Liss Birgit, Haeckel Olga, Wildmann Johannes, Miki Takashi, Seino Susumu, Roeper Jochen
Molecular Neurobiology, Department of Physiology, Marburg University Deutschhausstrasse 2, 35037 Marburg, Germany.
Nat Neurosci. 2005 Dec;8(12):1742-51. doi: 10.1038/nn1570. Epub 2005 Nov 20.
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.
黑质（SN）中多巴胺能（DA）中脑神经元的选择性退化是帕金森病的一个标志。相邻腹侧被盖区（VTA）中的DA神经元受影响明显较小。DA神经元这种差异易损性的机制尚不清楚。我们确定ATP敏感性钾（K-ATP）通道的选择性激活是一种潜在机制。我们发现，对诱发帕金森病的毒素作出反应时，SN DA神经元而非VTA DA神经元的电生理活动因K-ATP通道的激活而丧失。这种K-ATP通道的选择性激活受SN和VTA DA神经元之间线粒体解偶联差异的控制。在两种机制不同的多巴胺能退化小鼠模型——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weaver小鼠中，K-ATP通道孔形成亚基Kir6.2的基因失活导致SN DA神经元而非VTA DA神经元的选择性挽救。因此，K-ATP通道激活在促进慢性疾病中DA神经元死亡方面具有意想不到的作用。
