ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity

Kainate receptors (KARs) regulate neuronal excitability and network function. Most KARs contain the subunit GluK2 and the properties of these receptors are determined in part by ADAR2-mediated mRNA editing of GluK2 that changes a genomically encoded glutamine (Q) to arginine (R). ADAR2-dependent Q/R editing of GluK2 is reduced during homeostatic plasticity induced by suppression of synaptic activity. However, the mechanism underlying this reduction in GluK2 editing has not been addressed. Here we show that induction of KAR up-scaling results in proteasomal degradation of ADAR2, which reduces GluK2 Q/R editing. Because KARs incorporating unedited GluK2(Q) assemble and exit the ER more efficiently this leads to increased surface expression and up-scaling of KARs. Consistent with this, we demonstrate that partial ADAR2 knockdown phenocopies and occludes KAR scaling. Moreover, we show that although the AMPAR subunit GluA2 also undergoes ADAR2-dependent Q/R editing, this process does not mediate AMPAR scaling. These data demonstrate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing are key determinants of KAR, but not AMPAR, trafficking and homeostatic plasticity.