calcimycin and alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate

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-IP(3)R pathway and the signalling module GluR5·PSD-95·nNOS (the former is more important), led to Ca(2+) 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.

Topics: Animals; Apoptosis; Calcimycin; Calcium Signaling; Disks Large Homolog 4 Protein; GTP-Binding Protein alpha Subunits, Gq-G11; HEK293 Cells; Hippocampus; Humans; Inositol 1,4,5-Trisphosphate Receptors; Intracellular Signaling Peptides and Proteins; Isoxazoles; Membrane Potentials; Membrane Proteins; N-Methylaspartate; Neurons; Nitric Oxide Synthase Type I; Patch-Clamp Techniques; Propionates; Protein Multimerization; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid; Type C Phospholipases