A peptide activator of endogenous tyrosine kinase enhances synaptic currents mediated by NMDA receptors

N-methyl-D-aspartic acid (NMDA) receptor currents in cultured cells or expression systems are increased by the addition of purified tyrosine kinases. However, there is no direct demonstration of this effect at NMDA receptors in intact synapses of rat brain slices. Transmitters which might be used to activate tyrosine kinases in situ are unlikely to have a sufficiently selective action to allow a clear interpretation of their effects. Therefore, we used a phosphotyrosine-containing decapeptide which can be included in recording electrodes to activate postsynaptic src-family tyrosine kinases, This peptide enhanced NMDA responses in dissociated hippocampal CA1 neurons. These effects were not reproduced by a non-phosphorylated peptide or a scrambled-sequence phosphopeptide. The enhancement of NMDA responses was blocked by a tyrosine kinase inhibitor. In brain slices the phosphopeptide, but not control peptide, increased NMDA receptor-mediated synaptic current indicating that endogenous tyrosine kinase can upregulate the response of NMDA receptors at glutamatergic synapses in the hippocampus.