LAUSR

Epilepsy is a chronic brain disease affecting millions of individuals. Kainate receptors, especially kainate‐type of ionotropic glutamate receptor 2 (GluK2), play an important role in epileptogenesis. Recent data showed that GluK2 could undergo post‐translational modifications in terms of S‐nitrosylation (SNO), and affect the signaling pathway of cell death in cerebral ischemia‐reperfusion. However, it is unclear whether S‐nitrosylation of GluK2 (SNO‐GluK2) contributes to cell death induced by epilepsy. Here, we report that kainic acid‐induced SNO‐GluK2 is mediated by GluK2 itself, regulated by neuronal nitric oxide synthase (nNOS) and the level of cytoplasmic calcium in vivo and in vitro hippocampus neurons. The whole‐cell patch clamp recordings showed the influence of SNO‐GluK2 on ion channel characterization of GluK2‐Kainate receptors. Moreover, immunohistochemistry staining results showed that inhibition of SNO‐GluK2 by blocking nNOS or GluK2 or by reducing the level of cytoplasmic calcium‐protected hippocampal neurons from kainic acid‐induced injury. Finally, immunoprecipitation and western blotting data revealed the involvement of assembly of a GluK2‐PSD95‐nNOS signaling complex in epilepsy. Taken together, our results showed that the SNO‐GluK2 plays an important role in neuronal injury of epileptic rats by forming GluK2‐PSD95‐nNOS signaling module in a cytoplasmic calcium‐dependent way, suggesting a potential therapeutic target site for epilepsy.