Oxidative Stress Induces Disruption of the Axon Initial Segment.
Oxidative Stress Induces Disruption of the Axon Initial Segment.
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DOI：
10.1177/1759091417745426
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发表时间：
2017-11
期刊：
影响因子：
4.7
通讯作者：
Dupree JL
中科院分区：
文献类型：
--
作者：
Clark K;Sword BA;Dupree JL
轴突起始段（AIS）是负责动作电位启动和维持神经元极性的区域，在多种中枢神经系统病理损伤中会成为被破坏的目标。我们实验室先前的研究表明，在两种不同的中枢神经系统炎症小鼠模型中，氧化应激是AIS结构改变的潜在介导因素，因为在清除活性氧和消除NADPH氧化酶 - 2后，这些影响会减弱。虽然这些研究表明氧化应激在AIS的调节中起作用，但活性氧和氮物质（ROS/RNS）对该区域稳定性的直接影响仍不清楚。在此，我们证明通过用3 - 吗啉代斯德酮亚胺（SIN - 1，一种自发的ROS/RNS产生剂）处理所诱导的氧化应激，会促使体外原代皮质神经元中AIS蛋白聚集的可逆性丧失。对电压依赖性和细胞内钙（Ca2 +）通道的药理学抑制表明，这种AIS破坏机制涉及Ca2 +特别通过L型电压依赖性Ca2 +通道进入以及从IP3门控的细胞内储存库中释放。此外，ROS/RNS诱导的AIS破坏依赖于钙蛋白酶的激活，钙蛋白酶是一种先前已被证明可驱动AIS调节的Ca2 +激活的蛋白酶。总体而言，我们首次证明通过外源性应用ROS/RNS所诱导的氧化应激能够促使AIS复合物的结构改变。
The axon initial segment (AIS), the domain responsible for action potential initiation and maintenance of neuronal polarity, is targeted for disruption in a variety of central nervous system pathological insults. Previous work in our laboratory implicates oxidative stress as a potential mediator of structural AIS alterations in two separate mouse models of central nervous system inflammation, as these effects were attenuated following reactive oxygen species scavenging and NADPH oxidase-2 ablation. While these studies suggest a role for oxidative stress in modulation of the AIS, the direct effects of reactive oxygen and nitrogen species (ROS/RNS) on the stability of this domain remain unclear. Here, we demonstrate that oxidative stress, as induced through treatment with 3-morpholinosydnonimine (SIN-1), a spontaneous ROS/RNS generator, drives a reversible loss of AIS protein clustering in primary cortical neurons in vitro. Pharmacological inhibition of both voltage-dependent and intracellular calcium (Ca2+) channels suggests that this mechanism of AIS disruption involves Ca2+ entry specifically through L-type voltage-dependent Ca2+ channels and its release from IP3-gated intracellular stores. Furthermore, ROS/RNS-induced AIS disruption is dependent upon activation of calpain, a Ca2+-activated protease previously shown to drive AIS modulation. Overall, we demonstrate for the first time that oxidative stress, as induced through exogenously applied ROS/RNS, is capable of driving structural alterations in the AIS complex.
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