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Title: Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes
Dilated cardiomyopathy (DCM) is the third most common cause of heart failure and the primary reason for heart transplantation; upward of 70% of DCM cases are considered idiopathic. Our in-vitro experiments showed that reduced hybrid/complex N-glycosylation in mouse cardiomyocytes is linked with DCM. Further, we observed direct effects of reduced N-glycosylation on K v gating. However, it is difficult to rigorously determine the effects of glycosylation on K v activity, because there are multiple K v isoforms in cardiomyocytes contributing to the cardiac excitation. Due to complex functions of K v isoforms, only the sum of K + currents (I Ksum ) can be recorded experimentally and decomposed later using exponential fitting to estimate component currents, such as I Kto , I Kslow , and I Kss . However, such estimation cannot adequately describe glycosylation effects and K v mechanisms. Here, we propose a framework of simulation modeling of K v kinetics in mouse ventricular myocytes and model calibration using the in-vitro data under normal and reduced glycosylation conditions through ablation of the Mgat1 gene (i.e., Mgat1KO). Calibrated models facilitate the prediction of K v characteristics at different voltages that are not directly observed in the in-vitro experiments. A model calibration procedure is developed based on the genetic algorithm. Experimental results show that, in the Mgat1KO group, both I Kto and I Kslow densities are shown to be significantly reduced and the rate of I Kslow inactivation is much slower. The proposed approach has strong potential to couple simulation models with experimental data for gaining a better understanding of glycosylation effects on K v kinetics.  more » « less
Award ID(s):
1856199 1146882 1660928 1856132
NSF-PAR ID:
10334788
Author(s) / Creator(s):
; ; ;
Date Published:
Journal Name:
Frontiers in Physiology
Volume:
13
ISSN:
1664-042X
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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