Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit
| Autor: | Katherine W. Roche, Angelo Keramidas, Liming Yang, Jing Zhi Anson Tan, Lingrui Zhang, Jocelyn Widagdo, Xiumin Chen, Xiaojun Yu, Xuan Ling Hilary Yong, Brett M. Collins, Joseph W. Lynch, Emma Livingstone, Mintu Chandra, Victor Anggono, Marta Vieira |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Cell reports |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2021.109338 |
| Popis: | 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. Graphical Abstract 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. |
| Databáze: | OpenAIRE |
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