Regulation of PINK1 by NR2B-containing NMDA receptors in ischemic neuronal injury.
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.
Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
Yuexin
Y
Shan
Baosong
B
Liu
Lijun
L
Li
Ning
N
Chang
Lei
L
Li
Hanbin
H
Wang
Dianshi
D
Wang
Hua
H
Feng
Carol
C
Cheung
Mingxia
M
Liao
Tianyuan
T
Cui
Shuzo
S
Sugita
Qi
Q
Wan
D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000172:deficiency*; D049452:Green Fluorescent Proteins / Q000235:genetics; D000860:Hypoxia; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D011247:Pregnancy; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D000099202:PTEN-Induced Putative Kinase
D018691:Excitatory Amino Acid Antagonists; D005947:Glucose; D049452:Green Fluorescent Proteins; D007770:L-Lactate Dehydrogenase; D011494:Protein Kinases; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D000099202:PTEN-Induced Putative Kinase; C121001:NR2B NMDA receptor