Transport of Neurotransmitter Into Synaptic Vesicles

将神经递质转运到突触小泡中

基本信息

项目摘要

DESCRIPTION (provided by applicant): The regulated release of neurotransmitter by exocytosis depends on transport of the transmitter into neurosecretory vesicles. We previously found that several so-called type I phosphate transporters in fact transport glutamate into synaptic vesicles, providing the first unambiguous markers for neurons that use glutamate as a transmitter. Vesicular glutamate transporters (VGLUTs) 1 and 2 exhibit an almost mutually exclusive pattern of expression in the adult brain, with VGLUT1 in cortex and hippocampus, and VGLUT2 in the thalamus and brainstem. The isoforms do not apparently differ in intrinsic transport activity, but the analysis of VGLUT1 knock-out mice suggests differences in response of the two isoforms to high frequency stimulation, presumably due to differences in membrane trafficking. We have now found that VGLUT1 contains multiple internalization motifs, only one of which is shared with VGLUT2, and we have begun to identify the proteins that interact with these sequences. In addition, the VGLUT1 knock-out has suggested a transient, developmental role for VGLUT2 in cortical and hippocampal neurons destined to make only VGLUT1 in adulthood. In contrast to VGLUT1 and 2, VGLUTS is expressed by a number of cell populations not traditionally considered to release glutamate, including cholinergic interneurons of the striatum, GABAergic interneurons in the cortex and hippocampus, serotonin and perhaps dopamine neurons. The long-term objectives of this program are to understand how the release of glutamate influences neural development, synaptic transmission and behavior. The strategy is to study the function and trafficking of VGLUTs using biophysical methods, and to determine their role in vivo by genetic manipulation in mice. In terms of specific aims, we will: 1) Characterize the protein interactions of VGLUT1. To understand how protein interactions influence the trafficking of VGLUT1, we will use optical imaging in live neurons. 2) Determine the role of transient VGLUT2 expression during development. We will use conditional VGLUT2 knock-out mice to determine the effects of early VGLUT2 expression on axon guidance, synapse development, function and plasticity. 3) Identify the roles of glutamate release by cell populations expressing VGLUTS. We will use VGLUTS knock-out and BAG transgenic mice that label VGLUT3+ neurons with GFP to assess the physiological and behavioral roles of VGLUTS expression by diverse neural systems. We will also produce a conditional knock-out to distinguish among the behavioral effects of VGLUTS expressed by different neurons.
描述(申请人提供):通过胞吐作用调节神经递质的释放依赖于递质进入神经分泌小泡的运输。我们之前发现,几种所谓的I型磷酸转运体实际上将谷氨酸运输到突触小泡中,为使用谷氨酸作为递质的神经元提供了第一个明确的标记。囊泡谷氨酸转运体(VGLUT)1和2在成人脑中的表达模式几乎是互斥的,VGLUT1在皮质和海马区表达,VGLUT2在丘脑和脑干表达。这两种异构体在内在转运活性上没有明显差异,但对VGLUT1基因敲除小鼠的分析表明,这两种异构体对高频刺激的反应不同,可能是由于膜运输的不同。我们现在已经发现VGLUT1包含多个内化基序,其中只有一个与VGLUT2共享,我们已经开始鉴定与这些序列相互作用的蛋白质。此外,VGLUT1基因敲除表明VGLUT2在皮质和海马神经元中具有短暂的发育作用,成年后注定只能制造VGLUT1。与VGLUT1和VGLU2不同,VGLUTS由许多传统上不被认为释放谷氨酸的细胞群表达,包括纹状体的胆碱能中间神经元、皮质和海马区的GABA能中间神经元、5-羟色胺和可能还有多巴胺神经元。该计划的长期目标是了解谷氨酸的释放如何影响神经发育、突触传递和行为。该策略是利用生物物理方法研究VGLUT的功能和转运,并通过在小鼠身上进行遗传操作来确定它们在体内的作用。就具体目标而言,我们将:1)表征VGLUT1的蛋白质相互作用。为了了解蛋白质相互作用如何影响VGLUT1的运输,我们将使用活神经元的光学成像。2)确定瞬时VGLUT2表达在发育过程中的作用。我们将使用条件性VGLUT2基因敲除小鼠来确定早期VGLUT2表达对轴突引导、突触发育、功能和可塑性的影响。3)确定表达VGLUTS的细胞群在谷氨酸释放中的作用。我们将使用VGLUTS基因敲除和BAG转基因小鼠,用GFP标记VGLUT3+神经元来评估VGLUTS在不同神经系统中表达的生理和行为作用。我们还将产生一个条件基因敲除,以区分不同神经元表达的VGLUT的行为影响。

项目成果

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ROBERT H EDWARDS其他文献

ROBERT H EDWARDS的其他文献

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{{ truncateString('ROBERT H EDWARDS', 18)}}的其他基金

Glutamate Transport into Synaptic Vesicles
谷氨酸转运至突触小泡
  • 批准号:
    10568125
  • 财政年份:
    2022
  • 资助金额:
    $ 11.17万
  • 项目类别:
The Function of Synuclein
突触核蛋白的功能
  • 批准号:
    10569089
  • 财政年份:
    2019
  • 资助金额:
    $ 11.17万
  • 项目类别:
The Function of Synuclein
突触核蛋白的功能
  • 批准号:
    10335272
  • 财政年份:
    2019
  • 资助金额:
    $ 11.17万
  • 项目类别:
Neurotransmitter Corelease
神经递质共释放剂
  • 批准号:
    9927697
  • 财政年份:
    2017
  • 资助金额:
    $ 11.17万
  • 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
  • 批准号:
    9258506
  • 财政年份:
    2015
  • 资助金额:
    $ 11.17万
  • 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
  • 批准号:
    9920217
  • 财政年份:
    2015
  • 资助金额:
    $ 11.17万
  • 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
  • 批准号:
    8964141
  • 财政年份:
    2015
  • 资助金额:
    $ 11.17万
  • 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
  • 批准号:
    10614384
  • 财政年份:
    2015
  • 资助金额:
    $ 11.17万
  • 项目类别:
Structural Basis of Vesicular Neurotransmitter Transport
囊泡神经递质运输的结构基础
  • 批准号:
    10392888
  • 财政年份:
    2015
  • 资助金额:
    $ 11.17万
  • 项目类别:
Proteomic Analysis of Synaptic Vesicle Pools
突触小泡池的蛋白质组学分析
  • 批准号:
    8571951
  • 财政年份:
    2013
  • 资助金额:
    $ 11.17万
  • 项目类别:

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