Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity.
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.
Woods
Amina S
AS
NIH/NIDA IRP, Baltimore, Maryland 21224, USA. awoods@intra.nida.nih.gov
Kaminski
Rafal
R
Oz
Murat
M
Wang
Yun
Y
Hauser
Kurt
K
Goody
Robin
R
Wang
Hay-Yan J
HY
Jackson
Shelley N
SN
Zeitz
Peter
P
Zeitz
Karla P
KP
Zolkowska
Dorota
D
Schepers
Raf
R
Nold
Michael
M
Danielson
Jens
J
Gräslund
Astrid
A
Vukojevic
Vladana
V
Bakalkin
Georgy
G
Basbaum
Allan
A
Shippenberg
Toni
T
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
D018696:Neuroprotective Agents; D010455:Peptides; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D004399:Dynorphins