and 16 non-melancholic-depressed patients were evaluated for DPP4-like activities and the concentration of soluble DPP4 protein before and after treatment by anti-depressive therapies. Post-translational modification of DPP4-isoforms and degradation of NPY, Peptide YY (PYY), Galanin-like peptide (GALP), Orexin B (OrxB), OrxA, pituitary adenylate cyclase-activating polypeptide (PACAP) and substance P (SP) were studied in serum and in ex vivo human blood. N-terminal truncation of biotinylated NPY by endothelial membrane-bound DPP4 versus soluble DPP4 was determined in rat brain perfusates and spiked sera.
  
  
  RESULTS
  Lower DPP4 activities in depressed patients were reversed by anti-depressive treatment. In sera, DPP4 contributed to more than 90% of the overall DPP4-like activity and correlated with its protein concentration. NPY displayed equal degradation in serum and blood, and was equally truncated by serum and endothelial DPP4. In addition, GALP and rat OrxB were identified as novel substrates of DPP4.
  
  
  CONCLUSIONS
  NPY is the best DPP4-substrate in blood, being truncated by soluble and membrane DPP4, respectively. The decline of soluble DPP4 in acute depression could be reversed upon anti-depressive treatment. Peptidases from three functional compartments regulate the bioactivity of NPY in blood.
authors.affiliation: Deutschsprachige Selbsthilfegruppe für Alkaptonurie (DSAKU) e,V., Stuttgart, Germany; Probiodrug AG, Halle, Germany; Universitätsklinikum Erlangen, Department of Experimental Therapy, Erlangen, Germany. Electronic address: leona.wagner@dsaku.de.
authors.forename: Leona
authors.initials: L
authors.lastname: Wagner
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kaestner
authors.affiliation: Center for Clinical Chemistry, Microbiology and Transfusion, Klinikum St. Georg gGmbH, Germany; Probiodrug AG, Halle, Germany.
authors.forename: Raik
authors.initials: R
authors.lastname: Wolf
authors.affiliation: Scil Productions, Halle, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Stiller
authors.affiliation: Probiodrug AG, Halle, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heiser
authors.affiliation: Probiodrug AG, Halle, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Manhart
authors.affiliation: Center for Clinical Chemistry, Microbiology and Transfusion, Klinikum St. Georg gGmbH, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.affiliation: Fraunhofer-Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, 06120 Halle, Germany.
authors.forename: Jens-Ulrich
authors.initials: JU
authors.lastname: Rahfeld
authors.affiliation: Fraunhofer-Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, 06120 Halle, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany; St. Rochus-Hospital Telgte, 48291 Telgte, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rothermundt
authors.affiliation: Universitätsklinikum Erlangen, Department of Experimental Therapy, Erlangen, Germany. Electronic address: stephan.v.hoersten@uk-erlangen.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
mesh_terms: D000328:Adult; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D003866:Depressive Disorder / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D004727:Endothelium / Q000378:metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007527:Isoenzymes / Q000097:blood; D008297:Male; D008875:Middle Aged; D009478:Neuropeptide Y / Q000097:blood*; D000068797:Orexins / Q000097:blood; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000097:blood; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D051381:Rats; D013315:Stress, Psychological / Q000097:blood*; D013373:Substance P / Q000097:blood
chemical_list: D000928:Antidepressive Agents; D007527:Isoenzymes; D009478:Neuropeptide Y; D000068797:Orexins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013373:Substance P; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: Blood circulation; Dipeptidyl peptidase 4; MALDI-TOF-MS; Major depressive disorders; Neuropeptide Y; Neuropeptides