title: The AMPA receptor subunit GluR-B in its Q/R site-unedited form is not essential for brain development and function.
abstract: Calcium permeability of L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in excitatory neurons of the mammalian brain is prevented by coassembly of the GluR-B subunit, which carries an arginine (R) residue at a critical site of the channel pore. The codon for this arginine is created by site-selective adenosine deamination of an exonic glutamine (Q) codon at the pre-mRNA level. Thus, central neurons can potentially control the calcium permeability of AMPARs by the level of GluR-B gene expression as well as by the extent of Q/R-site editing, which in postnatal brain, positions the R codon into >99% of GluR-B mRNA. To study whether the small amount of unedited GluR-B is of functional relevance, we have generated mice carrying GluR-B alleles with an exonic arginine codon. We report that these mutants manifest no obvious deficiencies, indicating that AMPAR-mediated calcium influx into central neurons can be solely regulated by the levels of Q/R site-edited GluR-B relative to other AMPAR subunits. Notably, a targeted GluR-B gene mutant with 30% reduced GluR-B levels had 2-fold higher AMPAR-mediated calcium permeability in hippocampal pyramidal cells with no sign of cytotoxicity. This constitutes proof in vivo that elevated calcium influx through AMPARs need not generate pathophysiological consequences.
authors.affiliation: Department of Molecular Neuroscience, Max-Planck-Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kask
authors.forename: D
authors.initials: D
authors.lastname: Zamanillo
authors.forename: A
authors.initials: A
authors.lastname: Rozov
authors.forename: N
authors.initials: N
authors.lastname: Burnashev
authors.forename: R
authors.initials: R
authors.lastname: Sprengel
authors.forename: P H
authors.initials: PH
authors.lastname: Seeburg
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017136:Ion Transport / Q000502:physiology; D008297:Male; D051379:Mice; D009154:Mutation; D018091:Receptors, AMPA / Q000737:chemistry / Q000502:physiology*; D017470:Receptors, Glutamate / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C115953:glutamate receptor type B; D002118:Calcium