Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death.
Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death.
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DOI：
10.1038/cddis.2013.111
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发表时间：
2013-04-04
影响因子：
9
通讯作者：
Swanson, R. A.
中科院分区：
文献类型：
--
作者：
Brennan-Minnella, A. M.;Shen, Y.;Swanson, R. A.
神经元N-甲基D-天冬氨酸（NMDA）型谷氨酸受体的持续激活导致中风、创伤和神经退行性疾病中的兴奋性毒性细胞死亡。兴奋性毒性神经元死亡部分由神经元NADPH氧化酶（NOX 2）产生的超氧化物引起，但NMDA受体如何与神经元NOX 2活化偶联尚不清楚。在这里，我们确定了一个信号通路耦合NMDA受体激活NOX 2激活在原代神经元培养。通过NMDA受体的NR 2B亚基的钙内流导致磷酸肌醇3-激酶（PI 3 K）的激活。由PI 3 K形成的磷脂酰肌醇（3，4，5）-三磷酸（PI（3，4，5）P3）激活非典型蛋白激酶C，PKC ζ（PKC β），其进而磷酸化神经元NOX 2的p47 phox组织亚基。通过含NR 2B的NMDA受体的钙内流触发线粒体去极化、NOX 2活化、超氧化物形成和细胞死亡。然而，同等幅度的钙离子升高诱导的离子霉素没有诱导NOX 2激活或神经元死亡，尽管引起线粒体去极化。PI 3 K抑制剂渥曼青霉素阻止NMDA诱导的NOX 2活化和细胞死亡，而不阻止细胞肿胀、钙升高或线粒体去极化。渥曼青霉素的作用被PI 3 K产物PI（3，4，5）P3的外源性供应和蛋白激酶M（PKC β的组成性活性形式）的转染所规避。这些研究结果表明，超氧化物的形成和兴奋性神经元死亡可以从线粒体去极化分离，并确定了一个新的作用PI 3 K在这个细胞死亡途径。在这一途径的扰动可能会增加或减少超氧化物的产生响应NMDA受体激活，并可能因此影响神经系统疾病，其中兴奋性毒性是一个促成因素。
Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are coupled to neuronal NOX2 activation is not well understood. Here, we identify a signaling pathway coupling NMDA receptor activation to NOX2 activation in primary neuron cultures. Calcium influx through the NR2B subunit of NMDA receptors leads to the activation of phosphoinositide 3-kinase (PI3K). Formation of phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) by PI3K activates the atypical protein kinase C, PKC zeta (PKCζ), which in turn phosphorylates the p47phox organizing subunit of neuronal NOX2. Calcium influx through NR2B-containing NMDA receptors triggered mitochondrial depolarization, NOX2 activation, superoxide formation, and cell death. However, equivalent magnitude calcium elevations induced by ionomycin did not induce NOX2 activation or neuronal death, despite causing mitochondrial depolarization. The PI3K inhibitor wortmannin prevented NMDA-induced NOX2 activation and cell death, without preventing cell swelling, calcium elevation, or mitochondrial depolarization. The effects of wortmannin were circumvented by exogenous supply of the PI3K product, PI(3,4,5)P3, and by transfection with protein kinase M, a constitutively active form of PKCζ. These findings demonstrate that superoxide formation and excitotoxic neuronal death can be dissociated from mitochondrial depolarization, and identify a novel role for PI3K in this cell death pathway. Perturbations in this pathway may either increase or decrease superoxide production in response to NMDA receptor activation, and may thereby impact neurological disorders, in which excitotoxicity is a contributing factor.
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