Therapeutic Targets for Cerebral Ischemia Based on the Signaling Pathways of the GluN2B C Terminus.
Therapeutic Targets for Cerebral Ischemia Based on the Signaling Pathways of the GluN2B C Terminus.
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DOI：
10.1161/strokeaha.115.009314
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发表时间：
2015-08
期刊：
影响因子：
8.3
通讯作者：
Yongjun Sun;Linan Zhang;You Chen;Liying Zhan;Zibin Gao
中科院分区：
文献类型：
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作者：
Yongjun Sun;Linan Zhang;You Chen;Liying Zhan;Zibin Gao
脑缺血后N-甲基-d-天冬氨酸受体（NMDAR）的过度激活是神经元死亡的重要原因。尽管NMDAR拮抗剂在动物模型中表现出神经保护作用，但令人失望的是，在患者中发生了几种严重的副作用。NMDAR是一种异聚体，含有2个专性N-甲基-D-天冬氨酸受体1（GluN 1）亚基和多种GluN 2和GluN 3亚基。GluN 2亚单位，特别是有助于中风后神经元死亡，已被广泛研究。GluN 2A和GluN 2B亚基在介导细胞死亡和细胞存活中的相反作用被证实。1，2结果表明，GluN 2A亚基产生促存活活性，而GluN 2B亚基导致促死亡信号。然而，von Engelhardt等人3发现GluN 2A亚基也可在DIV 21培养物中介导NMDA依赖性毒性。这一矛盾可能是由于用于研究亚基组成的药理学方法并非毫无根据。4鉴于这一限制并根据分子生物学方法，Martel等人5证明，在脑缺血中，GluN 2B的C-末端结构域比GluN 2A更有效地促进神经元死亡。5简而言之，含有GluN 2B的NMDAR比含有GluN 2A的NMDAR更致命。由神经元型一氧化氮合酶（nNOS）、死亡相关蛋白激酶1（DAPK 1）、位于10号染色体上的磷酸酶和张力蛋白同源物（PTEN）以及钙/钙调蛋白依赖性蛋白激酶II（CaMKII）介导的促死亡信号传导途径已与GluN 2B活化相关联。本文将介绍基于GluN 2B羧基端（C端）信号通路的治疗靶点。GluN 2B-nNOS信号通路GluN 2B-nNOS信号通路在神经元死亡中发挥重要作用，是研究最广泛的GluN 2B通路（图1）。图1. GluN 2B-nNOS信号通路。基于PDZ结构域，突触后密度-95（PSD-95）将GluN 2B和nNOS组装成大分子复合物。在.之后
Overactivation of the N-methyl-d-aspartate receptor (NMDAR) after cerebral ischemia is a crucial reason for neuron death. Although NMDAR antagonists have exhibited neuroprotective effects in animal models, it is disappointing that several severe side effects have occurred in patients. NMDAR is a heteromer containing 2 obligate N-methyl-D-aspartate receptor 1 (GluN1) subunits and a variety of GluN2 and GluN3 subunits. The GluN2 subunit, which contributes specifically to neuron death after stroke, has been studied extensively. An opposing action of the GluN2A and GluN2B subunits in mediating cell death and cell survival was observed.1,2 The results indicate that the GluN2A subunit produces prosurvival activity, whereas the GluN2B subunit leads to a prodeath signal. However, von Engelhardt et al3 found that the GluN2A subunit can also mediate NMDA-dependent toxicity in DIV21 cultures. This paradox may have resulted because the pharmacological approach used to study subunit composition was not flawless.4 In view of this limitation and according to the methods of molecular biology, Martel et al5 demonstrated that the C-terminal domains of GluN2B promote neuronal death more efficiently than those of GluN2A in cerebral ischemia.5 In short, NMDARs containing GluN2B are more lethal than those containing GluN2A. Prodeath signaling pathways mediated by neuronal nitric oxide synthase (nNOS), death-associated protein kinase 1 (DAPK1), phosphatase and tensin homolog located on chromosome 10 (PTEN), and calcium/calmodulin-dependent protein kinase II (CaMKII) have been linked to GluN2B activation. Therapeutic targets based on these signaling pathways of the GluN2B carboxyl terminus (C terminus) will be introduced in this review. ### GluN2B–nNOS Signaling Pathway The GluN2B–nNOS signaling pathway, which plays an important role in neuron death, is the most widely studied GluN2B pathway (Figure 1). Figure 1. The GluN2B–nNOS signaling pathway. Based on the PDZ domains, postsynaptic density-95 (PSD-95) assembles GluN2B and nNOS into a macromolecular complex. After …