Ednie Andrew R, Bennett Eric S
From the Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612.
From the Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612
J Biol Chem. 2015 Jan 30;290(5):2769-83. doi: 10.1074/jbc.M114.605139. Epub 2014 Dec 18.
Voltage-gated K(+) channels (Kv) are responsible for repolarizing excitable cells and can be heavily glycosylated. Cardiac Kv activity is indispensable where even minimal reductions in function can extend action potential duration, prolong QT intervals, and ultimately contribute to life-threatening arrhythmias. Diseases such as congenital disorders of glycosylation often cause significant cardiac phenotypes that can include arrhythmias. Here we investigated the impact of reduced sialylation on ventricular repolarization through gene deletion of the sialyltransferase ST3Gal4. ST3Gal4-deficient mice (ST3Gal4(-/-)) had prolonged QT intervals with a concomitant increase in ventricular action potential duration. Ventricular apex myocytes isolated from ST3Gal4(-/-) mice demonstrated depolarizing shifts in activation gating of the transient outward (Ito) and delayed rectifier (IKslow) components of K(+) current with no change in maximum current densities. Consistently, similar protein expression levels of the three Kv isoforms responsible for Ito and IKslow were measured for ST3Gal4(-/-) versus controls. However, novel non-enzymatic sialic acid labeling indicated a reduction in sialylation of ST3Gal4(-/-) ventricular Kv4.2 and Kv1.5, which contribute to Ito and IKslow, respectively. Thus, we describe here a novel form of regulating cardiac function through the activities of a specific glycogene product. Namely, reduced ST3Gal4 activity leads to a loss of isoform-specific Kv sialylation and function, thereby limiting Kv activity during the action potential and decreasing repolarization rate, which likely contributes to prolonged ventricular repolarization. These studies elucidate a novel role for individual glycogene products in contributing to a complex network of cardiac regulation under normal and pathologic conditions.
电压门控钾离子通道（Kv）负责可兴奋细胞的复极化，且可被高度糖基化。心脏Kv活性不可或缺，即使功能出现极小程度的降低也会延长动作电位持续时间、延长QT间期，并最终导致危及生命的心律失常。诸如先天性糖基化障碍等疾病常常会引发显著的心脏表型，其中可能包括心律失常。在此，我们通过基因敲除唾液酸转移酶ST3Gal4来研究唾液酸化减少对心室复极化的影响。ST3Gal4基因敲除小鼠（ST3Gal4(-/-)）的QT间期延长，同时心室动作电位持续时间增加。从ST3Gal4(-/-)小鼠分离出的心室肌尖部细胞显示，钾离子电流的瞬时外向电流（Ito）和延迟整流电流（IKslow）成分的激活门控出现去极化偏移，而最大电流密度没有变化。同样，与对照组相比，负责Ito和IKslow的三种Kv亚型的蛋白质表达水平相似。然而，新型非酶促唾液酸标记表明，ST3Gal4(-/-)心室的Kv4.2和Kv1.5的唾液酸化减少，它们分别对Ito和IKslow有贡献。因此，我们在此描述了一种通过特定糖基因产物的活性来调节心脏功能的新形式。具体而言，ST3Gal4活性降低会导致亚型特异性Kv唾液酸化和功能丧失，从而在动作电位期间限制Kv活性并降低复极化速率，这可能导致心室复极化延长。这些研究阐明了单个糖基因产物在正常和病理条件下对心脏调节复杂网络的贡献中的新作用。
