PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A

Fyn, a member of the Src-family protein-tyrosine kinase (PTK), is implicate d in learning and memory that involves iv-methyl-D-aspartate (NMDA) recepto r function. In this study, we examined how Fyn participates in synaptic pla sticity by analyzing the physical and functional interaction between Fyn an d NMDA receptors, Results showed that tyrosine phosphorylation of NR2A, one of the NMDA receptor subunits, was reduced in fyn-mutant mice. NR2A was ty rosine phosphorylated in 293T cells when coexpressed with Fyn. Therefore, N R2A would be a substrate for Fyn in vivo. Results also showed that PSD-95, which directly binds to and coclusters with NMDA receptors, promotes Fyn-me diated tyrosine phosphorylation of NR2A, Different regions of PSD-95 associ ated with NR2A and Fyn, respectively, and so PSD-95 could mediate complex f ormation of Fyn with NR2A. PSD-95 also associated with other Src-family PTK s, Src, Yes, and Lyn. These results suggest that PSD-95 is critical for reg ulation of NMDA receptor activity by Fyn and other Src-family PTKs, serving as a molecular scaffold for anchoring these PTKs to NR2A.