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AMPA Receptors Commandeer an Ancient Cargo Exporter for Use as an Auxiliary Subunit for Signaling 1 2 3 3 1 3,4 Nadine Harmel , Barbara Cokic , Gerd Zolles , Henrike Berkefeld , Veronika Mauric , Bernd Fakler , 5 ¨ 1 Valentin Stein , Nikolaj Klocker * ¨ ¨ 1 Institute of Neuro- and Sensory Physiology, Medical Faculty, University of Dusseldorf, Dusseldorf, Germany, 2 Department of Synaptic Receptor Trafficking, Max-Planck- Institute of Neurobiology, Martinsried, Germany, 3 Institute of Physiology, University of Freiburg, Freiburg, Germany, 4 Center for Biological Signaling Studies (BIOSS), Freiburg, Germany, 5 Department of Physiology, University of Bonn, Bonn, Germany Abstract Fast excitatory neurotransmission in the mammalian central nervous system is mainly mediated by ionotropic glutamate receptors of the AMPA subtype (AMPARs). AMPARs are protein complexes of the pore-lining a-subunits GluA1-4 and auxiliary b-subunits modulating their trafficking and gating. By a proteomic approach, two homologues of the cargo exporter cornichon, CNIH-2 and CNIH-3, have recently been identified as constituents of native AMPARs in mammalian brain. In heterologous reconstitution experiments, CNIH-2 promotes surface expression of GluAs and modulates their biophysical properties. However, its relevance in native AMPAR physiology remains controversial. Here, we have studied the role of CNIH-2 in GluA processing both in heterologous cells and primary rat neurons. Our data demonstrate that CNIH-2 serves an evolutionarily conserved