Cargando…
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....
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931503/ https://www.ncbi.nlm.nih.gov/pubmed/35309072 http://dx.doi.org/10.3389/fphys.2022.816651 |
_version_ | 1784671280230825984 |
---|---|
author | Kim, Haedong Yang, Hui Ednie, Andrew R. Bennett, Eric S. |
author_facet | Kim, Haedong Yang, Hui Ednie, Andrew R. Bennett, Eric S. |
author_sort | Kim, Haedong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8931503 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89315032022-03-19 Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes Kim, Haedong Yang, Hui Ednie, Andrew R. Bennett, Eric S. Front Physiol Physiology 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. Frontiers Media S.A. 2022-03-04 /pmc/articles/PMC8931503/ /pubmed/35309072 http://dx.doi.org/10.3389/fphys.2022.816651 Text en Copyright © 2022 Kim, Yang, Ednie and Bennett. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Kim, Haedong Yang, Hui Ednie, Andrew R. Bennett, Eric S. Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes |
title | Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes |
title_full | Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes |
title_fullStr | Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes |
title_full_unstemmed | Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes |
title_short | Simulation Modeling of Reduced Glycosylation Effects on Potassium Channels of Mouse Cardiomyocytes |
title_sort | simulation modeling of reduced glycosylation effects on potassium channels of mouse cardiomyocytes |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931503/ https://www.ncbi.nlm.nih.gov/pubmed/35309072 http://dx.doi.org/10.3389/fphys.2022.816651 |
work_keys_str_mv | AT kimhaedong simulationmodelingofreducedglycosylationeffectsonpotassiumchannelsofmousecardiomyocytes AT yanghui simulationmodelingofreducedglycosylationeffectsonpotassiumchannelsofmousecardiomyocytes AT ednieandrewr simulationmodelingofreducedglycosylationeffectsonpotassiumchannelsofmousecardiomyocytes AT bennetterics simulationmodelingofreducedglycosylationeffectsonpotassiumchannelsofmousecardiomyocytes |