Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN

被引:151
作者
Ning, K
Pei, L
Liao, MX
Liu, BS
Zhang, YZ
Jiang, W
Mielke, JG
Li, L
Chen, YH
El-Hayek, YH
Fehlings, MG
Zhang, X
Liu, F
Eubanks, J
Wan, Q
机构
[1] Univ Hlth Network, Toronto Western Res Inst, Div Cellular & Mol Biol, Toronto, ON M5T 2S8, Canada
[2] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada
[3] Univ Toronto, Dept Surg, Toronto, ON M5S 1A8, Canada
[4] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada
[5] Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada
[6] Univ Saskatchewan, Neuropsychiat Res Unit, Saskatoon, SK S7N 5E4, Canada
关键词
phosphatase; NMDA receptor; cerebral ischemia; neuroprotection; stroke; synapse;
D O I
10.1523/JNEUROSCI.5449-03.2004
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is alipid and protein phosphatase. We report here that PTEN physically associates with the NR1 and NR2B subunits of NMDA receptors (NMDARs) in rat hippocampus. Downregulating the protein expression of PTEN inhibits the function of extrasynaptic NMDARs and decreases NMDAR surface expression, suggesting a crucial role for endogenous PTEN in the modulation of NMDAR-mediated neuronal function. Reducing PTEN expression also enhances Akt/Bad phosphorylation in hippocampal neurons. Importantly, suppressing lipid and protein phosphatase activity of PTEN, respectively, activates Akt and inhibits extrasynaptic NMDAR activity and thereby protects against ischemic neuronal death in vitro and in vivo. Thus, our study reveals a dual neuroprotective mechanism by which Akt/Bad and extrasynaptic NMDARs are regulated via downregulation of two distinct PTEN phosphatase activities and present the possibility of PTEN as a potential therapeutic target for stroke treatment.
引用
收藏
页码:4052 / 4060
页数:9
相关论文
共 53 条
[1]   Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease [J].
Backman, SA ;
Stambolic, V ;
Suzuki, A ;
Haight, J ;
Elia, A ;
Pretorius, J ;
Tsao, MS ;
Shannon, P ;
Bolon, B ;
Ivy, GO ;
Mak, TW .
NATURE GENETICS, 2001, 29 (04) :396-403
[2]   Subunit-specific NMDA receptor trafficking to synapses [J].
Barria, A ;
Malinow, R .
NEURON, 2002, 35 (02) :345-353
[3]   Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD [J].
Beattie, EC ;
Carroll, RC ;
Yu, X ;
Morishita, W ;
Yasuda, H ;
von Zastrow, M ;
Malenka, RC .
NATURE NEUROSCIENCE, 2000, 3 (12) :1291-1300
[4]   OPTIMIZED SURVIVAL OF HIPPOCAMPAL-NEURONS IN B27-SUPPLEMENTED NEUROBASAL(TM), A NEW SERUM-FREE MEDIUM COMBINATION [J].
BREWER, GJ ;
TORRICELLI, JR ;
EVEGE, EK ;
PRICE, PJ .
JOURNAL OF NEUROSCIENCE RESEARCH, 1993, 35 (05) :567-576
[5]   A system for stable expression of short interfering RNAs in mammalian cells [J].
Brummelkamp, TR ;
Bernards, R ;
Agami, R .
SCIENCE, 2002, 296 (5567) :550-553
[6]   NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity [J].
Carroll, RC ;
Zukin, RS .
TRENDS IN NEUROSCIENCES, 2002, 25 (11) :571-577
[7]  
CHOI DW, 1995, TRENDS NEUROSCI, V18, P58
[8]  
Colquhoun David, 1995, P483
[9]  
Dingledine R, 1999, PHARMACOL REV, V51, P7
[10]   Regulation of neuronal survival by the serine-threonine protein kinase Akt [J].
Dudek, H ;
Datta, SR ;
Franke, TF ;
Birnbaum, MJ ;
Yao, RJ ;
Cooper, GM ;
Segal, RA ;
Kaplan, DR ;
Greenberg, ME .
SCIENCE, 1997, 275 (5300) :661-665