SUBTYPE-SPECIFIC REGULATION OF RECOMBINANT NMDA RECEPTOR-CHANNELS BY PROTEIN-TYROSINE KINASES OF THE SRC FAMILY

1. Tyrosine kinases regulate NMDA receptor-channel activity in culture d neurons, and NMDA receptor subunits are tyrosine phosphorylated in t he brain. 2. Heteromeric NMDA receptor-channels were transiently expre ssed in human embryonic kidney (HEK) 293 cells and glutamate (100 mu m )-activated whole-cell currents (500 ms) were studied when tyrosine ki nases of the src gene family were included in the pipette solution. 3. Glutamate-activated currents (evoked every 20 s for up to 20 min) wer e increased by src and fyn kinases without affecting the desensitizati on and deactivation kinetics in NR1-NR2A but the kinases had no effect s in NR1-NR2B, NR1-NR2C and NR1-NR2D receptor-channels, suggesting tha t a phosphorylation site in NR2A is targeted. 4. In a mutant channel c onsisting of NR1 and a C-terminal deletion mutant of NR2A (NR2A Delta C), src and fyn kinases lost their potentiating effects indicating tha t the phosphorylation of tyrosine(s) in the C-terminal domain of NR2A affects the current flux through native NMDA receptor-channels.