The roles of voltage-gated K+ channels, Kv3.3 and Kv3.4 as oxidation sensor

Abstract

The functions and roles of voltage-gated potassium (Kv) channels in cell physiology, including cell proliferation, apoptosis, and wound healing, have been well investigated. However, the function of Kv channels as oxidation-sensitive channels have not yet been much investigated.<br/> The impact of oxidation-sensitive Kv channels on cell behavior was evaluated in the context of an increase in oxidative stress in this study. The function of the Kv3.1, Kv3.3, and Kv3.4 channels was the focus of the research because they have not been adequately investigated, despite being well-recognized as oxidation-sensitive channels. <br/> Kv3.3 was demonstrated to be involved in the hemin-induced erythroid differentiation of human leukemia cells, namely K562, via interaction with several signaling pathways, including mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB), and c-fos. Knockdown of Kv3.3 using siRNA-Kv3.3 increased hemin-induced erythroid differentiation, whereas overexpression of Kv3.3 did not have any effect on the cell differentiation. However, in the presence of fibronectin, the effect of siRNA-Kv3.3 contributed on the cell adhesion properties through the regulation of integrin β3 without having any effect on K562 erythroid differentiation. <br/> Kv3.4 was also found to play a pivotal role in the death of human SH-SY5Y neuroblastoma cells induced by oxidative stress and HIF-1α was suggested as a key regulator of Kv3.4. Accumulated HIF-1α by CoCl2 inhibited Kv3.4 to protect SH-SY5Y cells against CoCl2-induced oxidative damage. Although there was no accumulated HIF-1α by MPP+ treatment, inhibition of Kv3.4 using BDS-II, a Kv3.4 selective blocker, blocked apoptosis by inhibiting cytochrome c release from mitochondrial intermembrane space to cytosol and mitochondrial membrane potential depolarization during MPP+-induced SH-SY5Y cell death. <br/> Not normal cells but only cancer cells, such as A549 and MDA-MB-231 increased the expression levels of Kv3.1 and Kv3.4 in cell density dependent manner because they were exposed to the pericellular hypoxia and ROS accumulation according to the cell density increment. Increased Kv3.1 and Kv3.4 were involved in cancer cell migration and invasion to help the cells avoiding oxidative damage and excessive ROS accumulation and BDS-II blocked the cell migration and invasion by inhibiting pH regulation and ERK activation of the cancer cells.<br/> The present study demonstrates the role of the Kv channels as oxidation-sensitive channels and it would not only provide a new paradigm for studying Kv channels but also suggest oxidation-sensitive Kv channels as new biomarkers and therapeutic targets in oxidative stress-related disease.<br/>