Tyrosine Phosphorylation of the Kv2.1 Channel Contributes to Injury in Brain Ischemia.

Min-Young Song,Kang-Sik Park,Hye-Min Kang,Eun Ji Bae,Yong Jun Kim,Ji Yeon Hwang,Saesbyeol Kim,Chan Park

doi:10.3390/ijms21249538

Min-Young Song, Kang-Sik Park + Show 6 more

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https://doi.org/10.3390/ijms21249538

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Abstract

In brain ischemia, oxidative stress induces neuronal apoptosis, which is mediated by increased activity of the voltage-gated K+ channel Kv2.1 and results in an efflux of intracellular K+. The molecular mechanisms underlying the regulation of Kv2.1 and its activity during brain ischemia are not yet fully understood. Here this study provides evidence that oxidant-induced apoptosis resulting from brain ischemia promotes rapid tyrosine phosphorylation of Kv2.1. When the tyrosine phosphorylation sites Y124, Y686, and Y810 on the Kv2.1 channel are mutated to non-phosphorylatable residues, PARP-1 cleavage levels decrease, indicating suppression of neuronal cell death. The tyrosine residue Y810 on Kv2.1 was a major phosphorylation site. In fact, cells mutated Y810 were more viable in our study than were wild-type cells, suggesting an important role for this site during ischemic neuronal injury. In an animal model, tyrosine phosphorylation of Kv2.1 increased after ischemic brain injury, with an observable sustained increase for at least 2 h after reperfusion. These results demonstrate that tyrosine phosphorylation of the Kv2.1 channel in the brain may play a critical role in regulating neuronal ischemia and is therefore a potential therapeutic target in patients with brain ischemia.

Highlights

Oxidative stress has been shown to be a major risk factor for neuronal apoptosis and neurodegenerative diseases, as seen with Alzheimer’s and brain ischemia [1,2,3]
We explored the role of Kv2.1 tyrosine phosphorylation in the neuronal apoptosis induced by brain ischemia
We found that the Kv2.1 channel undergoes rapid tyrosine phosphorylation after oxidative stress in transfected HEK293 cells and in neurons after global brain ischemia (Figures 1A and 4C,D)

Summary

Introduction

Oxidative stress has been shown to be a major risk factor for neuronal apoptosis and neurodegenerative diseases, as seen with Alzheimer’s and brain ischemia [1,2,3]. The oxidative stress seen in ischemia in mammalian neurons is accompanied by enhancement of the K+ current [5]. This enhancement results in an efflux of K+ and is an essential factor for neuronal apoptosis [6]. Blocking Kv channels effectively attenuates cell death in many apoptotic models, which can be pharmacologically accomplished through the administration of staurosporine, an apoptotic drug [8]. This suggests that suppression of the K+ efflux via Kv channels can inhibit the apoptosis stimulated by oxidative stress [9]

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