CaMKII phosphorylates collapsin response mediator protein 2 and modulates axonal damage during glutamate excitotoxicity
CaMKII phosphorylates collapsin response mediator protein 2 and modulates axonal damage during glutamate excitotoxicity
复制标题
DOI：
10.1111/j.1471-4159.2009.06375.x
复制
发表时间：
2009-11-01
影响因子：
4.7
通讯作者：
Kaibuchi, Kozo
中科院分区：
文献类型：
--
作者：
Hou, Sheng T.;Jiang, Susan X.;Kaibuchi, Kozo
通过NMDA受体的细胞内钙内流触发了一系列有害的信号传导事件，导致神经系统疾病如中风中的神经元死亡。然而，目前尚不清楚的分子机制，从轴突和树突的早期损伤反应，这是重要的维持网络的生存神经元所必需的。在这里，我们研究了用谷氨酸处理的轴突的变化，并显示在神经元死亡出现之前轴突上出现β III-微管蛋白阳性的静脉曲张。地佐环平阻断了轴突静脉曲张的发生，表明这些微结构是由NMDA受体活性介导的。尽管早期增加表达的pCaMKII和pMAPK后仅10分钟的谷氨酸治疗，只有抑制剂钙/钙调蛋白依赖性蛋白激酶II（CaMKII）和钙蛋白酶防止轴突静脉曲张的发生。相比之下，Rho激酶，促分裂原活化蛋白激酶和磷酸肌醇3-激酶的抑制剂是无效的，也不能拯救神经元死亡，这表明CaMKII和钙蛋白酶是重要的轴突存活。激活的CaMK II直接磷酸化钙蛋白酶反应介导蛋白（CRMP）2，这是独立的钙蛋白酶介导的切割CRMP 2。CRMP 2的过度表达，而不是磷酸化抗性突变体CRMP 2-T555 A，增加了轴突对谷氨酸毒性的抗性，减少了静脉曲张的数量。pCRMP 2和pCaMKII的水平也在缺血性脑中的早期时间点内稳健地增加，并且这与缺血性神经元中轴突静脉曲张的出现相关。总的来说，这些研究证明了CaMK II在兴奋性毒性诱导的神经元死亡期间通过CRMP 2调节轴突完整性的重要作用。
Intracellular calcium influx through NMDA receptors triggers a cascade of deleterious signaling events which lead to neuronal death in neurological conditions such as stroke. However, it is not clear as to the molecular mechanism underlying early damage response from axons and dendrites which are important in maintaining a network essential for the survival of neurons. Here, we examined changes of axons treated with glutamate and showed the appearance of beta III-tubulin positive varicosities on axons before the appearance of neuronal death. Dizocilpine blocked the occurrence of varicosities on axons suggesting that these microstructures were mediated by NMDA receptor activities. Despite early increased expression of pCaMKII and pMAPK after just 10 min of glutamate treatment, only inhibitors to Ca2+/calmodulin-dependent protein kinase II (CaMKII) and calpain prevented the occurrence of axonal varicosities. In contrast, inhibitors to Rho kinase, mitogen-activated protein kinase and phosphoinositide 3-kinase were not effective, nor were they able to rescue neurons from death, suggesting CaMKII and calpain are important in axon survival. Activated CaMKII directly phosphorylates collapsin response mediator protein (CRMP) 2 which is independent of calpain-mediated cleavage of CRMP2. Over-expression of CRMP2, but not the phosphorylation-resistant mutant CRMP2-T555A, increased axonal resistance to glutamate toxicity with reduced numbers of varicosities. The levels of both pCRMP2 and pCaMKII were also increased robustly within early time points in ischemic brains and which correlated with the appearance of axonal varicosities in the ischemic neurons. Collectively, these studies demonstrated an important role for CaMKII in modulating the integrity of axons through CRMP2 during excitotoxicity-induced neuronal death.