Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, China.
Aging Cell. 2022 May;21(5):e13618. doi: 10.1111/acel.13618. Epub 2022 Apr 20.
Accumulating evidence suggests that ATP-sensitive potassium (K ) channels play an important role in the selective degeneration of dopaminergic neurons in the substantia nigra (SN). Furthermore, the expression of the K channel subunit sulfonylurea receptor 1 (SUR1) is upregulated in the remaining nigral dopaminergic neurons in Parkinson's disease (PD). However, the mechanism underlying this selective upregulation of the SUR1 subunit and its subsequent roles in PD progression are largely unknown. In 3-, 6-, and 9-month-old A53T α-synuclein transgenic (α-SynA53T ) mice, only the SUR1 subunit and not SUR2B or Kir6.2 was upregulated, accompanied by neuronal damage. Moreover, the occurrence of burst firing in dopaminergic neurons was increased with the upregulation of the SUR1 subunit, whereas no changes in the firing rate were observed except in 9-month-old α-SynA53T mice. After interference with SUR1 expression by injection of lentivirus into the SN, the progression of dopaminergic neuron degeneration was delayed. Further studies showed that elevated expression of the transcription factors FOXA1 and FOXA2 could cause the upregulation of the SUR1 subunit in α-SynA53T mice. Our findings revealed the regulatory mechanism of the SUR1 subunit and the role of K channels in the progression of dopaminergic neuron degeneration, providing a new target for PD drug therapy.
越来越多的证据表明，三磷酸腺苷敏感性钾（K）通道在黑质（SN）中多巴胺能神经元的选择性退化中起着重要作用。此外，在帕金森病（PD）中，剩余的黑质多巴胺能神经元中 K 通道亚单位磺酰脲受体 1（SUR1）的表达上调。然而，SUR1 亚基这种选择性上调的机制及其在 PD 进展中的后续作用在很大程度上尚不清楚。在 3、6 和 9 月龄 A53T ɑ-突触核蛋白转基因（α-SynA53T）小鼠中，只有 SUR1 亚基而不是 SUR2B 或 Kir6.2 上调，伴随着神经元损伤。此外，随着 SUR1 亚基的上调，多巴胺能神经元的爆发性放电增加，而除了 9 月龄的 α-SynA53T 小鼠外，放电率没有变化。通过向 SN 注射慢病毒干扰 SUR1 表达后，多巴胺能神经元退化的进展被延迟。进一步的研究表明，转录因子 FOXA1 和 FOXA2 的高表达可导致 α-SynA53T 小鼠中 SUR1 亚基的上调。我们的研究结果揭示了 SUR1 亚基的调节机制以及 K 通道在多巴胺能神经元退化进展中的作用，为 PD 药物治疗提供了新的靶点。
