Sodium Channel Differential Sialylation Throughout Development

埃里克·S·班尼特IBN-98 16685我们的身体依靠离子在细胞膜上移动产生的电力运转。电压门控钠通道是钠跨膜移动的调节管道。在细胞的负静止膜电位下，通道处于静止状态。在膜去极化之后，通道以某种方式“感觉”膜电位的变化，并通过形成一个水孔来激活，钠通过这个孔进入细胞。因此，被称为动作电位的电信号被启动和传播。钠通道感受到的膜电位的任何变化都会影响通道的活动，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胞外部分。例如，成熟的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。这种唾液酸可能造成表面负电荷，从而改变蛋白质感受到的膜电位，从而改变通道活性。多种钠通道类型在全身和整个发育过程中表达，产生一系列钠通道唾液酸水平。随着水平和/或位置的变化，这种差异唾液酸化对钠通道功能的影响也可能不同，作为调节通道活动的一种手段。确定这种差异唾液酸化的机制和生理影响是该项目的主要焦点。骨骼肌钠通道在整个发育过程中的研究将被用作一个模型系统。成人骨骼肌表达一种非常严重的唾液酸化通道，而胚胎骨骼肌表达第二种类型的钠通道，其唾液酸化程度要低得多。此外，第二个高度唾液酸化的亚基~，显然只在成人组织中表达。因此，胚胎骨骼肌钠通道与成人骨骼肌钠通道的唾液酸总水平差别很大。通过在一个孤立的系统中直接比较这两种通道类型，可以确定这种差异唾液酸化影响通道闪烁的机制。这种差别化唾液酸化的生理影响将通过研究发育中的心肌细胞的钠通道活性来确定。

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.