Differential regulation of AMPA receptor GluA1 phosphorylation at serine 831 and 845 associated with activation of NMDA receptor subpopulations

AMPA receptors and NMDA receptors are the main subtypes of ionotropic glutamate receptors in the vertebrate central nervous system. Accumulating evidence demonstrates that two serine sites, S831 and S845, on the AMPA receptor GluA1 subunit, are phosphorylation-regulated and profoundly involved in NMDA receptor-dependent synaptic plasticity. On the other hand, recent studies have revealed distinct functional consequences of activating synaptic or extrasynaptic NMDA receptors, or of activating GluN2A- or GluN2B-containing NMDA receptors. Therefore, it is essential to determine how phosphorylation of the GluA1 at S831 and S845 is regulated by NMDA receptor subpopulations. In this study, we demonstrated transiently increased phosphorylation of GluA1 at S831 and persistently decreased phosphorylation of GluA1 at S845 by bath application of NMDA to hippocampal slices from rats. Interestingly, we also found a differential regulation of phosphorylation of GluA1 at S831 and S845 by activation of NMDA receptor subpopulations: the synaptic and/or the GluN2A-containing NMDA receptors were more likely to mediate up-regulation of GluA1 phosphorylation at S831 and down-regulation of GluA1 phosphorylation at S845, while the extrasynaptic NMDA receptors down-regulated GluA1 phosphorylation at S831. Taken together, our results suggest the NMDA receptor subpopulations differentially regulate GluA1 phosphorylation, which may contribute to NMDA receptor-dependent synaptic plasticity.

► We investigated regulation of phosphorylation of GluA1 by NMDA receptors activation. ► Phosphorylation changes of GluA1 were dose-related by NMDA application. ► We found phosphorylation changes of GluA1 was time dependent. ► Synaptic and extrasynaptic NMDARs differentially regulate phosphorylation of GluA1. ► NR2A containing NMDARs may contribute to the regulation of phosphorylation of GluA1.