Kv3.4 is modulated by HIF-1α to protect SH-SY5Y cells against oxidative stress-induced neural cell death

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(2) are reactive oxygen species (ROS)-generating reagents that induce oxidative stress. However, only CoCl(2) decreases the expression and function of Kv3.4. HIF-1α, which accumulates in response to CoCl(2) treatment, is a key factor in Kv3.4 regulation. In particular, mitochondrial Kv3.4 was more sensitive to CoCl(2). 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.