Activation of calcium/calmodulin-dependent protein kinases after traumatic brain injury
Activation of calcium/calmodulin-dependent protein kinases after traumatic brain injury
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DOI：
10.1038/sj.jcbfm.9600301
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发表时间：
2006-12-01
影响因子：
6.3
通讯作者：
Hu, Bing-Ren
中科院分区：
文献类型：
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作者：
Atkins, Coleen M.;Chen, Shaoyi;Hu, Bing-Ren
创伤性脑损伤后的一个突出的认知障碍是海马区依赖的记忆丧失。尽管脑损伤后脑组织的病理变化已有很好的文献记载，但导致记忆丧失的潜在生化机制尚未完全阐明。因此，我们确定了脑损伤后钙/钙调蛋白依赖的蛋白激酶(CaMKs)是否受到调控，CaMKs是形成海马依赖记忆所必需的。Spraogue-Dawley大鼠在右侧顶叶皮质接受中度矢状面旁液压冲击脑损伤。Western blotting检测同侧海马和顶叶皮质磷酸化、活化的α-钙/钙调蛋白依赖性蛋白激酶11(α-CaMKII)、CaMKIV和CaMKI。脑损伤后30分钟，大鼠海马区和顶叶皮层的膜亚细胞组分中α-钙/钙调素依赖的蛋白激酶11被激活。CaMKI和CaMKIV被激活的时间较晚，在脑损伤后1h磷酸化水平增加。膜组分中活化的α-CaMKII的增加伴随着细胞质中总的α-CaMKII的减少，提示重新分布到膜上。利用共聚焦显微镜，我们观察到α-CaMKII在齿状回、CA3和CA1区的海马神经元中被激活。α-CaMKII的两个下游底物，AMPA型谷氨酸受体GluR1和细胞质多聚腺苷酸化元件结合蛋白，在脑损伤后1h，伴随着海马区和皮质中磷酸化水平的增加。这些结果表明，在脑外伤后的神经元中，一些有助于记忆形成的生化级联被非选择性地激活。由于记忆的形成需要激活特定神经元突触上的CaMKII信号通路，非选择性地激活所有突触中的CaMKII信号可能会扰乱记忆形成的机制，导致脑损伤后的记忆丧失。
A prominent cognitive impairment after traumatic brain injury (TBI) is hippocampal-dependent memory loss. Although the histopathologic changes in the brain are well documented after TBI, the underlying biochemical mechanisms that contribute to memory loss have yet to be thoroughly delineated. Thus, we determined if calcium/calmodulin-dependent protein kinases (CaMKs), known to be necessary for the formation of hippocampal-dependent memories, are regulated after TBI. Sprague-Dawley rats underwent moderate parasagittal fluid-percussion brain injury on the right side of the parietal cortex. The ipsilateral hippocampus and parietal cortex were Western blotted for phosphorylated, activated alpha-calcium/calmodulin-dependent protein kinase 11 (alpha-CaMKII), CaMKIV, and CaMKI. alpha-Calcium/calmodulin-dependent protein kinase 11 was activated in membrane subcellular fractions from the hippocampus and parietal cortex 30 mins after TBI. CaMKI and CaMKIV were activated in a more delayed manner, increasing in phosphorylation 1 h after TBI. The increase in activated alpha-CaMKII in membrane fractions was accompanied by a decrease in cytosolic total alpha-CaMKII, suggesting redistribution to the membrane. Using confocal microscopy, we observed that alpha-CaMKII was activated within hippocampal neurons of the dentate gyrus, CA3, and CA1 regions. Two downstream substrates of alpha-CaMKII, the AMPA-type glutamate receptor GluR1, and cytoplasmic polyadenylation element-binding protein, concomitantly increased in phosphorylation in the hippocampus and cortex 1 h after TBI. These results demonstrate that several of the biochemical cascades that subserve memory formation are activated unselectively in neurons after TBI. As memory formation requires activation of CaMKII signaling pathways at specific neuronal synapses, unselective activation of CaMKII signaling in all synapses may disrupt the machinery for memory formation, resulting in memory loss after TBI.