Sodium Channel Differential Sialylation Throughout Development

整个发育过程中钠通道差异唾液酸化

• 批准号: 9816685
• 负责人: Eric Bennett
• 金额: $ 38万
• 依托单位: University of South Florida
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9816685&HistoricalAwards=false
• 关键词: Sodium; Channel; Differential; Sialylation; Throughout

Eric S. BennettIBN-98 16685Our body runs on electricity produced by the movement of ions across the cell membrane. Voltage-gated sodium channels are regulated conduits for the movement of sodium across this membrane. Channels are quiescent at the cell's negative resting membrane potential. Following a membrane depolarization, channels somehow "sense" this change in membrane potential and activate by forming an aqueous pore through which sodium moves into the cell. Thus, the electrical signal known as the action potential is initiated and propagated.Any change in the membrane potential sensed by the sodium channel will affect channel activity, and thus the overall excitability of the cell. Large numbers of carbohydrate typically are attached to the extracellular portions of transmembrane proteins. For example, about 30% of the total mass of the mature sodium channel protein are carbohydrate, of which 40% are negatively charged sialic acid residues. This sialic acid may contribute to negative surface charges that alter the membrane potential sensed by the protein, and thus alter channel activity.A diversity of sodium channel types is expressed throughout the body and throughout development, producing a range in the levels of sodium channel sialic acids. As the levels and/or locations change, the impact of this differential sialylation on sodium channel function may also vary, serving as a means by which channel activity is regulated. Determining the mechanism and physiological impact of this differential sialylation is the major focus of the project.Studies of skeletal muscle sodium channels throughout development will be used as a model system. Adult skeletal muscle expresses a very heavily sialylated channel, while embryonic skeletal muscle expresses a second type of sodium channel that is much less sialylated. In addition, a second, heavily sialylated subunit, ~, is apparently expressed only in adult tissue. Thus, the overall levels of sialic acid attached to the embryonic versus adult skeletal muscle sodium channel vary considerably. Through direct comparison of these two channel types in an isolated system, one can determine the mechanism by which this differential sialylation impacts channel flinction. The physiological impact of this differential sialylation will be determined by studying sodium channel activity in developing myocytes.

我们的身体靠离子在细胞膜上运动所产生的电能运转。电压门控钠通道是钠通过该膜运动的调节通道。当细胞静息膜电位为负时，通道处于静止状态。在膜去极化之后，通道以某种方式“感知”到膜电位的变化，并通过形成一个水孔来激活钠离子进入细胞。因此，被称为动作电位的电信号被启动并传播。钠离子通道感知的膜电位的任何变化都会影响通道的活性，从而影响细胞的整体兴奋性。大量的碳水化合物通常附着在跨膜蛋白的细胞外部分。例如，成熟钠通道蛋白总质量的30%左右是碳水化合物，其中40%是带负电荷的唾液酸残基。这种唾液酸可能产生表面负电荷，从而改变蛋白质感知的膜电位，从而改变通道活性。钠通道类型的多样性在整个身体和整个发育过程中表达，产生钠通道唾液酸水平的范围。随着水平和/或位置的变化，这种差异唾液化对钠通道功能的影响也可能发生变化，作为通道活性调节的一种手段。确定这种差异唾液化的机制和生理影响是该项目的主要重点。骨骼肌钠通道在整个发育过程中的研究将作为一个模型系统。成人骨骼肌表达一种非常严重的唾液化通道，而胚胎骨骼肌表达第二种钠通道，唾液化程度要低得多。此外，第二种严重唾液化的亚基~显然只在成人组织中表达。因此，附着在胚胎和成人骨骼肌钠通道上的唾液酸的总体水平差异很大。通过在孤立系统中直接比较这两种通道类型，可以确定这种差异唾液化影响通道弯曲的机制。这种差异唾液化的生理影响将通过研究发育中的肌细胞中的钠通道活性来确定。