Tyrosine Phosphorylation of the K2.1 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 K2.1 and results in an efflux of intracellular K. The molecular mechanisms underlying the regulation of K2.1 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 K2.1. When the tyrosine phosphorylation sites Y124, Y686, and Y810 on the K2.1 channel are mutated to non-phosphorylatable residues, PARP-1 cleavage levels decrease, indicating suppression of neuronal cell death. The tyrosine residue Y810 on K2.1 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 K2.1 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 K2.1 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.