title: Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery.
abstract: The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor selectivity by dipeptidyl peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids, and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P, secreted meprin-A (Mep-A), and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S, and tissue kallikrein could also be identified. The expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive angiotensin-converting enzyme inhibitors, while it ablates suspected hypertensive side effects of only antidiabetic DP4-inhibitors application. The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor selectivity by dipeptidyl peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids, and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P, secreted meprin-A (Mep-A), and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S, and tissue kallikrein could also be identified. The expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive angiotensin-converting enzyme inhibitors, while it ablates suspected hypertensive side effects of only antidiabetic DP4-inhibitors application.
authors.affiliation: Deutschsprachige Selbsthilfegruppe für Alkaptonurie (DSAKU) e.V., Stuttgart, Germany.|Probiodrug AG, Halle, Germany.|Department of Experimental Therapy, Preclinical Experimental Center, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Leona
authors.initials: L
authors.lastname: Wagner
authors.affiliation: Probiodrug AG, Halle, Germany.
authors.forename: Raik
authors.initials: R
authors.lastname: Wolf
authors.affiliation: Paul-Flechsig-Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zeitschel
authors.affiliation: Paul-Flechsig-Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Rossner
authors.affiliation: Translational Neuroendocrine Research Unit, Lund University, Lund, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Petersén
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia and Children's and Women's Hospital, Vancouver, BC, Canada.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.affiliation: Department of Psychiatry, University of Muenster, Muenster, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kästner
authors.affiliation: Department of Psychiatry, University of Muenster, Muenster, Germany.|St. Rochus-Hospital Telgte, Telgte, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rothermundt
authors.affiliation: Probiodrug AG, Halle, Germany.
authors.forename: Ulf-Torsten
authors.initials: UT
authors.lastname: Gärtner
authors.affiliation: Julius Bernstein Institute for Physiology, Martin Luther University of Halle-Wittenberg, Halle, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gündel
authors.affiliation: Fraunhofer-Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Halle, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Schlenzig
authors.affiliation: Department of Experimental Therapy, Preclinical Experimental Center, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Frerker
authors.affiliation: Department of Experimental Therapy, Preclinical Experimental Center, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Schade
authors.affiliation: Probiodrug AG, Halle, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Manhart
authors.affiliation: Fraunhofer-Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, 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, Halle, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.affiliation: Department of Experimental Therapy, Preclinical Experimental Center, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000134:cerebrospinal fluid; D002402:Cathepsin D / Q000134:cerebrospinal fluid; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D017933:Peripheral Nervous System / Q000166:cytology*; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic
chemical_list: D009478:Neuropeptide Y; D010446:Peptide Fragments; D002097:C-Reactive Protein; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4; D002402:Cathepsin D
keywords: Proteolysis; cathepsin D; dipeptidyl peptidase 4; median eminence; meprin-A