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PNAS 98 (20): 11055-11061

Copyright © 2001 by the National Academy of Sciences.

Colloquium Paper


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

Pat Manzerra, M. Margarita Behrens, Lorella M. T. Canzoniero, Xue Qing Wang, Valérie Heidinger, Tomomi Ichinose, Shan Ping Yu, and Dennis W. Choi*

Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, MO 63105

Abstract: 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.

* To whom reprint requests should be addressed at: Department of Neurology, Box 8111, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63105. E-mail: wildersp{at}

This paper was presented at the Inaugural Arthur M. Sackler Colloquium of the National Academy of Sciences, "Neural Signaling," held February 15–17, 2001, at the National Academy of Sciences in Washington, DC.

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