title: Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis.
abstract: The subunit composition determines AMPA receptor (AMPA-R) function and trafficking. Mechanisms underlying channel assembly are thus central to the efficacy and plasticity of glutamatergic synapses. We previously showed that RNA editing at the Q/R site of the GluR2 subunit contributes to the assembly of AMPA-R heteromers by attenuating formation of GluR2 homotetramers. Here we report that this function of the Q/R site depends on subunit contacts between adjacent ligand binding domains (LBDs). Changes of LBD interface contacts alter GluR2 assembly properties, forward traffic, and expression at synapses. Interestingly, developmentally regulated RNA editing within the LBD (at the R/G site) produces analogous effects. Our data reveal that editing to glycine reduces the self-assembly competence of this critical subunit and slows GluR2 maturation in the endoplasmic reticulum (ER). Therefore, RNA editing sites, located at strategic subunit interfaces, shape AMPA-R assembly and trafficking in a developmentally regulated manner.
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom. ig@mrc-lmb.cam.ac.uk
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Greger
authors.forename: Pearl
authors.initials: P
authors.lastname: Akamine
authors.forename: Latika
authors.initials: L
authors.lastname: Khatri
authors.forename: Edward B
authors.initials: EB
authors.lastname: Ziff
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D018507:Gene Expression Regulation, Developmental; D005998:Glycine / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009473:Neuronal Plasticity / Q000235:genetics; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics; D017393:RNA Editing / Q000235:genetics*; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D018091:Receptors, AMPA; D012313:RNA; C104722:glutamate receptor ionotropic, AMPA 2; D005998:Glycine