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

doi:10.1021/pr060016+

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 journal › Article › peer-review

34 Citations (Scopus)

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 language	English
Pages (from-to)	1017-1023
Number of pages	7
Journal	Journal of Proteome Research
Volume	5
Issue number	4
DOIs	https://doi.org/10.1021/pr060016+
Publication status	Published - Apr 2006
Externally published	Yes

Keywords

Dynorphin
NMDA receptor
Neurotoxicity
Noncovalent interaction
Paralysis

ASJC Scopus subject areas

Biochemistry
Chemistry(all)

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10.1021/pr060016+

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Woods, A. S., Kaminski, R., Oz, M., Wang, Y., Hauser, K., Goody, R., Wang, H. Y. J., Jackson, S. N., Zeitz, P., Zeitz, K. P., Zolkowska, D., Schepers, R., Nold, M., Danielson, J., Gräslund, A., Vukojevic, V., Balkalkin, G., Basbaum, A., & Shippenberg, T. (2006). Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity. Journal of Proteome Research, 5(4), 1017-1023. https://doi.org/10.1021/pr060016+

Woods, AS, Kaminski, R, Oz, M, Wang, Y, Hauser, K, Goody, R, Wang, HYJ, Jackson, SN, Zeitz, P, Zeitz, KP, Zolkowska, D, Schepers, R, Nold, M, Danielson, J, Gräslund, A, Vukojevic, V, Balkalkin, G, Basbaum, A & Shippenberg, T 2006, 'Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity', Journal of Proteome Research, vol. 5, no. 4, pp. 1017-1023. https://doi.org/10.1021/pr060016+

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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 (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.",

keywords = "Dynorphin, NMDA receptor, Neurotoxicity, Noncovalent interaction, Paralysis",

author = "Woods, {Amina S.} and Rafal Kaminski and Murat Oz and Yun Wang and Kurt Hauser and Robin Goody and Wang, {Hay Yan J.} and Jackson, {Shelley N.} and Peter Zeitz and Zeitz, {Karla P.} and Dorota Zolkowska and Raf Schepers and Michael Nold and Jens Danielson and Astrid Gr{\"a}slund and Vladana Vukojevic and Georgy Balkalkin and Alan Basbaum and Toni Shippenberg",

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T1 - Decoy peptides that bind dynorphin noncovalently prevent NMDA receptor-mediated neurotoxicity

AU - Woods, Amina S.

AU - Kaminski, Rafal

AU - Oz, Murat

AU - Wang, Yun

AU - Hauser, Kurt

AU - Goody, Robin

AU - Wang, Hay Yan J.

AU - Jackson, Shelley N.

AU - Zeitz, Peter

AU - Zeitz, Karla P.

AU - Zolkowska, Dorota

AU - Schepers, Raf

AU - Nold, Michael

AU - Danielson, Jens

AU - Gräslund, Astrid

AU - Vukojevic, Vladana

AU - Balkalkin, Georgy

AU - Basbaum, Alan

AU - Shippenberg, Toni

PY - 2006/4

Y1 - 2006/4

N2 - 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.

AB - 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.

KW - Dynorphin

KW - NMDA receptor

KW - Neurotoxicity

KW - Noncovalent interaction

KW - Paralysis

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

Abstract

Keywords

ASJC Scopus subject areas

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