title: Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity.
abstract: Prodynorphin-derived peptides elicit various pathological effects including neurological dysfunction and cell death. These actions are reduced by N-methyl-d-aspartate receptor (NMDAR) but not opioid receptor antagonists suggesting NMDAR-mediation. Here, we show that a conserved epitope (KVNSEEEEEDA) of the NR1 subunit of the NMDAR binds dynorphin peptides (DYNp) noncovalently. Synthetic peptides containing this epitope form stable complexes with DYNp and prevent the potentiation of NMDAR-gated currents produced by DYNp. They attenuate DYNp-evoked cell death in spinal cord and prevent, as well as reverse, DYNp-induced paralysis and allodynia. The data reveal a novel mechanism whereby prodynorphin-derived peptides facilitate NMDAR function and produce neurotoxicity. Furthermore, they suggest that synthetic peptides that bind DYNp, thus preventing their interaction with NMDAR, may be novel therapeutic agents for the treatment of spinal cord injury.
authors.affiliation: NIH/NIDA IRP, Baltimore, Maryland 21224, USA. awoods@intra.nida.nih.gov
authors.forename: Amina S
authors.initials: AS
authors.lastname: Woods
authors.forename: Rafal
authors.initials: R
authors.lastname: Kaminski
authors.forename: Murat
authors.initials: M
authors.lastname: Oz
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Kurt
authors.initials: K
authors.lastname: Hauser
authors.forename: Robin
authors.initials: R
authors.lastname: Goody
authors.forename: Hay-Yan J
authors.initials: HY
authors.lastname: Wang
authors.forename: Shelley N
authors.initials: SN
authors.lastname: Jackson
authors.forename: Peter
authors.initials: P
authors.lastname: Zeitz
authors.forename: Karla P
authors.initials: KP
authors.lastname: Zeitz
authors.forename: Dorota
authors.initials: D
authors.lastname: Zolkowska
authors.forename: Raf
authors.initials: R
authors.lastname: Schepers
authors.forename: Michael
authors.initials: M
authors.lastname: Nold
authors.forename: Jens
authors.initials: J
authors.lastname: Danielson
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.forename: Vladana
authors.initials: V
authors.lastname: Vukojevic
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
authors.forename: Allan
authors.initials: A
authors.lastname: Basbaum
authors.forename: Toni
authors.initials: T
authors.lastname: Shippenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D017124:Conserved Sequence; D004399:Dynorphins / Q000378:metabolism*; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008845:Microinjections; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000378:metabolism; D010243:Paralysis / Q000139:chemically induced; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014981:Xenopus
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D004399:Dynorphins