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

• Published in: Cell reports (Cambridge) 2021-07, Vol.36 (1), p.109338-109338, Article 109338
• Main Authors: Yong, Xuan Ling Hilary, Zhang, Lingrui, Yang, Liming, Chen, Xiumin, Tan, Jing Zhi Anson, Yu, Xiaojun, Chandra, Mintu, Livingstone, Emma, Widagdo, Jocelyn, Vieira, Marta M., Roche, Katherine W., Lynch, Joseph W., Keramidas, Angelo, Collins, Brett M., Anggono, Victor
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CaMKII; endosomal recycling; epilepsy; Female; genetic variant; Glycine; HEK293 Cells; Humans; Ion Channel Gating; Models, Biological; Mutation - genetics; Nerve Tissue Proteins; NMDA receptors; Phosphorylation; Phosphoserine - metabolism; Protein Subunits - metabolism; Rats; Rats, Sprague-Dawley; receptor trafficking; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; retromer; sorting nexin; Synapses - metabolism; synaptic potentiation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109338

NMDA receptor (NMDAR)-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. Most synaptic NMDAR currents in the adult forebrain are mediated by GluN2A-containing receptors, which are rapidly inserted into synapses during long-term potentiation (LTP); however, the underlying molecular mechanisms remain poorly understood. In this study, we show that GluN2A is phosphorylated at Ser-1459 by Ca2+/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. [Display omitted] •CaMKIIα phosphorylates GluN2A at Ser-1459 in response to glycine stimulation•CaMKIIα and SNX27 are required for the glycine-induced increase in surface GluN2A•GluN2A Ser-1459 is a critical residue that controls the gating of NMDA receptors•The epilepsy-associated GluN2A S1459G variant prolongs open channel duration Yong et al. identify that activity-dependent phosphorylation of Ser-1459 in the GluN2A C-terminal domain by CaMKIIα promotes its interaction with the SNX27-retromer complex, thereby enhancing the surface expression of NMDARs during synaptic potentiation. Mutations of Ser-1459 prolong the decay times of NMDAR-mediated synaptic currents by increasing the duration of channel opening.