Zinc induces a Src family kinase-mediated up-regulation of NMDA receptor activity and excitotoxicity

Zinc is coreleased with glutamate from excitatory nerve terminals throughou t the central nervous system and acutely inhibits N-methyl-D-aspartate (NMD A) receptor activation. Here we report that cultured murine cortical neuron s briefly exposed to sublethal concentrations of zinc developed increased i ntracellular free Na+, phosphorylation of Src kinase at tyrosine 220, and t yrosine phosphorylation of NMDA receptor 2A/2B subunits, in a fashion sensi tive to the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)7-(t-buty l)pyrazolo[3,4-d]pyrimidine, PP2. Functionally, this zinc exposure produced a delayed increase in NMDA receptor current in perforated patch but not co nventional whole-cell recordings, as well as an increase in NMDA receptor-m ediated cell death. These observations suggest that the effect of synaptica lly released zinc on neuronal NMDA receptors may be biphasic: acute block, followed by Src family kinase-mediated up-regulation of NMDA receptor activ ity and cytotoxicity.