Ampa Receptor Synthesis And Regulated Exit From The Endoplasmic Reticulum

AMPARs are hetero-tetrameric molecules7 composed of different combinations of GluR1, GluR2, GluR3, and GluR4 subunits8. In the mature hippocampus, most AMPARs are composed of GluR1-GluR2 or GluR2-GluR3 combinations9, whereas GluR4-containing AMPARs are expressed mainly in early postnatal development10. These oligomeric combinations are formed in the endoplasmic reticulum (ER) through mechanisms that are not well understood but that seem to depend on interactions between the luminal, N-terminal domains of the subunits11 and the presence of an edited arginine residue (R607) at the channel pore of the GluR2 subunit12. GluR1-GluR2 hetero-oligomers exit the ER rapidly, and traffic to the Golgi compartment where they become fully glycosylated13. In contrast, GluR2-GluR3 hetero-tetramers have a much longer residence time at the ER. In fact, a significant fraction of the GluR2 subunit is retained within the ER as an immature protein, in an active manner that depends on the presence of the positively charged R607 at the channel pore13. GluR1, GluR3, and GluR4 mRNAs are not edited at this position, and therefore, these subunits contain a noncharged glutamine residue at the channel pore and do not undergo retention at the ER. The retention protein that prevents immature GluR2 from exiting the ER is not known; however, a fraction of AMPARs associates with the ER chaperones BiP and calnexin14, and GluR2 colocalizes extensively with BiP in the ER13. Therefore, it is plausible that chaperones residing at the ER are related with the retention mechanism.

Additionally, export of AMPARs from the ER may require the interaction of the cytoplasmic, C-terminal domain of the AMPAR subunits with other proteins. The GluR2 C-terminus has a PDZ motif (-SVKI) that interacts with several PDZ domain-containing proteins, including PICK115, which is thought to be necessary for GluR2's exit from the ER13. The GluR1 C-terminus also contains a PDZ motif (-ATGL), which interacts with SAP9716. This interaction is known to occur early in the secretory pathway, probably while the receptor is still in the ER17. However, it is not known whether the SAP97-GluR1 interaction is necessary for this subunit to exit the ER.

Finally, AMPAR exit from the ER and acquisition of mature glycosylation at the Golgi complex is assisted by a family of transmembrane AMPA receptor regulatory proteins (TARPs)18, of which stargazin is the founding member19. Indeed, TARPs are currently considered as auxiliary proteins for AMPARs20,21, which may have chaperone-like functions during their early trafficking stages. The relevance of this family of proteins for the delivery of AMPARs into the cell surface and into synapses is discussed below.

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