Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning.
Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning.
复制标题
DOI：
10.1111/j.1471-4159.2009.06106.x
复制
发表时间：
2009-07
影响因子：
4.7
通讯作者：
Aizenman E
中科院分区：
文献类型：
--
作者：
Aras MA;Hara H;Hartnett KA;Kandler K;Aizenman E
细胞死亡过程的亚致死激活启动促存活信号级联。由于细胞内Zn 2+释放介导神经元死亡途径，我们测试了游离Zn 2+的亚致死性增加是否也可以触发神经保护。神经元游离Zn 2+短暂增加预处理后，是必要的和足够的兴奋性毒性耐受。致死暴露于NMDA导致延迟增加的Zn2+，在非预处理的神经元，但不是在耐受性神经元兴奋性毒性，除非预处理诱导的游离Zn2+被螯合。因此，预处理可以触发Zn2+调节过程的表达，这反过来又防止随后的Zn2+介导的毒性。事实上，预处理增加锌+调节的基因在神经元中的表达。检查的分子信号传导机制，导致这种早期的Zn 2+信号揭示了蛋白激酶C（PKC）活性的关键作用，这表明PKC可能直接作用于细胞内的Zn 2+源。我们在金属硫蛋白（MT）的丝氨酸-32（S32）处发现了一个保守的PKC磷酸化位点，该位点在调节Zn 2+调节的基因表达和赋予兴奋性毒性耐受性方面非常重要。重要的是，我们在免疫纯化的MT1中观察到PKC诱导的丝氨酸磷酸化增加，但在突变型MT1（S32A）中没有。这些结果表明，神经元Zn 2+作为一个重要的，高度调节的信号成分负责启动的神经保护途径。
Sub-lethal activation of cell death processes initiate pro-survival signaling cascades. As intracellular Zn2+ liberation mediates neuronal death pathways, we tested whether a sub-lethal increase in free Zn2+ could also trigger neuroprotection. Neuronal free Zn2+ transiently increased following preconditioning, and was both necessary and sufficient for conferring excitotoxic tolerance. Lethal exposure to NMDA led to a delayed increase in Zn2+ that contributed significantly to excitotoxicity in non-preconditioned neurons, but not in tolerant neurons, unless preconditioning-induced free Zn2+ was chelated. Thus, preconditioning may trigger the expression of Zn2+-regulating processes, which, in turn, prevent subsequent Zn2+-mediated toxicity. Indeed, preconditioning increased Zn2+-regulated gene expression in neurons. Examination of the molecular signaling mechanism leading to this early Zn2+ signal revealed a critical role for protein kinase C (PKC) activity, suggesting that PKC may act directly on the intracellular source of Zn2+. We identified a conserved PKC phosphorylation site at serine-32 (S32) of metallothionein (MT) that was important in modulating Zn2+-regulated gene expression and conferring excitotoxic tolerance. Importantly, we observed increased PKC-induced serine phosphorylation in immunopurified MT1, but not in mutant MT1(S32A). These results indicate that neuronal Zn2+ serves as an important, highly regulated signaling component responsible for the initiation of a neuroprotective pathway.
登录
查看更多内容
影响因子：
3.8
作者：
Hidalgo, J;Aschner, M;Vasák, M
通讯作者：
Vasák, M
影响因子：
4
作者：
Devinney, MJ;Reynolds, IJ;Dineley, KE
通讯作者：
Dineley, KE
影响因子：
4.8
作者：
LaRochelle, O;Gagné, V;Séguin, C
通讯作者：
Séguin, C
影响因子：
5.3
作者：
Lee, Jin-Yeon;Kim, Yu-Jin;Kim, Yang-Hee
通讯作者：
Kim, Yang-Hee
影响因子：
16.2
作者：
Bossy-Wetzel, E;Talantova, MV;Lipton, SA
通讯作者：
Lipton, SA