Functional Effects of Cornichon Proteins on Homomeric Glua1 AMPAR Single-Channels

Abstract

Fast excitatory synaptic transmission in the brain is mediated mainly by AMPA receptors (AMPARs). AMPAR subunits associate with auxiliary transmembrane AMPAR regulatory proteins (TARPs) that have well established roles in modulating AMPAR trafficking, kinetics, and pharmacology. It has recently been proposed that the trafficking and kinetics of native AMPARs are also modulated by members of the cornichon family of proteins (Schwenk et al, 2009). There is also recent evidence that cornichons act only as intracellular trafficking chaperones for AMPARs in neurons (Shi et al, 2010). To determine the influence of cornichons on AMPAR single-channel properties we co-expressed GluA1 and cornichon 3 (CNIH3) in tsA201 cells and examined AMPARs in outside-out patches. The weighted mean single-channel conductance was increased in a dose-dependent manner when increasing amounts of CNIH3 cDNA were included in the transfection mix. Up to three open channel conductance levels were detected, with the lower conductance levels being more prevalent in cells with a low CNIH3/GluA1 cDNA ratio, and higher level conductance levels predominating in cells with a high CNIH3/ GluA1 cDNA ratio. CNIH3 also increased the burst duration of GluA1 single-channels. Fast application of glutamate onto excised patches indicated that CNIH3 slowed the rate of desensitization. As our data indicated that AMPAR channel properties were markedly altered by cornichons, we considered whether these proteins were expressed at the surface of cells where such modulation may be functionally important. Positive cell surface labeling of cornichons was not seen in neurons (see also Shi et al. 2010) but was detected in glial cells which express AMPARs. Supported by the Wellcome Trust. Schwenk, J. et al. (2009). Science, 323, 1313-9. Shi, Y., et al. (2010). Proc Natl Acad Sci USA, 107, 16315-9.