Regulated sialylation modulates cardiac excitability and conduction

电信号发生在所有细胞中，对可兴奋的细胞功能至关重要。神经元、骨骼肌和心肌通过产生和传导称为动作电位(AP)的电信号进行通信，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变化往往会导致兴奋性的改变。一些离子通道的功能依赖于糖基，称为葡聚糖，它可能占成熟离子通道质量的15%-30%。大多数研究表明，糖依赖的门控效应主要是由末端残基唾液酸施加的。然而，在体内，人们对唾液酸化是否以及如何调节兴奋性和传导知之甚少。因此，关于(机械地)调节唾液酸化是否以及如何调节心脏兴奋性和传导的问题将被调查。包括分子、细胞、组织、整个动物和计算技术在内的广泛的方法将在几个组织水平上用于动物模型，该动物模型包括1)唾液酸转移酶(ST)基因敲除菌株产生较少附着唾液酸的蛋白质，以及2)酶法去除唾液酸和N-糖链。这项拟议的研究旨在测试一种新的机制的可行性，通过这种机制，在体内和在硅胶中，多糖可以调节电信号。贯穿这项工作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影响。由于离子通道的活动涉及到人体所有细胞的功能，而且几乎所有的离子通道都是糖基化的，了解糖基化在电信号中的功能作用可能会有广泛的科学影响。如果研究表明多糖结构影响离子通道功能，那么未来的研究应该解决与离子通道功能相关的多糖对离子通道结构的影响。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在内，将通过利用各种技术提出基本问题来接受科学方法方面的培训。产生的科学发现将与普通科学界、非专业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.