The death-associated protein kinase 1 (DAPK1) is a potent mediator of neuronal cell death. Here, we find that DAPK1 also functions in synaptic plasticity by regulating the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII). CaMKII and T286 autophosphorylation are required for both long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory, and cognition. T286-autophosphorylation induces CaMKII binding to the NMDA receptor (NMDAR) subunit GluN2B, which mediates CaMKII synaptic accumulation during LTP. We find that the LTP specificity of CaMKII synaptic accumulation is due to its LTD-specific suppression by calcineurin (CaN)-dependent DAPK1 activation, which in turn blocks CaMKII binding to GluN2B. This suppression is enabled by competitive DAPK1 versus CaMKII binding to GluN2B. Negative regulation of DAPK1/GluN2B binding by Ca2+/CaM results in synaptic DAPK1 removal during LTP but retention during LTD. A pharmacogenetic approach showed that suppression of CaMKII/GluN2B binding is a DAPK1 function required for LTD.

译文

死亡相关蛋白激酶1 (DAPK1) 是神经元细胞死亡的有效介质。在这里,我们发现DAPK1还通过调节Ca2/钙调蛋白 (CaM) 依赖性蛋白激酶II (CaMKII) 在突触可塑性中起作用。长期增强 (LTP) 和抑郁 (LTD) 都需要CaMKII和T286自磷酸化,这是学习,记忆和认知基础的突触可塑性的两种相反形式。T286-autophosphorylation诱导CaMKII与NMDA受体 (NMDAR) 亚基GluN2B结合,后者在LTP期间介导CaMKII突触积累。我们发现CaMKII突触积累的LTP特异性是由于钙调神经磷酸酶 (CaN) 依赖性DAPK1激活对其LTD特异性的抑制,这反过来又阻止了CaMKII与GluN2B的结合。通过竞争性DAPK1与CaMKII结合GluN2B来实现这种抑制。Ca2 +/CaM对DAPK1/GluN2B结合的负调节导致LTP期间突触DAPK1去除,但在LTD.期间保留。药物遗传学方法表明,抑制CaMKII/GluN2B结合是LTD所需的DAPK1功能。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录