Intracellular Trafficking of AMPA Receptors

描述(由申请人提供)： 神经传递需要精确的受体数量和排列，以及 神经细胞质膜上的离子通道。本地化中的更改 或膜中这些蛋白质的水平调节突触功能，从而 强化或削弱大脑中的突触连接。在所有的真核生物中 细胞，膜蛋白的内化、循环和降解是 通过内吞途径被调控的运输所控制。虽然 以前的研究帮助确定了许多非神经细胞中的这一途径。 突触后细胞内转运的类型和机制 受体与突触中树突状细胞内体转运的作用 传播和可塑性仍然是未知的。 为了解决这些重要问题，我的实验室启动了一个项目 生化和细胞生物学研究以分析细胞内转运 AMPA型谷氨酸受体。AMPA受体是FAST的主要介体 脑内兴奋性传递与数量和功能的改变 AMPA受体是突触可塑性的重要特征。我们有 最近发现AMPA受体在循环和循环之间是有区别的 以及内吞作用后的降解途径。这个排序决定是在 转体受AMPA和NMDA型谷氨酸相对活性的控制 突触后膜上的受体。利用这些初步的 数据和我们监测和操纵AMPA受体贩运的能力 神经元，我们建议定义潜在的分子和细胞机制 AMPA受体的胞内转运并测定其功能 对突触成熟和维持的影响。这项工作将提供 洞察突触形成和形成的基本机制 突触可塑性。此外，鉴于兴奋性突触的重要性 传递和AMPA受体激活在多发性硬化发病机制中的作用 精神和神经疾病，这些研究为 开发新的治疗策略。

DESCRIPTION (provided by applicant): Neurotransmission requires a precise number and arrangement of receptors and ion channels in the neuronal plasma membrane. Alterations in the localization or levels of these proteins in the membrane regulates synapse function, thereby strengthening or weakening synaptic connections in the brain. In all eukaryotic cells, the internalization, recycling, and degradation of membrane proteins is controlled by regulated trafficking through the endocytic pathway. Although previous studies have helped define this pathway in many nonneuronal cell types, the mechanisms underlying endocytic trafficking of postsynaptic receptors and the role of dendritic endosomal transport in synaptic transmission and plasticity remain unknown. To address these important questions, my laboratory has initiated a program of biochemical and cell biological studies to analyze the endocytic trafficking of AMPA-type glutamate receptors. AMPA receptors are the major mediators of fast excitatory transmission in the brain, and alteration of the number and function of AMPA receptors is a critical feature of synaptic plasticity. We have recently found that AMPA receptors are differentially sorted between recycling and degradative pathways following endocytosis. This sorting decision is in turn controlled by the relative activation of AMPA and NMDA-type glutamate receptors in the postsynaptic membrane. Taking advantage of these preliminary data and our ability to monitor and manipulate AMPA receptor trafficking in neurons, we propose to define the underlying molecular and cellular mechanisms of AMPA receptor endocytic trafficking and determine the functional consequences for synapse maturation and maintenance. This work will provide insight into fundamental mechanisms that underlie synapse formation and synaptic plasticity. Moreover, given the importance of excitatory synaptic transmission and AMPA receptor activation in the pathogenesis of numerous psychiatric and neurologic diseases, these studies hold promise for the development of novel therapeutic strategies.