Cellular excitability is not only determined by the type but also by the number of ion channels present in the plasma membrane. Their surface expression might be controlled beyond the level of biosynthesis by protein-protein interactions that govern their anterograde or retrograde transport steps along the secretory pathway.

We have recently identified a novel family of auxiliary subunits of ionotropic glutamate receptors of the AMPA subtype (AMPARs), referred to as auxAMPARs. Functionally, auxAMPARs slow channel gating and promote their surface expression. Here, we investigated the molecular mechanism underlying the increase in AMPAR surface expression. To this end, the subcellular distribution of auxAMPARs was characterized upon heterologous expression in HeLa cells and in dissociated hippocampal neurons. Colocalization with respective marker proteins demonstrated that auxAMPARs reside predominantly in the Golgi complex and to lower extent in the endoplasmic reticulum (ER). Mutation of a hydrophobic consensus motif in their cytoplasmic C-terminus, known to recruit the coat protein complex II (COPII) which mediates selective ER export, abolished Golgi localization of auxAMPARs and retained them within the ER. Coexpression of this mutant with the AMPAR subtype GluRA led to a significant retention of the channel in the ER thereby reducing its surface expression.

These findings suggest that auxAMPARs interact with AMPARs at the level of the ER and promote their surface expression by facilitating their selective export from the ER.

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