Tyrosine Phosphorylation of the K v 2.1 Channel Contributes to Injury in Brain Ischemia

In brain ischemia, oxidative stress induces neuronal apoptosis, which is mediated by increased activity of the voltage-gated K channel K 2.1 and results in an efflux of intracellular K . The molecular mechanisms underlying the regulation of K 2.1 and its activity during brain ischemia are not yet fu...

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Bibliographic Details
Published in:International journal of molecular sciences 2020-12, Vol.21 (24)
Main Authors: Song, Min-Young, Hwang, Ji Yeon, Bae, Eun Ji, Kim, Saesbyeol, Kang, Hye-Min, Kim, Yong Jun, Park, Chan, Park, Kang-Sik
Format: Article
Language:English
Subjects:
2,2'-Dipyridyl - analogs & derivatives
2,2'-Dipyridyl - pharmacology
Animals
Apoptosis - drug effects
Apoptosis - genetics
Brain Ischemia - genetics
Brain Ischemia - metabolism
Cell Survival - drug effects
Cell Survival - genetics
Disulfides - pharmacology
HEK293 Cells
Humans
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Mutation
Neurons - drug effects
Neurons - metabolism
Oxidative Stress - drug effects
Phosphorylation
Poly (ADP-Ribose) Polymerase-1 - metabolism
Rats
Shab Potassium Channels - genetics
Shab Potassium Channels - metabolism
Tyrosine - metabolism
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Summary:In brain ischemia, oxidative stress induces neuronal apoptosis, which is mediated by increased activity of the voltage-gated K channel K 2.1 and results in an efflux of intracellular K . The molecular mechanisms underlying the regulation of K 2.1 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 K 2.1. When the tyrosine phosphorylation sites Y124, Y686, and Y810 on the K 2.1 channel are mutated to non-phosphorylatable residues, PARP-1 cleavage levels decrease, indicating suppression of neuronal cell death. The tyrosine residue Y810 on K 2.1 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 K 2.1 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 K 2.1 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.
ISSN:1422-0067