死亡相关蛋白激酶1（DAPK1）通过使钙/钙调蛋白依赖性蛋白激酶II（CaMKII）/谷氨酸受体2B亚基（GluN2B）结合长时程增强（LTP）具有特异性来介导长时程抑制（LTD）。
DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific.
作者信息
Goodell Dayton J, Zaegel Vincent, Coultrap Steven J, Hell Johannes W, Bayer K Ulrich
机构信息
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.
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
出版信息
Cell Rep. 2017 Jun 13;19(11):2231-2243. doi: 10.1016/j.celrep.2017.05.068.
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 Ca/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 Ca/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.
死亡相关蛋白激酶1（DAPK1）是神经元细胞死亡的有力介导因子。在此，我们发现DAPK1还通过调节钙/钙调蛋白（CaM）依赖性蛋白激酶II（CaMKII）在突触可塑性中发挥作用。长期增强（LTP）和长期抑制（LTD）是学习、记忆和认知背后两种相反形式的突触可塑性，CaMKII及其T286位点的自磷酸化对于这两者均是必需的。T286位点的自磷酸化诱导CaMKII与N-甲基-D-天冬氨酸受体（NMDAR）亚基GluN2B结合，这在LTP期间介导CaMKII的突触积累。我们发现，CaMKII突触积累的LTP特异性是由于其被钙调神经磷酸酶（CaN）依赖性DAPK1激活进行LTD特异性抑制，这反过来又阻断了CaMKII与GluN2B的结合。这种抑制是通过DAPK1与CaMKII竞争性结合GluN2B实现的。Ca/CaM对DAPK1/GluN2B结合的负调节导致LTP期间突触中的DAPK1被清除，但在LTD期间保留。一种药物遗传学方法表明，抑制CaMKII/GluN2B结合是LTD所需的DAPK1功能。
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