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Free keywords:
LONG-TERM POTENTIATION; ENDOPLASMIC-RETICULUM; ER EXPORT; SYNAPTIC
PLASTICITY; KINETIC-PROPERTIES; GLUTAMATE RECEPTORS; CORNICHON
PROTEINS; LENTIVIRAL VECTORS; TRAFFICKING; CHANNELSBiology;
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
alpha-subunits GluA1-4 and auxiliary beta-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.
