Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity |
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Authors: | Woods Amina S Kaminski Rafal Oz Murat Wang Yun Hauser Kurt Goody Robin Wang Hay-Yan J Jackson Shelley N Zeitz Peter Zeitz Karla P Zolkowska Dorota Schepers Raf Nold Michael Danielson Jens Gräslund Astrid Vukojevic Vladana Bakalkin Georgy Basbaum Allan Shippenberg Toni |
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Institution: | NIH/NIDA IRP, Baltimore, Maryland 21224, USA. awoods@intra.nida.nih.gov |
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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. |
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