Different domains of AMPA receptors direct stargazin-mediated trafficking and stargazin-mediated modulation of kinetics

Abstract

Transmembrane AMPA Receptor Regulatory Proteins (TARPs) are the first transmembrane proteins known to associate with AMPA receptors. There are four known TARPs: γ-2, γ-3, γ-4, and γ-8. TARPs are expressed differentially in the brain but there is some overlap. Of these, γ-2, or stargazin is the most extensively studied. There is significant homology between the TARPs and all four have been shown to increase the relative amount of AMPA receptor surface expression in HEK293 cells as well as in several other recombinant expression systems. Additionally, stargazin slows both AMPA receptor desensitization and deactivation kinetics. The major purpose of this work was to determine the nature of the stargazin-AMPA receptor interaction. This work provides strong evidence that the AMPA receptor domains required for stargazin-modulation of gating and trafficking are separable. An intracellular interaction between the cytoplasmic tails of the two proteins is necessary for an enhancement of surface expression while this same site is not necessary for stargazin-mediated modulation of desensitization kinetics. This interaction appears to occur early in the biosynthetic pathway.