title: AMPA receptors commandeer an ancient cargo exporter for use as an auxiliary subunit for signaling.
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 α-subunits GluA1-4 and auxiliary β-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 role as a cargo exporter from the endoplasmic reticulum (ER). CNIH-2 cycles continuously between ER and Golgi complex to pick up cargo protein in the ER and then to mediate its preferential export in a coat protein complex (COP) II dependent manner. Interaction with GluA subunits breaks with this ancestral role of CNIH-2 confined to the early secretory pathway. While still taking advantage of being exported preferentially from the ER, GluAs recruit CNIH-2 to the cell surface. Thus, mammalian AMPARs commandeer CNIH-2 for use as a bona fide auxiliary subunit that is able to modify receptor signaling.
authors.affiliation: Institute of Neuro- and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Harmel
authors.forename: Barbara
authors.initials: B
authors.lastname: Cokic
authors.forename: Gerd
authors.initials: G
authors.lastname: Zolles
authors.forename: Henrike
authors.initials: H
authors.lastname: Berkefeld
authors.forename: Veronika
authors.initials: V
authors.lastname: Mauric
authors.forename: Bernd
authors.initials: B
authors.lastname: Fakler
authors.forename: Valentin
authors.initials: V
authors.lastname: Stein
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Klöcker
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D019143:Evolution, Molecular; D006367:HeLa Cells; D006801:Humans; D010802:Phylogeny; D061251:Primary Cell Culture; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D021381:Protein Transport / Q000235:genetics*; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
chemical_list: D021122:Protein Subunits; D018091:Receptors, AMPA; C539313:Cnih2 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins