ATPA induced GluR5-containing kainite receptor S-nitrosylation via activation of GluR5–Gq–PLC–IP3R pathway and signalling module GluR5·PSD-95·nNOS

GluR5-containing kainite receptor (GluR5–KAR) plays an important role in the pathophysiology of nervous system diseases, while S-nitrosylation exerts a variety of effects on biological systems. However, the mechanism of GluR5–KAR S-nitrosylation is still unclear up to now. Here our researches found that GluR5–KAR selective agonist ATPA stimulation activated the nonclassical GluR5–KAR–Gq–PLC–IP3R pathway and the signalling module GluR5·PSD-95·nNOS (the former is more important), led to Ca2+ release from intracellular calcium stores endoplasmic reticulum (ER) to cytoplasm and extracellular calcium indrawal, respectively, which further resulted in nNOS activation and GluR5–KAR S-nitrosylation, and then inhibited GluR5-mediated whole-cell current attenuation and induced apoptosis in primary cultured hippocampal neurons. Clarification of the primary mechanisms of GluR5–KAR S-nitrosylation induced by ATPA and identification of critical cysteine for GluR5-2a S-nitrosylation (Cys231 and Cys804) open up a brand-new field for revealing downstream signalling pathway of GluR5–KAR and its molecular characteristics, exploring the pathogenesis of neurological diseases and searching for promising therapies.

GluR5–KAR selective agonist ATPA stimulation activated the nonclassical GluR5–KAR–Gq–PLC–IP3R pathway and the signalling module GluR5·PSD-95·nNOS (the former is the most important), led to Ca2+ release from intracellular calcium store endoplasmic reticulum (ER) to cytoplasm and extracellular calcium indrawal, respectively, which further resulted in nNOS activation and GluR5–KAR S-nitrosylation, and then inhibited GluR5-mediated whole-cell current attenuation and induced apoptosis in primary cultured hippocampal neurons. 7NI, U-73122, 2-APB and BAPTA have a significant protective effect on hippocampal neurons.Figure optionsDownload high-quality image (203 K)Download as PowerPoint slide