Multi-scale modeling of glycosylation modulation dynamics in cardiac electrical signaling

Abstract

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.