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Activity of human ether-a-go-gorelated gene (hERG) 1 voltage-gated K+ channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N-glycosylation modified hERG channel function. Voltage-dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N-glycans, and following enzymatic deglycosylation of surface N-glycans. For each condition of reduced glycosylation, hERG channel steady-state activation and inactivation relationships were shifted linearly by significant depolarizing ~9 and ~18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing ~ 10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20-80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50-70-ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N-glycosylation; reduced channel sialylation increases hERG channel activity during die action potential, thereby increasing the rate of action potential repolarization. [ABSTRACT FROM AUTHOR]

The cardiac action potential (AP) is produced by the orchestrated functions of ion channel dynamics. The coordinated functions can be simulated by computational cardiac cell models, which could not only overcome the practical and ethical limitations in physical experiments but also provide predictive insights on the underlying mechanisms. This investigation is aimed at modeling the variations of cardiac electrical signaling due to changes in glycosylation of a voltage-gated K+ channel, hERG, responsible for late phase 2 and phase 3 of the human ventricular AP. The voltage-dependence of hERG channels steady-state activation and inactivation under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich and N-Glycanase treated, demonstrated that reduced glycosylation modulates hERG channel gating. Here, the proposed multi-scale computer model incorporates the measured changes in hERG channel gating observed under conditions of reduced glycosylation, and further predicts the electrical behaviors of cardiac cells and tissues (cable/ring). The multi-scale modeling results show that reduced glycosylation would act to shorten the repolarization period of cardiac APs, and distort the AP propagation in cardiac tissues. This multi-scale modeling investigation reveals novel mechanisms of hERG channel modulation by regulated glycosylation that also impact cardiac myocyte and tissue functions. It can potentially lead to new pharmaceutical treatments and drug designs for long QT syndrome and cardiac arrhythmia.