Intracellular Trafficking of AMPA Receptors

描述（由申请人提供）： 神经传递需要受体的精确数量和排列， 神经元质膜上的离子通道。本地化的变更 或者这些蛋白质在膜中的水平调节突触功能， 加强或削弱大脑中的突触连接。在所有真核生物中， 在细胞中，膜蛋白的内化、再循环和降解是 通过内吞途径受调控的运输控制。虽然 以前的研究已经帮助确定了许多非神经元细胞中的这一通路 类型，内吞运输突触后的机制 受体和树突状细胞内体转运在突触 传输和可塑性仍然未知。 为了解决这些重要问题，我的实验室启动了一个项目， 生物化学和细胞生物学研究，以分析 AMPA型谷氨酸受体。AMPA受体是快速代谢的主要介质。 兴奋性传递在大脑中，和改变的数量和功能 是突触可塑性的关键特征。我们有 最近发现，AMPA受体在回收和再利用之间存在差异， 和内吞作用后的降解途径。这一排序决定是在 由AMPA和NMDA型谷氨酸的相对激活控制的转向 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 的AMPA受体内吞运输，并确定功能 突触成熟和维持的后果。这项工作将提供 深入了解突触形成的基本机制， 突触可塑性此外，考虑到兴奋性突触的重要性， AMPA受体激活在许多疾病的发病机制中起重要作用。 精神和神经系统疾病，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.