Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit

NMDAR-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. In the adult forebrain, the majority of synaptic NMDAR currents are mediated by GluN2A-containing NMDARs. These receptors are rapidly inserted into synapses during LTP; however, the underlying molecular mechanisms remain poorly understood. Here we show that GluN2A is phosphorylated at Ser-1459 by CaMKIIα in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the SNX27-retromer complex, therefore enhancing the endosomal recycling of NMDARs. Loss of SNX27 or CaMKIIα function blocks the glycine-induced increase in GluN2A-NMDARs on the neuronal membrane. Interestingly, mutations of Ser-1459, including the rare S1459G human epilepsy variant, prolong decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the active duration of channel openings. Taken together, these findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but also explain how the S1459G epilepsy variant dysregulates NMDAR function.