Sodium Channel Differential Sialylation Throughout Development

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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.