PSD-95 is a negative regulator of the tyrosine kinase Src in the NMDA receptor complex

The tyrosine kinase Src upregulates the activity of the N ‐methyl‐ D ‐aspartate subtype of glutamate receptor (NMDAR) and tyrosine phosphorylation of this receptor is critical for induction of NMDAR‐dependent plasticity of synaptic transmission. A binding partner for Src within the NMDAR complex is the protein PSD‐95. Here we demonstrate an interaction of PSD‐95 with Src that does not require the well‐characterized domains of PSD‐95. Rather, we show binding to Src through a 12‐amino‐acid sequence in the N‐terminal region of PSD‐95, a region not previously known to participate in protein–protein interactions. This region interacts directly with the Src SH2 domain. Contrary to typical SH2 domain binding, the PSD‐95–Src SH2 domain interaction is phosphotyrosine‐independent. Binding of the Src‐interacting region of PSD‐95 inhibits Src kinase activity and reduces NMDAR phosphorylation. Intracellularly administering a peptide matching the Src SH2 domain‐interacting region of PSD‐95 depresses NMDAR currents in cultured neurons and inhibits induction of long‐term potentiation in hippocampus. Thus, the PSD‐95–Src SH2 domain interaction suppresses Src‐mediated NMDAR upregulation, a finding that may be of broad importance for synaptic transmission and plasticity.