The role of S‐nitrosylation of kainate‐type of ionotropic glutamate receptor 2 in epilepsy induced by kainic acid. Issue 3 (26th December 2017)

• Record Type: Journal Article
• Authors: Wang, Linxiao; Liu, Yanyan; Lu, Rulan; Dong, Guoying; Chen, Xia; Yun, Wenwei; Zhou, Xianju
• Is Part Of: Journal of neurochemistry. Volume 144:Issue 3(2018)
• Page Start: 255
• Page End: 270
• Publication Date: 2017-12-26
• Subjects: calcium flow -- cell death -- epilepsy -- GluK2 -- nNOS -- S‐nitrosylation; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14266
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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. Abstract : GluK2 (kainate‐type of ionotropic glutamate receptor 2) plays an important role in epileptogenesis. However, the precise mechanisms are still unclear. In this study, kainic acid (KA)‐induced SNO‐GluK2 has a close connection with nitric oxide (NO) and cytoplasmic Ca 2+ . Activation of GluK2 by KA causes a progressive increase in cytoplasmic Ca 2+, not only facilitating Ca 2+ influx via voltage‐gated calcium channels (VGCCs) from the extracellular space, but also triggering RyR‐dependent calcium‐induced calcium release of endoplasmic reticulum (ER). This Ca 2+ rise activates nNOS and subsequently leads to S‐nitrosylation of GluK2 (SNO‐GluK2), promoting the assembling of GluK2‐PSD95‐nNOS signaling module, and eventually causing neuronal injury and death. These results suggest that SNO‐GluK2 may serve as a potential therapeutic target site for epilepsy. KARs, kainate receptors; RyRs, ryanodine receptors; PSD95, post‐synaptic density protein 95; nNOS, neuronal nitric oxide synthase;l ‐Arg, l ‐Arginine.