ATP-sensitive potassium (K-ATP) channels express in the central nervous system extensively which coupling cell metabolism and cellular electrical activity. K-ATP channels in mature substantia nigra (SN) dopaminergic (DA) neurons are composed of inwardly rectifying potassium channel (Kir) subunit 6.2 and sulfonylurea receptor 1 (SUR1). Our previous study revealed that regulating K-ATP channel exerts the protective effect on DA neurons in a mouse model of Parkinson's disease (PD). However, the detailed mechanism underlying the role of Kir6.2/K-ATP remains unclear. In the present study, we found the deletion of Kir6.2 dramatically alleviated PD-like motor dysfunction of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD model. We further found that Kir6.2 knockout selectively restored the reduction of both DA neuronal number and dopamine transmitter level in the nigrostriatal of MPTP-treated PD mice. To gain some understanding on the molecular basis of this effect, we focused on the regulation of Kir6.2 deletion on iron metabolism which is tightly associated with DA neuron damage. We found that Kir6.2 knockout suppressed the excessive iron accumulation in MPTP-treated mouse midbrain and inhibited the upregulation of ferritin light chain (FTL), which is a main intracellular iron storage protein. We probed further and found out that the deletion of Kir6.2 inhibited the excessive production of FTL via IRP-IRE regulatory system, and thereby protecting SN DA neurons against MPTP challenge. Our findings suggest that Kir6.2 plays a crucial role in the pathogenesis of PD and regulating Kir6.2/K-ATP channel may be a promising strategy for PD treatment.

ATP敏感性钾（K-ATP）通道在中枢神经系统中广泛表达，与细胞代谢和细胞电活动耦合。成熟的黑质（SN）多巴胺能（DA）神经元中的K-ATP通道由向内整流的钾通道（Kir）亚基6.2和磺酰脲受体1（SUR1）组成。我们以前的研究表明，调节帕金森氏病（PD）小鼠模型中的K-ATP通道对DA神经元具有保护作用。但是，Kir6.2 / K-ATP作用的详细机制尚不清楚。在本研究中，我们发现Kir6.2的缺失极大地减轻了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）PD模型的PD样运动功能障碍。我们进一步发现了Kir6。2基因敲除选择性地恢复了MPTP治疗的PD小鼠黑纹状体中DA神经元数量和多巴胺递质水平的降低。为了对这种作用的分子基础有所了解，我们集中研究了铁代谢中与Kir神经元损伤紧密相关的Kir6.2缺失的调控。我们发现，Kir6.2基因敲除抑制了MPTP处理的小鼠中脑中过多的铁蓄积，并抑制了铁蛋白轻链（FTL）（一种主要的细胞内铁存储蛋白）的上调。我们进一步探查，发现Kir6.2的缺失通过IRP-IRE调节系统抑制了FTL的过量产生，从而保护了SN DA神经元免受MPTP攻击。我们的发现表明，Kir6.2在PD的发病机理和调节Kir6中起着至关重要的作用。