Phosphoproteomic Analysis Identifies Potassium Voltage-Gated Channel KCNQ2 and Anxa6 Alleviates Syt1-Mediated Ischemic Neuron Injury

Cerebral stroke is one of the leading causes of death in adults worldwide. However, the molecular mechanisms of stroke-induced neuron injury are not fully understood. Here, we obtained phosphoproteomic and proteomic profiles of acute ischemic hippocampus by LC-MS/MS analysis. Quantitative phosphoproteomic analyses revealed that the dysregulated phosphoproteins involved in synaptic components and neurotransmission. We further demonstrated that phosphorylation of synaptotagmin-1 (Syt1) at Thr112 site in cultured hippocampal neuron aggravated oxygen-glucose deprivation (OGD)-induced neuron injury. Immature neurons with Low expression of Syt1 exhibit slight neuron injury in cerebral ischemia model. Administration of Tat-Syt1T112A peptide protects neurons against cerebral ischemia-induced injury in vitro and in vivo. Surprisingly, potassium voltage-gated channel subfamily KQT member2 (KCNQ2) interacted with Syt1 and Anxa6, respectively, and alleviated Syt1-mediated neuron injury upon OGD treatment. These results reveal a mechanism underlying neuron injury and may provide new targets for neuroprotection after acute cerebral ischemia onset.