Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 20, Pages 11055-11061Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.191353598
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- NINDS NIH HHS [R01 NS030337, NS 30337] Funding Source: Medline
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Zinc is coreleased with glutamate from excitatory nerve terminals throughout the central nervous system and acutely inhibits N-methyl-D-aspartate (NMDA) receptor activation. Here we report that cultured murine cortical neurons briefly exposed to sublethal concentrations of zinc developed increased intracellular free Na+, phosphorylation of Src kinase at tyrosine 220, and tyrosine phosphorylation of NMDA receptor 2A/2B subunits, in a fashion sensitive to the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)7-(t-butyl)pyrazolo[3,4-d]pyrimidine, PP2. Functionally, this zinc exposure produced a delayed increase in NMDA receptor current in perforated patch but not conventional whole-cell recordings, as well as an increase in NMDA receptor-mediated cell death. These observations suggest that the effect of synaptically released zinc on neuronal NMDA receptors may be biphasic: acute block, followed by Src family kinase-mediated up-regulation of NMDA receptor activity and cytotoxicity.
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