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Characterization of the trafficking of plasma membrane syntaxins and the scaffolding interactions of inward rectifier potassium channel Kir2.3.

机译：质膜syntaxin的运输和向内整流钾通道Kir2.3的脚手架相互作用的表征。

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摘要

Neurons are compartmentalized into functionally distinct domains---axons and dendrites---designed for transmission and processing of information, which underlies every aspect of brain function. Neuronal signaling is predicated on mechanisms that control the targeting of proteins to specific subcellular domains as well as the recruitment of ion channels to dendritic spines, which serve as primary sites of synaptic communication.;SNAREs are a family of proteins involved in mediating membrane fusion events of trafficking vesicles that deliver protein and lipid cargo to specific intracellular destinations, but their role in neuronal polarity and selective protein targeting are unknown. Using a combination of optical and molecular approaches, we have now determined that plasma membrane SNAREs, syntaxins 3 and 4, respectively, are expressed in hippocampal neurons and that polarized expression of syntaxin 3 confers specificity to axonal protein trafficking. Syntaxin 3 localizes to the axonal plasma membrane, particularly to axonal tips, whereas syntaxin 4 localizes to the somatodendritic plasma membrane. Mutating residues in the conserved N-terminal targeting motif causes mislocalization of syntaxin 3, resulting in simultaneous mistargeting of the axonal protein NgCAM, but not of the somatodendritic transferrin receptor. RNA interference-mediated knockdown of endogenous syntaxin 3 leads to partial mistargeting of NgCAM, demonstrating that syntaxin 3 is critical to axonal targeting.;Scaffolding proteins at postsynaptic sites are crucial for organizing ion channels into signaling complexes essential for synaptic transmission. Inward rectifier potassium Kir2.3 channels are enriched at spines, when expressed in cultured hippocampal neurons, but the mechanisms underlying channel localization are unclear. We used mutational analysis to determine how protein-interacting motifs in the C-terminus of Kir2.3 influence its localization. We show that Kir2.3 channels traffic to spines and that synaptic localization requires a previously identified C-terminal PDZ (postsynaptic density-95/Discs large/zona-occludent-1)-binding motif. We also identify a polyproline motif in the C-terminus of Kir2.3 that associates with Homer-1 and Homer-2 in brain. Deleting the PDZ-binding motif abolishes binding of PSD-95 with Kir2.3 and dramatically reduces Kir2.3 synaptic localization, whereas mutating residues in the polyproline motif has little effect on channel localization. Using RNA interference, we show that PSD-95 is necessary for localizing Kir2.3 to spines.
机译：神经元被划分为功能不同的域-轴突和树突状-旨在传输和处理信息，这是大脑功能的各个方面的基础。神经元信号传导的机制是控制蛋白质靶向特定亚细胞结构域以及控制离子通道向树突棘的募集的机制，树突棘是突触通讯的主要位点。SNARE是参与调节膜融合事件的蛋白质家族。运送蛋白质和脂质货物至特定细胞内目的地的运输小泡的数量，但它们在神经元极性和选择性蛋白质靶向中的作用尚不清楚。使用光学和分子方法的组合，我们现在已经确定海马神经元中分别表达质膜SNARE，syntaxins 3和4，syntaxin 3的极化表达赋予轴突蛋白运输特异性。 Syntaxin 3定位于轴突质膜，特别是轴突尖端，而Syntaxin 4定位于体树突状质膜。保守的N端靶向基序中的突变残基导致语法素3的错误定位，从而导致轴突蛋白NgCAM而不是体树突状转铁蛋白受体的同时误靶向。 RNA干扰介导的内源句法3的敲低导致NgCAM的部分错误靶向，表明句法3对轴突靶向至关重要。突触后位点的脚手架蛋白对于将离子通道组织成突触传递必不可少的信号复合体至关重要。当在培养的海马神经元中表达时，内向整流钾钾Kir2.3通道在棘中富集，但是尚不清楚通道定位的潜在机制。我们使用突变分析来确定Kir2.3 C末端中的蛋白质相互作用基序如何影响其定位。我们表明，Kir2.3通道交通到脊柱和突触的本地化需要一个事先确定的C端PDZ（突触后密度95 /盘大/ zona-occludent-1）绑定的主题。我们还确定了与大脑中的Homer-1和Homer-2相关联的Kir2.3 C末端的多脯氨酸基序。删除PDZ结合基序消除了PSD-95与Kir2.3的结合，并大大降低了Kir2.3突触的定位，而多脯氨酸基序中的突变残基对通道定位几乎没有影响。使用RNA干扰，我们表明PSD-95是将Kir2.3定位于棘突所必需的。

著录项

  • 作者

    Soo Hoo, Linda.;

  • 作者单位

    University of California, Santa Barbara.;

  • 授予单位 University of California, Santa Barbara.;
  • 学科 Biology Molecular.;Biology Neuroscience.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 200 p.
  • 总页数 200
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;神经科学;细胞生物学;
  • 关键词

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