CaMKII versus DAPK1 Binding to GluN2B in Ischemic Neuronal Cell Death after Resuscitation from Cardiac Arrest
CaMKII versus DAPK1 Binding to GluN2B in Ischemic Neuronal Cell Death after Resuscitation from Cardiac Arrest
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DOI：
10.1016/j.celrep.2019.11.076
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发表时间：
2020-01-07
期刊：
影响因子：
8.8
通讯作者：
Bayer, K. Ulrich
中科院分区：
文献类型：
--
作者：
Buonarati, Olivia R.;Cook, Sarah G.;Bayer, K. Ulrich
据报道，DAPK1与GluN2B结合可在体内介导缺血细胞死亡。DAPK1和CaMKII结合到相同的GluN2B区域，并且它们的结合是相互排斥的。在这里，我们表明突变GluN2B(L1298A/R1300Q)上的结合区可以保护神经细胞免受心脏骤停后复苏引起的神经细胞死亡。重要的是，GluN2B突变选择性地仅取消了CaMKII，而不是DAPK1结合。在缺血或兴奋性毒性损伤时，CaMKII在兴奋性突触处进一步积聚，这种积聚是由GluN2B结合介导的。有趣的是，缺血后突触外GluN2B减少，但其与DAPK1的相对关联性增加。因此，缺血性神经元死亡需要CaMKII与突触GluN2B结合，而DAPK1结合的任何潜在作用仅限于不同的、可能的突触外GluN2B群体。
DAPK1 binding to GluN2B was prominently reported to mediate ischemic cell death in vivo. DAPK1 and CaMKII bind to the same GluN2B region, and their binding is mutually exclusive. Here, we show that mutating the binding region on GluN2B (L1298A/R1300Q) protected against neuronal cell death induced by cardiac arrest followed by resuscitation. Importantly, the GluN2B mutation selectively abolished only CaMKII, but not DAPK1, binding. During ischemic or excitotoxic insults, CaMKII further accumulated at excitatory synapses, and this accumulation was mediated by GluN2B binding. Interestingly, extra-synaptic GluN2B decreased after ischemia, but its relative association with DAPK1 increased. Thus, ischemic neuronal death requires CaMKII binding to synaptic GluN2B, whereas any potential role for DAPK1 binding is restricted to a different, likely extra-synaptic population of GluN2B.