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Regulation of PINK1 by NR2B‐containing NMDA receptors in ischemic neuronal injury
Author(s) -
Shan Yuexin,
Liu Baosong,
Li Lijun,
Chang Ning,
Li Lei,
Wang Hanbin,
Wang Dianshi,
Feng Hua,
Cheung Carol,
Liao Mingxia,
Cui Tianyuan,
Sugita Shuzo,
Wan Qi
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06398.x
Subject(s) - pink1 , neuroprotection , protein kinase b , nmda receptor , neurodegeneration , microbiology and biotechnology , phosphorylation , biology , receptor , neuron , neurotoxicity , pi3k/akt/mtor pathway , neuroscience , kinase , pharmacology , signal transduction , medicine , apoptosis , biochemistry , autophagy , mitophagy , disease , toxicity
Abstract Dysfunction of PTEN‐induced kinase‐1 (PINK1) is implicated in neurodegeneration. We report here that oxygen‐glucose deprivation (OGD), an in vitro insult mimicking ischemic neuron injury, resulted in a significant reduction of PINK1 protein expression in cultured cortical neurons. The decrease of PINK1 expression was blocked by the antagonists of NMDA receptors. We revealed that the overactivation of NR2B‐containing NMDA receptors (NR2BRs) was responsible for the OGD‐induced PINK1 reduction. The overactivated NR2BRs also inhibited the phosphorylation, but not the protein expression, of the cell survival‐promoting kinase Akt after OGD insult, indicating that OGD‐induced reduction of PINK1 protein is specific in the injury paradigm. We further showed that enhancing the protein expression of PINK1 antagonized OGD‐induced reduction of Akt phosphorylation, suggesting that Akt may be a downstream target of PINK1 in ischemic neuron injury. Importantly, we provided evidence that both NR2BR antagonist and PINK1 over‐expression protected against OGD‐induced neuronal death. These results suggest that the overactivation of NR2BRs may contribute to ischemic neuron death through suppressing PINK1‐dependent survival signaling. Thus, selectively antagonizing NR2BR signal pathway‐induced neurotoxicity may be a potential neuroprotection strategy.