Regulation of NMDA receptors by the tyrosine kinase Fyn

Authors

  • Catherine H. Trepanier,

    1.  Department of Pharmacology and Toxicology, University of Toronto, ON, Canada
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  • Michael F. Jackson,

    1.  Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, ON, Canada
    2.  Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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  • John F. MacDonald

    1.  Department of Pharmacology and Toxicology, University of Toronto, ON, Canada
    2.  Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, ON, Canada
    3.  Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
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J. F. MacDonald, Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, 100 Perth Dr., London, ON, Canada N6A 5K8
Fax: +1 519 931 5721
Tel: +1 519 931 5777
E-mail: jfmacdonald@robarts.ca

Abstract

The phosphorylation and trafficking of N-methyl-d-aspartate (NMDA) receptors are tightly regulated by the Src family tyrosine kinase Fyn, through dynamic interactions with various scaffolding proteins in the NMDA receptor complex. Fyn acts as a point of convergence for many signaling pathways that upregulate GluN2B-containing NMDA receptors. In the following review, we focus on Fyn signaling downstream of different G-protein-coupled receptors: the dopamine D1 receptor, and receptors cognate to the pituitary adenylate cyclase-activating polypeptide. The net result of activation of each of these signaling pathways is upregulation of GluN2B-containing NMDA receptors. The NMDA receptor is a major target of ethanol in the brain, and accumulating evidence suggests that Fyn mediates the effects of ethanol by regulating the phosphorylation of GluN2B NMDA receptor subunits. Furthermore, Fyn has been shown to regulate alcohol withdrawal and acute tolerance to ethanol through a GluN2B-dependent mechanism. In addition to its effects on NMDA receptor function, Fyn also modifies the threshold for synaptic plasticity at CA1 synapses, an effect that probably contributes to the effects of Fyn on spatial and contextual fear learning.

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