MECHANISMS OF THE VOLTAGE-DEPENDENT SODIUM CHANNEL

电压依赖性钠通道的机制

基本信息

  • 批准号:
    2891582
  • 负责人:
  • 金额:
    $ 25.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1993
  • 资助国家:
    美国
  • 起止时间:
    1993-07-01 至 2001-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION: Progress in the previous award period provides strong evidence that channel sialylation plays a role in the gating behavior of sodium channels. Specifically, it has been shown that the removal of sialic acids from channels results in a reduction in the voltage and calcium sensitivity of sodium channel gating. The manner of these effects suggest that sialic acids influence sodium channel gating through an electrostatic mechanism. In this renewal application, this basic hypothesis and its biological significance will be addressed by exploring two questions: 1) What is the actual magnitude of the effect of sialylation on sodium channel gating in vivo? 2) Is variable channel sialylation a potential means of controlling sodium channel gating behavior in vivo? The specific aims proposed are as follows: 1) To determine the effects of increased sialylation on the gating of sodium channels expressed in transfected cell lines. These studies are intended as a further test of the hypothetical electrostatic role of sialic acid in channel gating by complementing previous experiments that removed sialic acid. In these experiments, channel sialylation will be increased through the chimeric addition of glycosylation sites to channels, sialylation of both wild-type and chimeric channels will be increased through expression in cell lines transfected with cloned sialytransferases. 2) To characterize the gating of glycosylation-deficient rSkM1 mutants expressed in skeletal muscle fibers. The gating of mutants of rSkM1 will be determined when these glycosylation-site deletion mutants are transfected into rat skeletal muscle fibers. These studies will provide a direct assessment of the actual contribution of channel sialylation to channel gating in vivo. 3) To investigate whether correlative variations in channel sialylation and gating occur for a given channel isoform in the nervous system and during development. Through the use of isoform-specific antibodies, the sialylation levels of channels will be determined in different parts of the adult and developing nervous system. Variations of such sialylation levels will be correlated with the gating properties of brain sodium channels using the CHO cell expression system developed in Aim #1. Further, the molecular basis for such variations will be addressed through study of the expression of endogenous sialyltransferases. Thus these experiments will determine whether variable sialylation is a potential channel modulation mechanism in the nervous system. These studies are relevant to the understanding of neuromuscular dysfunction that is present in disorders of calcium and glycoprotein metabolism, particularly those involving genetic defects of glycosylation. Furthermore, the project may provide insight into changes in electrical excitability that occur in aging brain, Alzheimer s disease, and epilepsy.
描述:前一授权期的进展提供了强有力的证据 通道唾液酸化在钠的门控行为中起作用 频道。具体地说,已经表明,唾液酸的去除 导致电压和钙敏感性的降低 钠离子通道门控。这些影响的方式表明唾液酸 酸通过静电机制影响钠通道门控。 在这一更新应用中,这一基本假设及其生物学 意义将通过探索两个问题来解决:1)什么是 唾液酸化对钠通道门控作用的实际大小 体内?2)可变通道唾液酸化是一种潜在的控制手段 体内钠通道门控行为? 提出的具体目标如下:1)确定 增加唾液酸化对钠通道门控的影响 转染型细胞系。这些研究旨在进一步测试 唾液酸在通道选通中的静电作用假说 补充了之前去除唾液酸的实验。在这些 实验中,通道唾液酸化将通过嵌合体增加 将糖基化位点加到通道上,使两种野生型唾液酸化 嵌合通道将通过在细胞系中的表达而增加 用克隆的唾液酸转移酶转染组。2)刻画门控 骨骼肌纤维中表达的糖基化缺陷rSkM1突变体。 RSkM1突变体的门控将在这些 糖基化位点缺失突变体导入大鼠骨骼肌的实验研究 纤维。这些研究将提供对实际 体内通道唾液酸化对通道门控的贡献。3)至 调查通道唾液酸化和门控是否存在相关变化 在神经系统中发生在给定的通道异构体和 发展。通过使用异构体特异性抗体, 渠道的唾液酸化水平将在不同的部分确定 成体和发育中的神经系统。这种唾液酸化水平的变化 将与大脑钠通道的门控特性相关,使用 在Aim#1中开发的CHO细胞表达系统。此外,分子 这种变化的基础将通过对表达式的研究来解决 内源性唾液酸基转移酶。因此,这些实验将确定 可变唾液酸化是否是一种潜在的通道调制机制 神经系统。 这些研究与了解神经肌肉功能障碍有关。 这表现在钙和糖蛋白代谢紊乱上, 尤其是涉及糖基化基因缺陷的基因。此外, 该项目可能提供对电兴奋性变化的洞察, 发生于脑老化、阿尔茨海默病、S病和癫痫。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Simon R LEVINSON其他文献

Simon R LEVINSON的其他文献

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{{ truncateString('Simon R LEVINSON', 18)}}的其他基金

REGULATION OF SODIUM CHANNEL DISTRIBUTION IN NEURONAL CELLS
神经细胞钠通道分布的调节
  • 批准号:
    6338954
  • 财政年份:
    2000
  • 资助金额:
    $ 25.45万
  • 项目类别:
REGULATION OF SODIUM CHANNEL DISTRIBUTION IN NEURONAL CELLS
神经细胞钠通道分布的调节
  • 批准号:
    6205058
  • 财政年份:
    1999
  • 资助金额:
    $ 25.45万
  • 项目类别:
CLUSTER OF VOLTAGE SENSITIVE NA CHANNELS ON AXONS IS INDEPENDENT OF SCHWANN CELL
轴突上的电压敏感 NA 通道簇独立于施万细胞
  • 批准号:
    6121831
  • 财政年份:
    1999
  • 资助金额:
    $ 25.45万
  • 项目类别:
REGULATION OF SODIUM CHANNEL DISTRIBUTION IN NEURONAL CELLS
神经细胞钠通道分布的调节
  • 批准号:
    6112562
  • 财政年份:
    1998
  • 资助金额:
    $ 25.45万
  • 项目类别:
CLUSTER OF VOLTAGE SENSITIVE NA CHANNELS ON AXONS IS INDEPENDENT OF SCHWANN CELL
轴突上的电压敏感 NA 通道簇独立于施万细胞
  • 批准号:
    6282144
  • 财政年份:
    1998
  • 资助金额:
    $ 25.45万
  • 项目类别:
REGULATION OF SODIUM CHANNEL DISTRIBUTION IN NEURONAL CELLS
神经细胞钠通道分布的调节
  • 批准号:
    6243855
  • 财政年份:
    1997
  • 资助金额:
    $ 25.45万
  • 项目类别:
CLUSTERING OF NA CHANNELS ON AXONS IS INDEPENDENT OF DIRECT SCHWANN CELL CONTACT
轴突上 NA 通道的聚集独立于施万细胞的直接接触
  • 批准号:
    6252944
  • 财政年份:
    1997
  • 资助金额:
    $ 25.45万
  • 项目类别:
MECHANISMS OF THE VOLTAGE-DEPENDENT SODIUM CHANNEL
电压依赖性钠通道的机制
  • 批准号:
    2262903
  • 财政年份:
    1993
  • 资助金额:
    $ 25.45万
  • 项目类别:
MECHANISMS OF THE VOLTAGE-DEPENDENT SODIUM CHANNEL
电压依赖性钠通道的机制
  • 批准号:
    6186974
  • 财政年份:
    1993
  • 资助金额:
    $ 25.45万
  • 项目类别:
MECHANISMS OF THE VOLTAGE-DEPENDENT SODIUM CHANNEL
电压依赖性钠通道的机制
  • 批准号:
    2262901
  • 财政年份:
    1993
  • 资助金额:
    $ 25.45万
  • 项目类别:
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