Oxidative modification of M-type K+ channels as a mechanism of cytoprotective neuronal silencing
Oxidative modification of M-type K+ channels as a mechanism of cytoprotective neuronal silencing
复制标题
DOI：
10.1038/sj.emboj.7601374
复制
发表时间：
2006-10-18
期刊：
影响因子：
11.4
通讯作者：
Shapiro, Mark S.
中科院分区：
文献类型：
--
作者：
Gamper, Nikita;Zaika, Oleg;Shapiro, Mark S.
Kv 7家族的电压门控K+通道是调节动作电位放电的神经元M电流的基础。M电流的抑制增加兴奋性，其增强可使神经元沉默。我们在这里表明，五个Kv 7通道进行强烈增强其活性的氧化修饰诱导的生理浓度的过氧化氢。通道S2-S3接头中的三重半胱氨酸口袋对于这种效应至关重要。氧化诱导的M电流的增强产生了超极化和大鼠交感神经元的动作电位放电频率显着减少。由于过氧化氢在缺氧诱导的氧化应激过程中大量产生，我们使用了氧/葡萄糖剥夺神经变性模型，该模型显示神经元死亡被M电流阻断严重加速。这种阻断对常氧神经元的存活没有影响。这项工作描述了一种新的M通道调节途径，并提出了M通道在氧化应激过程中保护神经元沉默的作用。
Voltage-gated K+ channels of the Kv7 family underlie the neuronal M current that regulates action potential firing. Suppression of M current increases excitability and its enhancement can silence neurons. We here show that three of five Kv7 channels undergo strong enhancement of their activity by oxidative modification induced by physiological concentrations of hydrogen peroxide. A triple cysteine pocket in the channel S2-S3 linker is critical for this effect. Oxidation-induced enhancement of M current produced a hyperpolarization and a dramatic reduction of action potential firing frequency in rat sympathetic neurons. As hydrogen peroxide is robustly produced during hypoxia-induced oxidative stress, we used an oxygen/glucose deprivation neurodegeneration model that showed neuronal death to be severely accelerated by M current blockade. Such blockade had no effect on survival of normoxic neurons. This work describes a novel pathway of M-channel regulation and suggests a role for M channels in protective neuronal silencing during oxidative stress.