Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER retention and regulates the surface delivery of NMDA receptors

Neuropharmacology. 2003 Nov;45(6):755-67. doi: 10.1016/s0028-3908(03)00250-8.


Endoplasmic reticulum (ER) retention mediated by the RXR (Arg-X-Arg) motif is an important quality control mechanism used by G-protein coupled receptors and ion channels, including N-methyl-D-aspartate (NMDA) receptors, to ensure the proper assembly and trafficking of multimeric complexes. During assembly, RXR motifs are masked by intersubunit interactions thereby allowing ER release. Here, we find that PKA and PKC phosphorylation sites flanking the RXR motif of the NMDA receptor NR1 subunit suppress ER retention and regulate receptor forward trafficking. These sites are differentially phosphorylated during the trafficking of NR1 subunits in vivo, and phosphorylation at these sites occurs in early secretory compartments. In addition, residues near the RXR motif not involved in phosphorylation are also required for ER retention. These results indicate that ER retention of NMDA receptors is tightly regulated, and suggest that coordinated phosphorylation by PKA and PKC mediates release of receptors from the ER for subsequent traffic to synapses. Phosphorylation-induced ER export of RXR-containing channels and receptors may serve as a novel quality control mechanism for creating a readily releasable pool of receptors sensitive to the activation of intracellular signaling pathways.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Arginine / physiology*
  • COS Cells
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Molecular Sequence Data
  • Neurons / metabolism
  • Phosphorylation
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Kinase C / physiology
  • Rats
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*


  • NR1 NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Arginine
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C