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Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit
- Source :
- Cell reports
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- SUMMARY 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.<br />Graphical Abstract<br />In brief 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.
- Subjects :
- SNX27
Glycine
Nerve Tissue Proteins
Gating
Models, Biological
Receptors, N-Methyl-D-Aspartate
Article
General Biochemistry, Genetics and Molecular Biology
Rats, Sprague-Dawley
Phosphoserine
Ca2+/calmodulin-dependent protein kinase
Animals
Humans
Amino Acid Sequence
Phosphorylation
Chemistry
musculoskeletal, neural, and ocular physiology
Long-term potentiation
Cell biology
Protein Subunits
Sorting nexin
HEK293 Cells
nervous system
Mutation
Synapses
Synaptic plasticity
NMDA receptor
Female
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ion Channel Gating
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Cell Reports
- Accession number :
- edsair.doi.dedup.....2b87614f56a02afdb2b97b641c3635db