The transmembrane AMPA receptor regulatory protein gamma 4 is a more effective modulator of AMPA receptor function than stargazin (gamma 2).

AMPA receptors mediate the majority of the fast excitatory synaptic transmission in the brain. A family of recently described auxiliary proteins, the transmembrane AMPA receptor regulatory proteins (TARPs) gamma2, gamma3, gamma4, and gamma8, have been shown to modulate the trafficking of receptors to the plasma membrane as well as electrophysiological key properties. Most studies published to date focus exclusively on gamma2 (stargazin), neglecting the other three members of the TARP family. Here, we analyzed the modulation of electrophysiological properties of AMPA receptors by gamma4 and compare it with gamma2, using heterologous coexpression in human embryonic kidney 293 cells. We show for the first time that gamma4, a previously poorly examined TARP, modulates the desensitization properties of AMPA receptors significantly stronger than gamma2 does. In contrast, other properties such as kainate efficacy and current-voltage relationships are modulated in a similar way by both of these TARPs. From these TARP-specific effects, we propose an interaction mechanism between AMPA receptors and TARPs and address the physiological relevance of gamma4 and its regulatory effects, particularly on AMPA receptor desensitization properties, to developmental and regulatory processes in the brain.