Tullis Jonathan E, Buonarati Olivia R, Coultrap Steven J, Bourke Ashley M, Tiemeier Erika L, Kennedy Matthew J, Herson Paco S, Bayer K Ulrich
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Program in Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
iScience. 2021 Oct 2;24(10):103214. doi: 10.1016/j.isci.2021.103214. eCollection 2021 Oct 22.
Binding of two different CaM kinases, CaMKII and DAPK1, to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B near S1303 has been implicated in excitotoxic/ischemic neuronal cell death. The GluN2B mutation (L1298A, R1300Q) is neuroprotective but abolishes only CaMKII but not DAPK1 binding. However, both kinases can additionally phosphorylate GluN2B S1303. Thus, we here tested S1303 phosphorylation for possible contribution to neuronal cell death. The GluN2B mutation completely abolished phosphorylation by CaMKII and DAPK1, suggesting that the mutation could mediate neuroprotection by disrupting phosphorylation. However, S1303 phosphorylation was not increased by excitotoxic insults in hippocampal slices or by global cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation . In hippocampal cultures, S1303 phosphorylation was induced by chemical LTD but not LTP stimuli. These results indicate that the additional effect of the GluN2B mutation on phosphorylation needs to be considered only in LTD but not in LTP or ischemia/excitotoxicity.
两种不同的钙调蛋白激酶，即钙/钙调蛋白依赖性蛋白激酶II（CaMKII）和死亡相关蛋白激酶1（DAPK1），与N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体（NMDAR）亚基GluN2B在S1303附近的结合，被认为与兴奋性毒性/缺血性神经元细胞死亡有关。GluN2B突变（L1298A，R1300Q）具有神经保护作用，但仅消除了CaMKII的结合，而没有消除DAPK1的结合。然而，这两种激酶都可以额外磷酸化GluN2B的S1303。因此，我们在此测试了S1303磷酸化对神经元细胞死亡的可能作用。GluN2B突变完全消除了CaMKII和DAPK1的磷酸化作用，这表明该突变可能通过破坏磷酸化作用来介导神经保护。然而，在海马切片中，兴奋性毒性损伤或心脏骤停及心肺复苏诱导的全脑缺血均未增加S1303的磷酸化。在海马培养物中，化学性长时程抑制（LTD）而非长时程增强（LTP）刺激可诱导S1303磷酸化。这些结果表明，GluN2B突变对磷酸化的额外影响仅需在LTD中考虑，而在LTP或缺血/兴奋性毒性中则无需考虑。
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