Hydrogen-peroxide-induced toxicity of rat striatal neurones involves activation of a non-selective cation channel
Hydrogen-peroxide-induced toxicity of rat striatal neurones involves activation of a non-selective cation channel
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DOI：
10.1113/jphysiol.2002.034561
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发表时间：
2003-03-01
影响因子：
5.5
通讯作者：
Ashford, MLJ
中科院分区：
文献类型：
--
作者：
Smith, MA;Herson, PS;Ashford, MLJ
纹状体神经元特别容易受到缺氧/缺血诱导的损伤，自由基被认为是这种神经元破坏的主要介质。研究表明，过氧化氢（H2 O2）通过产生自由基，通过激活非选择性阳离子通道诱导大鼠胰岛素瘤细胞死亡，这导致不可逆的细胞去极化和不受调节的Ca 2+进入细胞。在这里提出的研究中，我们表明，纹状体神经元（中棘神经元）的亚群是去极化过氧化氢通过产生自由基。从大鼠培养的纹状体神经元的细胞贴附记录表明，暴露于H2 O2打开一个大的电导通道，其特征是极长的开放时间（秒）。由内而外的记录表明，细胞质应用，β-烟酰胺腺嘌呤二核苷酸激活一个通道，几乎没有电压依赖性，线性电流-电压关系和70和90 pS之间的单通道电导。该通道可渗透Na+、K+和Ca 2+离子。Fura-2成像从培养的纹状体神经元显示，H2 O2暴露诱导双相细胞内Ca 2+增加的亚群的神经元，第二，后期阶段导致Ca 2+超载。这后一个组成部分的Ca 2+反应是依赖于细胞外Ca 2+的存在，是独立的突触活动或电压门控Ca 2+通道开放。因此，这个通道可能是自由基诱导的选择性纹状体神经元破坏的重要贡献者。这些结果是非常相似的胰岛素瘤细胞观察到的，并表明，这个家庭的非选择性阳离子通道在哺乳动物组织中有广泛的分布。
Striatal neurones are particularly vulnerable to hypoxia/ischaemia-induced damage, and free radicals are thought to be prime mediators of this neuronal destruction. It has been shown that hydrogen peroxide (H2O2), through the production of free radicals, induces rat insulinoma cell death by activation of a non-selective cation channel, which leads to irreversible cell depolarization and unregulated Ca2+ entry into the cell. In the study presented here, we demonstrate that a subpopulation of striatal neurones (medium spiny neurones) is depolarized by H2O2 through the production of free radicals. Cell-attached recordings from rat cultured striatal neurones demonstrate that exposure to H2O2 opens a large-conductance channel that is characterized by extremely long open times (seconds). Inside-out recordings show that cytoplasmically applied,beta-nicotinamide adenine dinucleotide activates a channel with little voltage dependence, a linear current-voltage relationship and a single-channel conductance of between 70 and 90 pS. This channel is permeable to Na+, K+ and Ca2+ ions. Fura-2 imaging from cultured striatal neurones reveals that H2O2 exposure induces a biphasic intracellular Ca2+ increase in a subpopulation of neurones, the second, later phase resulting in Ca2+ overload. This later component of the Ca2+ response is dependent on the presence of extracellular Ca2+ and is independent of synaptic activity or voltage-gated Ca2+ channel opening. Consequently, this channel may be an important contributor to free radical-induced selective striatal neurone destruction. These results are remarkably similar to those observed for insulinoma cells and suggest that this family of nonselective cation channels has a widespread distribution in mammalian tissues.