Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.

The neuroprotective activity of pyruvate has been confirmed in previous in vivo and in vitro studies. Here, we report a novel mechanism that pyruvate prevents SH-SY5Y cells from glutamate excitotoxicity by regulating death-associated protein kinase 1 (DAPK1) protein complex. Our results showed pyruv...

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Main Authors: Jingwei Tian, Jucan Cheng, Jianzhao Zhang, Liang Ye, Fangxi Zhang, Qiuju Dong, Hongbo Wang, Fenghua Fu
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2014-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3995922?pdf=render
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spelling doaj-fcedbdf782d549888a19fd4fa9404c142020-11-24T21:34:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0194e9577710.1371/journal.pone.0095777Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.Jingwei TianJucan ChengJianzhao ZhangLiang YeFangxi ZhangQiuju DongHongbo WangFenghua FuThe neuroprotective activity of pyruvate has been confirmed in previous in vivo and in vitro studies. Here, we report a novel mechanism that pyruvate prevents SH-SY5Y cells from glutamate excitotoxicity by regulating death-associated protein kinase 1 (DAPK1) protein complex. Our results showed pyruvate regulated DAPK1 protein complex to protect cells by two ways. First, pyruvate induced the dissociation of DAPK1 with NMDA receptors. The disruption of the DAPK1-NMDA receptors complex resulted in a decrease in NMDA receptors phosphorylation. Then the glutamate-stimulated Ca2+ influx was inhibited and intracellular Ca2+ overload was alleviated, which blocked the release of cytochrome c and cell death. In addition, increased Bcl-xL induced by pyruvate regulated Bax/Bak dependent death by inhibiting the release of cytochrome c from the mitochondrial inter-membrane space into the cytosol. As a result, the cytochrome c-initiated caspase cascade, including caspase-3 and caspase-9, was inhibited. Second, pyruvate promoted the association between DAPK1 and Beclin-1, which resulted in autophagy activation. The autophagy inhibitor 3-methyladenine reversed the protection afforded by pyruvate. Furthermore, the attenuation of mitochondrial damage induced by pyruvate was partly reduced by 3-methyladenine. This suggested autophagy mediated pyruvate protection by preventing mitochondrial damage. Taken together, pyruvate protects cells from glutamate excitotoxicity by regulating DAPK1 complexes, both through dissociation of DAPK1 from NMDA receptors and association of DAPK1 with Beclin-1. They go forward to protect cells by attenuating Ca2+ overload and activating autophagy. Finally, a convergence of the two ways protects mitochondria from glutamate excitotoxicity, which leads to cell survival.http://europepmc.org/articles/PMC3995922?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Jingwei Tian
Jucan Cheng
Jianzhao Zhang
Liang Ye
Fangxi Zhang
Qiuju Dong
Hongbo Wang
Fenghua Fu
spellingShingle Jingwei Tian
Jucan Cheng
Jianzhao Zhang
Liang Ye
Fangxi Zhang
Qiuju Dong
Hongbo Wang
Fenghua Fu
Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.
PLoS ONE
author_facet Jingwei Tian
Jucan Cheng
Jianzhao Zhang
Liang Ye
Fangxi Zhang
Qiuju Dong
Hongbo Wang
Fenghua Fu
author_sort Jingwei Tian
title Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.
title_short Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.
title_full Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.
title_fullStr Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.
title_full_unstemmed Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex.
title_sort protection of pyruvate against glutamate excitotoxicity is mediated by regulating dapk1 protein complex.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2014-01-01
description The neuroprotective activity of pyruvate has been confirmed in previous in vivo and in vitro studies. Here, we report a novel mechanism that pyruvate prevents SH-SY5Y cells from glutamate excitotoxicity by regulating death-associated protein kinase 1 (DAPK1) protein complex. Our results showed pyruvate regulated DAPK1 protein complex to protect cells by two ways. First, pyruvate induced the dissociation of DAPK1 with NMDA receptors. The disruption of the DAPK1-NMDA receptors complex resulted in a decrease in NMDA receptors phosphorylation. Then the glutamate-stimulated Ca2+ influx was inhibited and intracellular Ca2+ overload was alleviated, which blocked the release of cytochrome c and cell death. In addition, increased Bcl-xL induced by pyruvate regulated Bax/Bak dependent death by inhibiting the release of cytochrome c from the mitochondrial inter-membrane space into the cytosol. As a result, the cytochrome c-initiated caspase cascade, including caspase-3 and caspase-9, was inhibited. Second, pyruvate promoted the association between DAPK1 and Beclin-1, which resulted in autophagy activation. The autophagy inhibitor 3-methyladenine reversed the protection afforded by pyruvate. Furthermore, the attenuation of mitochondrial damage induced by pyruvate was partly reduced by 3-methyladenine. This suggested autophagy mediated pyruvate protection by preventing mitochondrial damage. Taken together, pyruvate protects cells from glutamate excitotoxicity by regulating DAPK1 complexes, both through dissociation of DAPK1 from NMDA receptors and association of DAPK1 with Beclin-1. They go forward to protect cells by attenuating Ca2+ overload and activating autophagy. Finally, a convergence of the two ways protects mitochondria from glutamate excitotoxicity, which leads to cell survival.
url http://europepmc.org/articles/PMC3995922?pdf=render
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