Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit
Xuan Ling Hilary Yong, Lingrui Zhang, Liming Yang, Xiumin Chen, Jing Zhi Anson Tan, Xiaojun Yu, Mintu Chandra, Emma K. Livingstone, Jocelyn Widagdo, Marta Vieira, Katherine W. Roche, Joseph W. Lynch, Angelo Keramidas, Brett M. Collins, Victor Anggono
Abstract
/calmodulin-dependent kinase IIα (CaMKIIα) in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the sorting nexin 27 (SNX27)-retromer complex, thereby 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 the decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the duration of channel opening. These findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but they also explain how the S1459G variant dysregulates NMDAR function.