tailieunhanh - báo cáo khoa hoc : Regulation of NMDA receptors by the tyrosine kinase Fyn

The phosphorylation and trafficking ofN-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. | fFEBS Journal MINIREVIEW Regulation of NMDA receptors by the tyrosine kinase Fyn Catherine H. Trepanier1 Michael F. Jackson2 3 and John F. MacDonald1 2 3 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 Keywords dopamine D1 receptor Fyn NMDA receptors Src family kinases synaptic plasticity Correspondence 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@ Received 6 June 2011 revised 18 August 2011 accepted 9 September 2011 doi 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