Hippocampal AMPA Receptor Gating Controlled by Both TARP and Cornichon Proteins

Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs gamma-4, gamma-7, and gamma-8, but not gamma-2, gamma-3, or gamma-5, cause AMPA receptors to resensitize upon continued glutamate application. With gamma-8, resensitization occurs with all GluA subunit combinations; however, gamma-8-containing hippocampal neurons do not display resensitization. In recombinant systems, CNIH-2 abrogates gamma-8-mediated resensitization and modifies AMPA receptor pharmacology and gating to match that of hippocampal neurons. In hippocampus, gamma-8 and CNIH-2 associate in postsynaptic densities and CNIH-2 protein levels are markedly diminished in gamma-8 knockout mice. Manipulating neuronal CNIH-2 levels modulates the electrophysiological properties of extrasynaptic and synaptic gamma-8-containing AMPA receptors. Thus, gamma-8 and CNIH-2 functionally interact with common hippocampal AMPA receptor complexes to modulate synergistically kinetics and pharmacology.