A novel action of stargazin as an enhancer of AMPA receptor activity.

Stargazin (gamma-2) is disrupted in the ataxic and epileptic mutant mouse, stargazer (stg). The striking defect in the stg cerebellum is the lack of functional AMPA receptors on granule cells. Recently, it has been reported that gamma-2 and its related molecules are crucial for the surface expression, synaptic targeting and recycling of AMPA receptors, being termed collectively as the transmembrane AMPA receptor regulatory proteins (TARPs). However, it is still unclear whether TARPs directly modulate AMPA receptor activity. Here we report that coexpression of GluRalpha1 (GluR1) with gamma-2 using HEK293 cells and Xenopus oocytes markedly enhanced glutamate-induced currents. This effect was far beyond the increase of AMPA receptor surface expression and accompanied by increased glutamate affinity and subunit cooperativity. Other member of TARPs (gamma-3, gamma-4, and gamma-8) also enhanced the current response through the AMPA receptors. The enhancing effect by gamma-2 coexpression was further observed for homomeric GluRalpha2 (GluR2) channels, which, when expressed alone, are known to produce only a small or negligible current response. These results suggest that gamma-2 not only promotes AMPA receptor surface expression but also directly modulates AMPA receptor activity.