K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons
K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons
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DOI：
10.1038/nn1570
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发表时间：
2005-12-01
影响因子：
25
通讯作者：
Roeper, J
中科院分区：
文献类型：
--
作者：
Liss, B;Haeckel, O;Roeper, J
中脑黑质多巴胺能神经元的选择性变性是帕金森病的标志。邻近腹侧被盖区（VTA）的DA神经元受到的影响明显较小。DA神经元这种差异脆弱性的机制尚不清楚。我们确定ATP敏感性钾（K-ATP）通道的选择性激活作为一个潜在的机制。我们表明，在响应帕金森病诱导毒素，SN DA神经元的电生理活性，但不是腹侧被盖区DA神经元，是由于K-ATP通道的激活丢失。这种选择性K-ATP通道激活是由SN和VTA DA神经元之间的线粒体解偶联差异控制的。K-ATP通道孔形成亚基Kir6.2的遗传失活导致在两种机制上不同的多巴胺能变性小鼠模型中选择性拯救SN而不是VTA DA神经元，神经毒理学1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）模型和突变型韦弗小鼠。因此，K-ATP通道激活在促进慢性疾病中DA神经元死亡中具有意想不到的作用。
The selective degeneration of dopaminergic (DA) midbrain neurons in the substantia nigra (SN) is a hallmark of Parkinson disease. DA neurons in the neighboring ventral tegmental area (VTA) are significantly less affected. The mechanisms for this differential vulnerability of DA neurons are unknown. We identified selective activation of ATP-sensitive potassium (K-ATP) channels as a potential mechanism. We show that in response to parkinsonism-inducing toxins, electrophysiological activity of SN DA neurons, but not VTA DA neurons, is lost owing to activation of K-ATP channels. This selective K-ATP channel activation is controlled by differences in mitochondrial uncoupling between SN and VTA DA neurons. Genetic inactivation of the K-ATP channel pore-forming subunit Kir6.2 resulted in a selective rescue of SN but not VTA DA neurons in two mechanistically distinct mouse models of dopaminergic degeneration, the neurotoxicological 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine ( MPTP) model and the mutant weaver mouse. Thus, K-ATP channel activation has an unexpected role in promoting death of DA neurons in chronic disease.