Protein oxidation inhibits NO-mediated signaling pathway for synaptic plasticity
Protein oxidation inhibits NO-mediated signaling pathway for synaptic plasticity
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DOI：
10.1016/j.neurobiolaging.2010.04.016
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发表时间：
2012-03
影响因子：
4.2
通讯作者：
S. Kakizawa;M. Shibazaki;N. Mori
中科院分区：
文献类型：
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作者：
S. Kakizawa;M. Shibazaki;N. Mori
氧化应激是导致老年动物脑功能障碍的主要因素。然而，氧化如何影响大脑功能还不完全清楚。在这里，我们发现氧化抑制了小脑突触可塑性所必需的信号通路。我们首次发现在老年小鼠的小脑切片中，依赖一氧化氮(NO)的平行纤维-浦肯野细胞突触(PF Synapse)的可塑性受到损害，这可能是内源性活性氧对蛋白质氧化的抑制作用。在用氧化剂或硫醇阻滞剂预先孵育的幼鼠小脑切片中，PF突触的可塑性也被阻断。由于用氧化剂处理脑片不影响兴奋性突触后电流(PF-EPSC)的基本电生理特性，也不阻断突触可塑性，因此氧化可以特异性地抑制PF-突触可塑性所必需的信号通路。最后，生化分析证实了蛋白质氧化对突触可塑性的抑制作用是通过损伤一氧化氮诱导的蛋白质S-亚硝化来实现的。因此，氧化以一种“竞争性”的方式抑制了对突触可塑性至关重要的S-亚硝化依赖的信号通路。
Oxidative stress is a primary factor inducing brain dysfunction in aged animals. However, how oxidation affects brain function is not fully understood. Here we show that oxidation inhibits signaling pathways essential for synaptic plasticities in the cerebellum. We first revealed that nitric oxide (NO)-dependent plasticities at the parallel fiber-Purkinje cell synapse (PF synapse) were impaired in the cerebellar slices from aged mice, suggesting a possible inhibitory action of protein oxidation by endogenous reactive oxygen species. PF-synaptic plasticities were also blocked in the cerebellar slices from young mice preincubated with oxidizing agents or thiol blocker. Because the treatment of the slices with the oxidizing agent did not affect basic electrophysiological properties of excitatory postsynaptic current of PF (PF-EPSC) and did not occlude the synaptic plasticities, oxidation was revealed to specifically inhibit signaling pathways essential for PF-synaptic plasticities. Finally, biochemical analysis confirmed the idea that inhibitory action of protein oxidation on the PF-synaptic plasticities was mediated by impairment of nitric oxide-induced protein S-nitrosylation. Therefore, oxidation was revealed to inhibit the S-nitrosylation-dependent signaling pathway essential for synaptic plasticity in a “competitive” manner.