Regulated sialylation modulates cardiac excitability and conduction

电信号发生在所有细胞中，并且对可兴奋细胞功能至关重要。神经元、骨骼肌和心肌通过称为动作电位（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的协调和高度调节的活动产生的膜的瞬时去极化。离子通道活性的轻微改变通常会导致兴奋性的改变。 一些离子通道功能依赖于糖基，称为聚糖，其可占成熟离子通道质量的约15-30%。大多数研究表明，糖依赖性门控效应主要由末端残基唾液酸施加。然而，很少有人知道是否以及如何调节唾液酸化调节兴奋性和传导，在体内。因此，质疑是否以及如何（机械）调节唾液酸化调节心脏兴奋性和传导将进行调查。将在动物模型的几个组织水平上使用广泛的方法，包括分子、细胞、组织、整个动物和计算技术，该动物模型包括1）唾液酸转移酶（ST）敲除菌株，其产生具有较少附着唾液酸的蛋白质，和2）唾液酸和N-聚糖的酶促去除。拟定的研究旨在测试聚糖在体内和计算机模拟中调节电信号的新机制的可行性。 在这项工作中研究的范式挑战和不同生物学领域的融合，包括离子通道和糖生物学，具有广泛的影响。由于离子通道活性参与身体所有细胞的功能，并且由于几乎所有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，则未来的研究应解决聚糖对离子通道结构的影响，因为它与通道功能相关。 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，通信和健康。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，将通过提出一个基本问题，利用各种技术的科学方法进行培训。所产生的科学发现将与一般科学界，公众和我们的合作者分享，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.