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

Yong, X. L. H.; Zhang, L.; Yang, L.; Chen, X.; Yu, X.; Chandra, M.; Livingstone, E.; Tan, J. Z. A.; Widagdo, J.; Vieira, M. M.; Roche, K. W.; Lynch, J. W.; Keramidas, A.; Collins, B. M.; Anggono, V.

doi:10.1101/2021.01.11.425709

bioRxiv · 10.1101/2021.01.11.425709

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

Yong, X. L. H.·Zhang, L.·Yang, L.·Chen, X.·Yu, X.·Chandra, M.·Livingstone, E.·Tan, J. Z. A.·Widagdo, J.·Vieira, M. M.·Roche, K. W.·Lynch, J. W.·Keramidas, A.·Collins, B. M.·Anggono, V.

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Abstract

NMDAR-dependent Ca2+ influx underpins multiple forms of synaptic plasticity. In the adult forebrain, the majority of synaptic NMDAR currents are mediated by GluN2A-containing NMDARs. These receptors are rapidly inserted into synapses during LTP; however, the underlying molecular mechanisms remain poorly understood. Here we show that GluN2A is phosphorylated at Ser-1459 by CaMKII in response to glycine stimulation that mimics LTP in primary neurons. Phosphorylation of Ser-1459 promotes GluN2A interaction with the SNX27-retromer complex, therefore enhancing the endosomal recycling of NMDARs. Loss of SNX27 or CaMKII 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 decay times of NMDAR-mediated synaptic currents in heterosynapses by increasing the active duration of channel openings. Taken together, these findings not only identify a critical role of Ser-1459 phosphorylation in regulating the function of NMDARs, but also explain how the S1459G epilepsy variant dysregulates NMDAR function.

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Yong, X. L. H., Zhang, L., Yang, L., Chen, X., Yu, X., Chandra, M., Livingstone, E., Tan, J. Z. A., Widagdo, J., Vieira, M. M., Roche, K. W., Lynch, J. W., Keramidas, A., Collins, B. M., Anggono, V.. 2021-01-11. Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit. https://doi.org/10.1101/2021.01.11.425709

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