Rab GTPases and Neuroendocytosis

Rab GTP 酶和神经内吞作用

• 批准号: 0343739
• 负责人: Lisa Elferink
• 金额: --
• 依托单位: University of Texas Medical Branch at Galveston
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0343739&HistoricalAwards=false
• 关键词: Rab; GTPases; Neuroendocytosis

Internalization and recycling of cell surface receptors by endocytosis regulates the intensity and duration of a cell's response to environmental signals. Perhaps nowhere is endocytosis more important than in the nervous system. Here the balance between regulating receptor internalization with recycling back to the cell surface is crucial for modulating neuronal communication and cell function in general. Early, and Pericentriolar Recycling Endosomes are critical sorting compartments that receive endocytosed receptors from the cell surface. However, little is known about the molecular mechanisms regulating the transit of endocytosed receptors through these distinct compartments. Endosomal rab GTPases have emerged as critical regulators of endocytic trafficking. They function by recruiting unique combinations of membrane specific effectors that underlie the distinct functional properties of each endosomal compartment. The novel GTPase Rab15, has formed the focal point for ongoing studies in this laboratory because of its unique localization to Early Endosomes and Pericentriolar Recycling Endosomes, and its demonstrated importance in regulating receptor transport through these compartments. When over expressed in cells, Rab15 inhibits receptor transport through both types of endosomes, suggesting that Rab15 function at these distinct compartments requires specific effector interactions. Consistent with this hypothesis, two novel endosomal proteins, RBP15 and REP15, have been identified, which specifically interact with Rab15 in Early Endosomes and Pericentriolar Recycling Endosomes respectively. The proposed experiments will define the individual roles of these novel endocytic proteins in receptor trafficking, and delineate the molecular steps in which they participate. These aims will be achieved using a combination of complementary molecular, cellular and optical approaches. The proposed studies will increase our fundamental understanding of how Rab GTPaes and their effectors regulate receptor transport through Early Endosomes and Pericentriolar Recycling Endosomes, a process pivotal for synaptic function and cell function in general.

通过内吞作用对细胞表面受体的内在化和回收，调节细胞对环境信号的反应的强度和持续时间。 在神经系统中，没有任何地方更重要的内吞作用。 在这里，调节受体内在化与回收回到细胞表面之间的平衡对于调节神经元通信和一般细胞功能至关重要。 早期和周围三环回收内体是关键的分选室，从细胞表面接收内吞受体。 然而，关于通过这些不同隔室调节内吞受体转运的分子机制知之甚少。 内体RAB GTPases已成为内吞贩运的关键调节剂。 它们通过募集膜特定效应子的独特组合来发挥作用，这些膜特定效应子是每个内体隔室的独特功能特性的基础。 新型的GTPase RAB15已成为该实验室正在进行研究的焦点，因为它独特地定位了早期内体和周围三环回收的内体，并且在通过这些隔离区调节受体运输方面表现出重要性。 当在细胞中表达过度时，RAB15会通过两种类型的内体抑制受体转运，这表明Rab15在这些不同的隔室中的功能需要特定的效应器相互作用。 与这一假设一致，已经鉴定出了两个新型内体蛋白RBP15和REP15，它们分别在早期内体和周围三元素回收内体中特别与RAB15相互作用。 提出的实验将定义这些新型内吞蛋白在受体运输中的各个作用，并描绘它们参与的分子步骤。这些目标将通过互补的分子，细胞和光学方法的结合来实现。 拟议的研究将增加我们对RAB GTPAE及其效应子如何通过早期内体和周围三环回收内体调节受体转运的基本理解，这是突触功能和细胞功能的过程关键。