Regulated sialylation modulates cardiac excitability and conduction

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Electrical signaling occurs in all cells and is of primary importance to excitable cell function. Neurons, skeletal and cardiac muscle communicate through production and conduction of electrical signals called action potentials (AP), a transient depolarization of the membrane produced by the concerted and highly regulated activities of many voltage-gated ion channels. Slight alterations in ion channel activity often lead to altered excitability. Some of the ion channel functions depend on sugar groups, called glycans, that may comprise ~15-30% of the mature ion channel mass. Most studies showed that sugar-dependent gating effects were imposed primarily by the terminal residue, sialic acid. However, little is known about whether and how regulated sialylation modulates excitability and conduction, in vivo. Thus, questioning whether and how (mechanistically) regulated sialylation modulates cardiac excitability and conduction will be investigated. A broad range of methods including molecular, cellular, tissue, whole animal, and computational techniques will be used at several organizational levels on an animal model comprised of 1) Sialyltransferase (ST) knockout strains producing proteins with fewer attached sialic acids, and 2) The enzymatic removal of sialic acids and N-glycans. The proposed studies are designed to test the viability of a novel mechanism by which glycans modulate electrical signaling, in vivo and in silico. The paradigm challenges being studied throughout this work and the melding of disparate biological areas including ion channel and glyco-biology, have broad implications. Because ion channel activity is involved in the function of all cells of the body, and since nearly all ion channels are glycosylated, gaining an understanding of a functional role for glycosylation in electrical signaling will likely have broad scientific impact. If the studies indicate that glycan structures influence ion channel function, then future studies should address the impact of glycans on ion channel structure as it relates to channel function. In addition to these broad scientific implications, the proposed studies will have broader impact that includes education, communication, and health. To address these broader issues, undergraduate, graduate, and medical students, particularly including minority students, will be trained in the scientific method by asking a fundamental question utilizing a variety of techniques. The generated scientific findings will be shared with the general scientific community, the lay public, and our collaborators, and effectively communicate the impact of these findings on the health of society.