Activation of mitochondrial, ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of bax translocation and cytochrome c release
Activation of mitochondrial, ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of bax translocation and cytochrome c release
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DOI：
10.1097/00004647-200204000-00007
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发表时间：
2002-04-01
影响因子：
6.3
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Liu, D;Lu, CB;Mattson, MP
神经元表达多种质膜钾通道，在调节神经元兴奋性和突触传递中发挥重要作用，但也含有线粒体 ATP 敏感钾通道，其功能尚不清楚。对心肌细胞的研究表明，类似的线粒体 ATP 敏感钾通道参与缺血预处理过程，表明其在调节细胞存活中发挥作用。作者报告说，给予二氮嗪（一种线粒体 ATP 敏感钾通道激活剂）的小鼠，在大脑中动脉永久闭塞后，皮质梗塞面积大幅减少（60% 至 70%）。二氮嗪可减少缺血皮质半暗区的神经元凋亡并增加星形胶质细胞的存活和激活。二氮嗪的神经保护作用被 5-羟基癸酸酯（线粒体 ATP 敏感钾通道的选择性拮抗剂）消除。对培养的海马神经元的研究表明，二氮嗪可以使线粒体去极化，阻止细胞色素 c 的释放，并保护细胞免受十字孢菌素和化学缺氧诱导的死亡。二氮嗪增加了 Bcl2 的水平，并抑制了受到凋亡损伤的神经元中 Bax 与线粒体的结合，这表明线粒体 ATP 敏感钾通道的激活可能通过差异调节促凋亡和抗凋亡蛋白来稳定线粒体功能。总的来说，数据表明线粒体 ATP 敏感钾通道在缺血条件下调节神经元存活中发挥关键作用，并确定激活线粒体 ATP 敏感钾通道的药物作为中风和相关神经退行性疾病的潜在治疗方法。
Neurons express a variety of plasma-membrane potassium channels that play important roles in regulating neuronal excitability and synaptic transmission, but also contain mitochondrial ATP-sensitive potassium channels, the functions of which are unknown. Studies of cardiac cells suggest that similar mitochondrial ATP-sensitive potassium channels are involved in the process of ischemic preconditioning, suggesting a role in regulating cell survival. The authors report that mice given diazoxide, an activator of mitochondrial ATP-sensitive potassium channels, exhibited a large (60% to 70%) decrease in cortical infarct size after permanent occlusion of the middle cerebral artery. Diazoxide decreases neuronal apoptosis and increases astrocyte survival and activation in the penumbral region of the ischemic cortex. The neuroprotective effect of diazoxide is abolished by 5-hydroxydecanoate, a selective antagonist of mitochondrial ATP-sensitive potassium channels. Studies of cultured hippocampal neurons reveal that diazoxide depolarizes mitochondria, prevents cytochrome c release, and protects cells against death induced by staurosporine and chemical hypoxia. Diazoxide increased the levels of Bcl2 and inhibited the association of Bax with mitochondria in neurons exposed to an apoptotic insult, suggesting that activation of mitochondrial ATP-sensitive potassium channels may stabilize mitochondrial function by differentially modulating proapoptotic and antiapoptotic proteins. Collectively, the data suggest that mitochondrial ATP-sensitive potassium channels play a key role in modulating neuronal survival under ischemic conditions, and identify agents that activate mitochondrial ATP-sensitive potassium channels as potential therapeutics for stroke and related neurodegenerative conditions.