Congenital Reductions in Cardiomyocyte N‐glycosylation Alter Voltage‐gated Ion Channel Glycosylation and Function Leading to Compromised Electromechanical Signaling
Authors: Ednie Andrew R. , Yip Kay‐Pong , Bennett Eric S 
Published: June 2021

The regulated process of glycosylation in the heart directly impacts cardiac electrical signaling by altering specific voltage‐gated ion channel gating mechanisms, a phenomenon typically ascribed to the effect of negatively charged sialic acids. In an effort to determine more directly the impact of aberrant N‐glycosylation on cardiomyocyte and cardiac electrical signaling, we created a mouse strain in which the glycosyltransferase responsible for initiating the formation of complex and hybrid N‐glycans, Mgat1, was deleted in cardiomyocytes only (Mgat1KO). Mgat1KO animals show significant cardiac arrhythmias at all ages tested, likely caused by the truncation of voltage‐gated Na+, Ca2+ and K+ channel (Nav, Cav and Kv respectively) N‐glycans that directly impact channel activity. Consistent with studies specifically focused on the impact of sialic acids, Mgat1KO myocyte voltage‐gated ion channels demonstrate depolarizing shifts in gating but to a larger degree than when sialylation only was reduced. In addition to the impact on channel gating, Kv channel current density is significantly reduced in Mgat1KO myocytes compared to WT, suggesting that the lack of complex and hybrid N‐glycans dramatically limits Kv channel activity. Kv channel inactivation kinetics, which are inherent properties of specific Kv isoforms, are also different in Mgat1KO myocytes compared to controls, suggesting significant Kv channel remodeling. Collectively, as a result of such altered channel activity, Mgat1KO myocyte action potential waveforms are significantly affected where a slower activation and marked prolongation of duration are observed. Mgat1KO myocytes also often demonstrate early afterdepolarizations, which are consistent with ECG measurements of Mgat1KO mice showing significant arrhythmias and altered conduction. To test whether the altered myocyte and cardiac electrical activity caused by deletion of Mgat1 would impact electro‐mechanical coupling, we next investigated myocyte intracellular Ca2+ signaling. Mgat1KO myocytes demonstrated a significant increase (~2.5 fold) in spontaneous Ca2+ spark activity compared to WT myocytes. The studies described here illustrate the vital nature of complete N‐linked glycosylation on cardiac function in that reduced levels of cardiomyocyte complex and hybrid N‐glycans lead to significant effects on cardiomyocyte electrical (e.g., ion channel activity) and mechanical (e.g., Ca2+ spark activity) activity in a manner consistent with severe human cardiomyopathies including many forms of congenital disorders of glycosylation.Support or Funding InformationThis work was supported, in part by two grants from the National Science Foundation [IOS‐1146882 and CMMI‐1266331]; an American Heart Association, Greater Southeast Affiliate Grant‐In‐Aid [14GRNT20450148]; an American Heart Association, Greater Southeast Affiliate Postdoctoral Fellowship [15POST25710010]; and a grant from the National Heart, Lung, Blood Institute [1R01HL102171].