In the present study, we have investigated the role of the mammalian cornichon homologue CNIH-2 in AMPAR processing in both heterologous as well as primary cells. We show that CNIH-2 interacts with GluAs early in the secretory pathway and promotes COPII-dependent ER export of the receptors. As a consequence, CNIH-2 increases the density of functional AMPARs on the cell surface of heterologous cell lines and neurons. Moreover, our study demonstrates for the first time that mammalian CNIH-2 escapes from its evolutionarily conserved subcellular localization behavior that is cycling between the ER and Golgi complex and reaches the cell surface when accompanied by GluA subunits. Thus, AMPA receptors commandeer the cargo exporter CNIH-2 for use as a bona fide auxiliary subunit, which is then able to modify both AMPAR trafficking and gating.
