title: ATPA induced GluR5-containing kainite receptor S-nitrosylation via activation of GluR5-Gq-PLC-IP(3)R pathway and signalling module GluR5·PSD-95·nNOS.
abstract: 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.
authors.affiliation: Research Center of Biochemistry and Molecular Biology and Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, China.
authors.forename: Hai-Jian
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D000001:Calcimycin / Q000494:pharmacology; D020013:Calcium Signaling; D000076122:Disks Large Homolog 4 Protein; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011422:Propionates / Q000494:pharmacology*; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000001:Calcimycin; D000076122:Disks Large Homolog 4 Protein; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles; D008565:Membrane Proteins; D016202:N-Methylaspartate; D052248:Nitric Oxide Synthase Type I; D011422:Propionates; D018092:Kainic Acid Receptors; D010738:Type C Phospholipases; C501449:Dlg4 protein, rat; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate