Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity

Amina S. Woods, Rafal Kaminski, Murat Oz, Yun Wang, Kurt Hauser, Robin Goody, Hay Yan J Wang, Shelley N. Jackson, Peter Zeitz, Karla P. Zeitz, Dorota Zolkowska, Raf Schepers, Michael Nold, Jens Danielson, Astrid Gräslund, Vladana Vukojevic, Georgy Balkalkin, Alan Basbaum, Toni Shippenberg

Research output: Contribution to journalArticlepeer-review

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 (KVN-SEEEEEDA) 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.

Original languageEnglish (US)
Pages (from-to)1017-1023
Number of pages7
JournalJournal of Proteome Research
Volume5
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Keywords

  • Dynorphin
  • Neurotoxicity
  • NMDA receptor
  • Noncovalent interaction
  • Paralysis

ASJC Scopus subject areas

  • Genetics
  • Biotechnology
  • Biochemistry

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