Montpetit Marty L, Stocker Patrick J, Schwetz Tara A, Harper Jean M, Norring Sarah A, Schaffer Lana, North Simon J, Jang-Lee Jihye, Gilmartin Timothy, Head Steven R, Haslam Stuart M, Dell Anne, Marth Jamey D, Bennett Eric S
Department of Molecular Pharmacology & Physiology, Programs in Cardiovascular Sciences and Neuroscience, University of South Florida College of Medicine, Tampa, FL 33612, USA.
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16517-22. doi: 10.1073/pnas.0905414106. Epub 2009 Aug 7.
Millions afflicted with Chagas disease and other disorders of aberrant glycosylation suffer symptoms consistent with altered electrical signaling such as arrhythmias, decreased neuronal conduction velocity, and hyporeflexia. Cardiac, neuronal, and muscle electrical signaling is controlled and modulated by changes in voltage-gated ion channel activity that occur through physiological and pathological processes such as development, epilepsy, and cardiomyopathy. Glycans attached to ion channels alter channel activity through isoform-specific mechanisms. Here we show that regulated and aberrant glycosylation modulate cardiac ion channel activity and electrical signaling through a cell-specific mechanism. Data show that nearly half of 239 glycosylation-associated genes (glycogenes) were significantly differentially expressed among neonatal and adult atrial and ventricular myocytes. The N-glycan structures produced among cardiomyocyte types were markedly variable. Thus, the cardiac glycome, defined as the complete set of glycan structures produced in the heart, is remodeled. One glycogene, ST8sia2, a polysialyltransferase, is expressed only in the neonatal atrium. Cardiomyocyte electrical signaling was compared in control and ST8sia2((-/-)) neonatal atrial and ventricular myocytes. Action potential waveforms and gating of less sialylated voltage-gated Na+ channels were altered consistently in ST8sia2((-/-)) atrial myocytes. ST8sia2 expression had no effect on ventricular myocyte excitability. Thus, the regulated (between atrium and ventricle) and aberrant (knockout in the neonatal atrium) expression of a single glycogene was sufficient to modulate cardiomyocyte excitability. A mechanism is described by which cardiac function is controlled and modulated through physiological and pathological processes that involve regulated and aberrant glycosylation.
数以百万计的恰加斯病和其他异常糖基化疾病患者出现与电信号改变一致的症状，如心律失常、神经元传导速度降低和反射减退。心脏、神经元和肌肉的电信号由电压门控离子通道活性的变化控制和调节，这些变化通过生理和病理过程发生，如发育、癫痫和心肌病。附着在离子通道上的聚糖通过异构体特异性机制改变通道活性。在这里，我们表明，受调控的和异常的糖基化通过细胞特异性机制调节心脏离子通道活性和电信号。数据显示，在239个与糖基化相关的基因（糖基因）中，近一半在新生儿和成人的心房和心室肌细胞中存在显著差异表达。心肌细胞类型中产生的N-聚糖结构明显不同。因此，被定义为心脏中产生的聚糖结构全集的心脏糖组发生了重塑。一个糖基因ST8sia2，一种多唾液酸转移酶，仅在新生儿心房中表达。在对照和ST8sia2基因敲除的新生儿心房和心室肌细胞中比较了心肌细胞的电信号。在ST8sia2基因敲除的心房肌细胞中，唾液酸化程度较低的电压门控钠通道的动作电位波形和门控始终发生改变。ST8sia2的表达对心室肌细胞的兴奋性没有影响。因此，单个糖基因的受调控（心房和心室之间）和异常（新生儿心房中的基因敲除）表达足以调节心肌细胞的兴奋性。本文描述了一种机制，通过该机制，心脏功能通过涉及受调控和异常糖基化的生理和病理过程来控制和调节。
