Department of Neurology and Neuroscience Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA 70112, USA.
Cell. 2010 Jan 22;140(2):222-34. doi: 10.1016/j.cell.2009.12.055.
N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extrasynaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2B(CT)). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2B(CT) that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca(2+) influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extrasynaptic sites and this interaction acts as a central mediator for stroke damage.
N-甲基-D-天冬氨酸（NMDA）受体在突触外位点构成谷氨酸受体的主要亚型，它们连接多个负责不可逆神经元死亡的细胞内分解代谢过程。在这里，我们报告大脑缺血会将死亡相关蛋白激酶 1（DAPK1）募集到成年小鼠大脑皮层的 NMDA 受体 NR2B 蛋白复合物中。DAPK1 直接与由氨基酸 1292-1304（NR2B(CT)）组成的 NMDA 受体 NR2B C 端尾部结合。组成性激活的 DAPK1 在 Ser-1303 处磷酸化 NR2B 亚基，进而增强 NR1/NR2B 受体通道电导。在体内，DAPK1 的基因缺失或给药 NR2B(CT)，可将激活的 DAPK1 与 NMDA 受体 NR2B 亚基分离，从而阻止突触外 NMDA 受体通道中有害的 Ca2+内流，并保护神经元免受脑缺血损伤。因此，DAPK1 在突触外位点与 NMDA 受体 NR2B 亚基在物理和功能上相互作用，这种相互作用是中风损伤的主要介导物。
