Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Korea.
Sci Rep. 2017 May 18;7(1):2075. doi: 10.1038/s41598-017-02129-w.
The Kv3.4 channel is characterized by fast inactivation and sensitivity to oxidation. However, the physiological role of Kv3.4 as an oxidation-sensitive channel has yet to be investigated. Here, we demonstrate that Kv3.4 plays a pivotal role in oxidative stress-related neural cell damage as an oxidation-sensitive channel and that HIF-1α down-regulates Kv3.4 function, providing neuroprotection. MPP and CoCl are reactive oxygen species (ROS)-generating reagents that induce oxidative stress. However, only CoCl decreases the expression and function of Kv3.4. HIF-1α, which accumulates in response to CoCl treatment, is a key factor in Kv3.4 regulation. In particular, mitochondrial Kv3.4 was more sensitive to CoCl. Blocking Kv3.4 function using BDS-II, a Kv3.4-specific inhibitor, protected SH-SY5Y cells against MPP-induced neural cell death. Kv3.4 inhibition blocked MPP-induced cytochrome c release from the mitochondrial intermembrane space to the cytosol and mitochondrial membrane potential depolarization, which are characteristic features of apoptosis. Our results highlight Kv3.4 as a possible new therapeutic paradigm for oxidative stress-related diseases, including Parkinson's disease.
Kv3.4 通道的特点是快速失活和对氧化的敏感性。然而，Kv3.4 作为氧化敏感通道的生理作用尚未得到研究。在这里，我们证明 Kv3.4 作为氧化敏感通道在氧化应激相关的神经细胞损伤中起着关键作用，并且 HIF-1α 下调 Kv3.4 功能，提供神经保护。MPP 和 CoCl 是产生活性氧（ROS）的试剂，可诱导氧化应激。然而，只有 CoCl 降低 Kv3.4 的表达和功能。HIF-1α 是一种关键因子，在 CoCl 处理时会积累，从而调节 Kv3.4。特别是，线粒体 Kv3.4 对 CoCl 更为敏感。使用 Kv3.4 特异性抑制剂 BDS-II 阻断 Kv3.4 功能可保护 SH-SY5Y 细胞免受 MPP 诱导的神经细胞死亡。Kv3.4 抑制阻断了 MPP 诱导的细胞色素 c 从线粒体间腔释放到细胞质和线粒体膜电位去极化，这是细胞凋亡的特征。我们的结果强调了 Kv3.4 作为氧化应激相关疾病（包括帕金森病）的一种新的可能的治疗范例。
