Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN
Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN
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DOI：
10.1523/jneurosci.5449-03.2004
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发表时间：
2004-04-21
影响因子：
5.3
通讯作者：
Wan, Q
中科院分区：
文献类型：
--
作者：
Ning, K;Pei, L;Wan, Q
肿瘤抑制因子 PTEN（10 号染色体上删除的磷酸酶和张力蛋白同源物）是脂肪和蛋白磷酸酶。我们在此报告，PTEN 与大鼠海马中 NMDA 受体 (NMDAR) 的 NR1 和 NR2B 亚基有物理联系。下调 PTEN 蛋白表达会抑制突触外 NMDAR 的功能并降低 NMDAR 表面表达，表明内源性 PTEN 在 NMDAR 介导的神经元功能调节中发挥着至关重要的作用。减少 PTEN 表达还会增强海马神经元中的 Akt/Bad 磷酸化。重要的是，抑制 PTEN 的脂质和蛋白磷酸酶活性，分别激活 Akt 并抑制突触外 NMDAR 活性，从而在体外和体内防止缺血性神经元死亡。因此，我们的研究揭示了一种双重神经保护机制，通过下调两种不同的 PTEN 磷酸酶活性来调节 Akt/Bad 和突触外 NMDAR，并提出 PTEN 作为中风治疗潜在治疗靶点的可能性。
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.