Cell surface expression of GluR5 kainate receptors is regulated by an endoplasmic reticulum retention signal

J Biol Chem. 2003 Dec 26;278(52):52700-9. doi: 10.1074/jbc.M309585200. Epub 2003 Oct 3.


Kainate receptors (KARs) are mediators of excitatory neurotransmission in the mammalian central nervous system, and their efficient targeting and trafficking is critical for normal synaptic function. A key step in the delivery of KARs to the neuronal plasma membrane is the exit of newly assembled receptors from the endoplasmic reticulum (ER). Here we report the identification of a novel ER retention signal in the alternatively spliced C-terminal domain of the GluR5-2b subunit, which controls receptor trafficking in both heterologous cells and neurons. The ER retention motif consists of a critical arginine (Arg-896) and surrounding amino acids, disruption of which promotes ER exit and surface expression of the receptors, as well as altering their physiological properties. The Arg-896-mediated ER retention of GluR5 is regulated by a mutation that mimics phosphorylation of Thr-898, but not by PDZ interactions. Furthermore, two positively charged residues (Arg-900 and Lys-901) in the C terminus were also found to regulate ER export of the receptors. Taken together, our results identify novel trafficking signals in the C-terminal domain of GluR5-2b and demonstrate that alternative splicing is an important mechanism regulating KAR function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Arginine / chemistry
  • Biotinylation
  • Blotting, Western
  • COS Cells
  • Cell Line
  • Cell Membrane / metabolism*
  • Electrophysiology
  • Endoplasmic Reticulum / metabolism*
  • Flow Cytometry
  • Gene Deletion
  • Gene Expression Regulation
  • Genetic Vectors
  • Humans
  • Immunoblotting
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Mutation
  • Neurons / metabolism
  • Phosphorylation
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Kainic Acid / biosynthesis*
  • Receptors, Kainic Acid / chemistry*
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Transfection


  • Gluk1 kainate receptor
  • Receptors, Kainic Acid
  • Arginine