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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >NR2A and NR2B subunits differentially mediate MAP kinase signaling and mitochondrial morphology following excitotoxic insult
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NR2A and NR2B subunits differentially mediate MAP kinase signaling and mitochondrial morphology following excitotoxic insult

机译：NR2A和NR2B亚基差异性介导兴奋性中毒后MAP激酶信号传导和线粒体形态

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NMDA receptors are essential for neurotransmission and key mediators of synaptic signaling, but they can also trigger deleterious degenerative processes that lead to cell death. Growing evidence suggests that selective blockade of the heterogeneous subunits that comprise the NMDA receptor may enable better control of pharmacotherapies for treating neurological diseases and injuries. We investigated the relationship between NMDAR activation, MAPK signaling, and mitochondrial shape following an excitotoxic insult. NR2A- and NR2B-containing NMDARs differentially mediated acute changes in cytosolic calcium, alterations in mitochondrial morphology, and phosphorylation of the MAPKs ERK and JNK. Activation of NR2A-containing NMDARs was associated with JNK phosphorylation that was neuroprotective in neuronal cultures subjected to excitotoxicity. In contrast, activation of NR2B-containing NMDARs triggered calcium accumulation in mitochondria that was strongly associated with mitochondrial swelling and neuronal cell death. Indeed, while blockade of NR2B-containing receptors was neuroprotective, this protection was lost when NR2A-initiated JNK phosphorylation was inhibited. Given the modest selectivity of the NR2A inhibitor, NVP-AAM077, the results highlight the significance of the relative, rather than absolute, activation of these two NMDA subtypes in modulating cell death pathways. Therefore, the balance between concurrent activation of NR2B-containing and NR2A-containing NMDARs dictates neuronal fate following excitotoxicity.
机译：NMDA受体对于神经传递和突触信号转导的关键介质至关重要，但它们也可能引发有害的变性过程，导致细胞死亡。越来越多的证据表明，选择性阻断包含NMDA受体的异质亚基可以更好地控制用于治疗神经系统疾病和损伤的药物疗法。我们调查了兴奋性中毒后NMDAR激活，MAPK信号传导和线粒体形状之间的关系。含NR2A和NR2B的NMDAR差异介导细胞质钙的急性变化，线粒体形态的改变以及MAPK ERK和JNK的磷酸化。含有NR2A的NMDARs的激活与JNK磷酸化有关，JNK磷酸化在遭受兴奋性毒性的神经元培养物中具有神经保护作用。相反，含NR2B的NMDAR的激活触发了线粒体中钙的积累，这与线粒体肿胀和神经元细胞死亡密切相关。确实，尽管对含NR2B的受体的阻断具有神经保护作用，但当NR2A引发的JNK磷酸化被抑制时，这种保护作用就会消失。考虑到NR2A抑制剂NVP-AAM077的适度选择性，结果突出了这两种NMDA亚型的相对激活而非绝对激活在调节细胞死亡途径中的重要性。因此，同时激活的含NR2B和含NR2A的NMDAR之间的平衡决定了兴奋性毒性后的神经元命运。

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