Ionotropic glutamate receptors of the AMPA subtype (AMPARs) mediate fast excitatory synaptic transmission in the CNS. They assemble as channel tetramers from four different subunits, GluRA-D, that are alternatively spliced and edited. Subunit composition regulates their vesicular traffic, synapse-specific targeting and their biophysical function. However, the molecular mechanism and the selectivity by which the assembly process occurs in the endoplasmic reticulum (ER) are not well understood. Recent experimental evidence suggests that ER quality control mechanisms detect conformational changes of AMPARs that are associated with its gating transitions. Thus, receptors that are competent of successfully sampling the gating cascade are preferably selected for ER export.

We have recently identified a novel family of transmembrane proteins as auxiliary subunits of AMPARs, referred to as auxAMPARs. Co-assembly of these proteins with AMPARs slows receptor gating kinetics and promotes its surface expression. Here, we investigated whether locking AMPARs in specific gating states affected the ability of auxAMPARs to increase receptor expression on the cell surface. Arrest of AMPARs in the open or the desensitized state significantly reduced potentiation of receptor surface expression by auxAMPARs, but did not completely abolish it. From these data, we conclude that at least part of the action of auxAMPARs on AMPAR surface expression critically depends on receptor conformation. We hypothesize that auxAMPARs stabilize gating states of AMPARs that favor export from the ER.

This study was supported by grants of the Deutsche Forschungsgemeinschaft to N. K. (SFB780/TPB4).