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J Biol Chem ; 285(46): 36032-9, 2010 Nov 12.
Article in English | MEDLINE | ID: mdl-20837486

ABSTRACT

AMPA receptors (AMPARs) are tetrameric ion channels that mediate rapid glutamate signaling in neurons and many non-neuronal cell types. Endoplasmic reticulum (ER) quality control mechanisms permit only correctly folded functional receptors to be delivered to the cell surface. We analyzed the biosynthetic maturation and transport of all 12 GluA1-4 subunit splice variants as homomeric receptors and observed robust isoform-dependent differences in ER exit competence and surface expression. In contrast to inefficient ER exit of both GluA3 splice forms and the flop variants of GluA1 and GluA4, prominent plasma membrane expression was observed for the other AMPAR isoforms. Surprisingly, deletion of the entire N-terminal domain did not alter the transport phenotype, nor did the different cytosolic C-terminal tail splice variants. Detailed analysis of mutant receptors led to the identification of distinct residues in the ligand-binding domain as primary determinants for isoform-specific maturation. Considered together with the essential role of bound agonist, our findings reveal the ligand-binding domain as the critical quality control target in AMPAR biogenesis.


Subject(s)
Endoplasmic Reticulum/metabolism , Protein Structure, Tertiary , Receptors, AMPA/chemistry , Receptors, AMPA/metabolism , Alternative Splicing , Amino Acid Sequence , Animals , Binding Sites/genetics , COS Cells , Cell Membrane/metabolism , Chlorocebus aethiops , HEK293 Cells , Humans , Immunoblotting , Ligands , Microscopy, Fluorescence , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Multimerization , Protein Subunits/chemistry , Protein Subunits/genetics , Protein Subunits/metabolism , Protein Transport , Receptors, AMPA/genetics , Sequence Homology, Amino Acid
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