RGD Reference Report - Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit. - Rat Genome Database

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

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 
Citation: Yong XLH, etal., Cell Rep. 2021 Jul 6;36(1):109338. doi: 10.1016/j.celrep.2021.109338.
RGD ID: 401940191
Pubmed: PMID:34233182   (View Abstract at PubMed)
PMCID: PMC8313361   (View Article at PubMed Central)
DOI: DOI:10.1016/j.celrep.2021.109338   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Camk2a  (calcium/calmodulin-dependent protein kinase II alpha)
Grin2a  (glutamate ionotropic receptor NMDA type subunit 2A)
Snx27  (sorting nexin 27)


Additional Information