Abstract
The number and subunit composition of synaptic N-methyl-d-aspartate receptors (NMDARs) play critical roles in synaptic plasticity, learning, and memory and are implicated in neurological disorders. Tyrosine phosphorylation provides a powerful means of regulating NMDAR function, but the underling mechanism remains elusive. In this study we identified a tyrosine site on the GluN2B subunit, Tyr-1070, which was phosphorylated by a proto-oncogene tyrosine-protein (Fyn) kinase and critical for the surface expression of GluN2B-containing NMDARs. The phosphorylation of GluN2B at Tyr-1070 was required for binding of Fyn kinase to GluN2B, which up-regulated the phosphorylation of GluN2B at Tyr-1472. Moreover, our results revealed that the phosphorylation change of GluN2B at Tyr-1070 accompanied the Tyr-1472 phosphorylation and Fyn associated with GluN2B in synaptic plasticity induced by both chemical and contextual fear learning. Taken together, our findings provide a new mechanism for regulating the surface expression of NMDARs with implications for synaptic plasticity.
Highlights
N-methyl-D-aspartate (NMDA) receptor trafficking is fine-tuned by tyrosine phosphorylation
GluN2B at the Tyr-1070 Site Is Phosphorylated by Fyn in Vivo and in Vitro—Previous mass spectral analysis has provided evidence that GluN2B is phosphorylated at several tyrosine sites, including Tyr-1070 [15], which lies in the conserved sequence VTYGNI within the carboxyl terminus (Fig. 1A)
In the present study we demonstrated that Tyr-1070 on GluN2B was a novel Fyn kinase-mediated tyrosine phosphorylation site in response to synaptic activity as well as contextual fear learning
Summary
N-methyl-D-aspartate (NMDA) receptor trafficking is fine-tuned by tyrosine phosphorylation. Conclusion: Phosphorylation of GluN2B at Tyr-1472 is regulated by a Tyr(P)-1070-mediated association of GluN2B with Fyn. Significance: This study sheds new light on the surface expression of NMDARs that are implicated in synaptic activity. Y.) and Natural Science Foundation of China Grants 91232303 and 81221003 Accumulating evidence has shown that Src family kinases such as Fyn and Src are required to up-regulate the tyrosine phosphorylation of NMDARs, further modulating synaptic plasticity and learning and memory [6, 11, 12]. In the present study we report a novel mechanism by which tyrosine phosphorylation of GluN2B Tyr-1070 (Tyr(P)1070) facilitates the surface expression of GluN2B-containing NMDARs through its interaction with Fyn and regulating the phosphorylation of GluN2B Tyr-1472 during neuronal activity. Term depression; ECS, extracellular solution; CIP, calf intestinal alkaline phosphatase; LV, lentivirus; EGFP, enhanced GFP
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