Calpain-cleaved collapsin response mediator protein-3 induces neuronal death after glutamate toxicity and cerebral ischemia
Calpain-cleaved collapsin response mediator protein-3 induces neuronal death after glutamate toxicity and cerebral ischemia
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DOI：
10.1523/jneurosci.4485-05.2006
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发表时间：
2006-02-22
影响因子：
5.3
通讯作者：
Kappler, J
中科院分区：
文献类型：
--
作者：
Hou, ST;Jiang, SX;Kappler, J
塌陷蛋白反应介导蛋白（CRMPs）介导生长锥在发育过程中的塌陷，但它们在成人大脑中的作用尚不清楚。在这里，我们报告的结果，全长CRMP-3（p63）是一个直接的目标钙蛋白酶切割CRMP-3的N端（+ 76个氨基酸）。有趣的是，激活的钙蛋白酶在体外兴奋性毒性和脑缺血在体内也裂解CRMP-3，和CRMP-3的裂解产物（p54）进行核转位过程中神经元死亡。p54的表达与谷氨酸处理的小脑颗粒神经元（CGNs）和位于局灶性脑缺血后梗死核心的缺血神经元中的末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记阳性核共定位，表明p54可能参与神经元死亡。过表达研究表明，p54，而不是p63，导致人胚肾细胞和CGN的死亡，而敲低CRMP-3表达的选择性小干扰RNA保护神经元免受谷氨酸毒性。总的来说，这些结果揭示了CRMP-3的新作用，即CRMP-3的钙蛋白酶裂解和随后的截短CRMP-3的核转位引起神经元死亡，以响应兴奋性毒性和脑缺血。我们的研究结果还建立了一个新的途径如何钙蛋白酶信号神经元死亡。
Collapsin response mediator proteins (CRMPs) mediate growth cone collapse during development, but their roles in adult brains are not clear. Here we report the findings that the full-length CRMP-3 (p63) is a direct target of calpain that cleaves CRMP-3 at the N terminus ( + 76 amino acid). Interestingly, activated calpain in response to excitotoxicity in vitro and cerebral ischemia in vivo also cleaved CRMP-3, and the cleavage product of CRMP-3 (p54) underwent nuclear translocation during neuronal death. The expression of p54 was colocalized with the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive nuclei in glutamate-treated cerebellar granule neurons (CGNs) and in ischemic neurons located in the infarct core after focal cerebral ischemia, suggesting that p54 might be involved in neuronal death. Overexpression studies showed that p54, but not p63, caused death of human embryonic kidney cells and CGNs, whereas knock-down CRMP-3 expression by selective small interfering RNA protected neurons against glutamate toxicity. Collectively, these results reveal a novel role of CRMP-3 in that calpain cleavage of CRMP-3 and the subsequent nuclear translocation of the truncated CRMP-3 evokes neuronal death in response to excitotoxicity and cerebral ischemia. Our findings also establish a novel route of how calpain signals neuron death.