Regulated sialylation modulates cardiac excitability and conduction

电信号发生在所有细胞中，对可兴奋细胞的功能至关重要。神经元、骨骼肌和心肌通过被称为动作电位（AP）的电信号的产生和传导进行通信，动作电位是由许多电压门控离子通道协调一致和高度调节的活动产生的膜的短暂去极化。离子通道活性的轻微改变常常导致兴奋性的改变。一些离子通道的功能依赖于糖基团，称为聚糖，它可能占成熟离子通道质量的15-30%。大多数研究表明糖依赖性门控效应主要是由末端残基唾液酸施加的。然而，关于唾液酰化是否以及如何调节体内的兴奋性和传导，我们知之甚少。因此，唾液酰化是否以及如何（机械地）调节心脏兴奋性和传导将被研究。广泛的方法，包括分子、细胞、组织、全动物和计算技术，将在几个组织水平上用于动物模型，包括1)唾液基转移酶（ST）敲除菌株产生具有较少附着唾液酸的蛋白质，以及2)酶去除唾液酸和n -聚糖。提出的研究旨在测试一种新机制的可行性，通过该机制，聚糖调节电信号，在体内和在硅。在整个工作中正在研究的范式挑战以及包括离子通道和糖生物学在内的不同生物学领域的融合具有广泛的意义。由于离子通道活性与机体所有细胞的功能有关，而且几乎所有的离子通道都是糖基化的，因此了解糖基化在电信号中的功能作用可能会产生广泛的科学影响。如果研究表明聚糖结构影响离子通道功能，那么未来的研究应该解决聚糖对离子通道结构的影响，因为它与通道功能有关。除了这些广泛的科学影响外，拟议的研究还将产生更广泛的影响，包括教育、交流和健康。为了解决这些更广泛的问题，本科生、研究生和医学生，特别是包括少数民族学生，将通过利用各种技术提出一个基本问题来训练科学方法。产生的科学发现将与一般科学界、非专业公众和我们的合作者共享，并有效地传达这些发现对社会健康的影响。

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.