Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
FEBS J. 2012 Jan;279(1):12-9. doi: 10.1111/j.1742-4658.2011.08391.x. Epub 2011 Dec 5.
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.
N-甲基-D-天冬氨酸（NMDA）受体的磷酸化和转运受到Src 家族酪氨酸激酶 Fyn 的严格调控，通过与 NMDA 受体复合物中的各种支架蛋白的动态相互作用。Fyn 作为许多上调含有 GluN2B 的 NMDA 受体的信号通路的汇聚点。在接下来的综述中，我们重点介绍了不同 G 蛋白偶联受体下游的 Fyn 信号：多巴胺 D1 受体和与垂体腺苷酸环化酶激活多肽同源的受体。这些信号通路的激活的净结果是上调含有 GluN2B 的 NMDA 受体。NMDA 受体是大脑中乙醇的主要靶标，越来越多的证据表明，Fyn 通过调节 GluN2B NMDA 受体亚基的磷酸化来介导乙醇的作用。此外，已经表明 Fyn 通过 GluN2B 依赖性机制调节酒精戒断和对乙醇的急性耐受。除了对 NMDA 受体功能的影响外，Fyn 还改变 CA1 突触的突触可塑性阈值，这种作用可能有助于 Fyn 对空间和情境恐惧学习的影响。
