TY - JOUR
T1 - In-silico modeling of glycosylation modulation dynamics in hERG ion channels and cardiac electrical signals
AU - Du, Dongping
AU - Yang, Hui
AU - Norring, Sarah A.
AU - Bennett, Eric S.
PY - 2014/1
Y1 - 2014/1
N2 - Cardiac action potentials (AP) are produced by the orchestrated functions of ion channels. A slight change in ion channel activity may affect the AP waveform, thereby potentially increasing susceptibility to abnormal cardiac rhythms. Cardiac ion channels are heavily glycosylated, with up to 30% of a mature protein's mass comprised of glycan structures. However, little is known about how reduced glycosylation impacts the gating of hERG ( human ether-a-go-go related gene) channel, which is partially responsible for late phase 2 and phase 3 of the AP. This paper integrates the data from in vitro experiments with in-silico models to predict the glycosylation modulation dynamics in hERG ion channels and cardiac electrical signals. The gating behaviors of hERG channels expressed in Chinese Hamster Ovary (CHO) cells were measured under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich. and N-glycanase treated. Further, we developed in-silico models to simulate glycosylation-channel interactions and predict the effects of reduced glycosylation on multiscale cardiac processes (i.e., cardiac cells, 1-D and 2-D tissues). From the in-silico models, reduced glycosylation was shown to shorten the repolarization phase of cardiac APs, thereby influencing electrical propagation in cardiac fibers and tissues. In addition, the patterns of derived electrocardiogram show that reduced glycosylation of hERG channel shortens the QT interval and decreases the re-entry rate of spiral waves. This work suggests new pharmaceutical targets for the long QT syndrome and potentially other cardiac disorders.
AB - Cardiac action potentials (AP) are produced by the orchestrated functions of ion channels. A slight change in ion channel activity may affect the AP waveform, thereby potentially increasing susceptibility to abnormal cardiac rhythms. Cardiac ion channels are heavily glycosylated, with up to 30% of a mature protein's mass comprised of glycan structures. However, little is known about how reduced glycosylation impacts the gating of hERG ( human ether-a-go-go related gene) channel, which is partially responsible for late phase 2 and phase 3 of the AP. This paper integrates the data from in vitro experiments with in-silico models to predict the glycosylation modulation dynamics in hERG ion channels and cardiac electrical signals. The gating behaviors of hERG channels expressed in Chinese Hamster Ovary (CHO) cells were measured under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich. and N-glycanase treated. Further, we developed in-silico models to simulate glycosylation-channel interactions and predict the effects of reduced glycosylation on multiscale cardiac processes (i.e., cardiac cells, 1-D and 2-D tissues). From the in-silico models, reduced glycosylation was shown to shorten the repolarization phase of cardiac APs, thereby influencing electrical propagation in cardiac fibers and tissues. In addition, the patterns of derived electrocardiogram show that reduced glycosylation of hERG channel shortens the QT interval and decreases the re-entry rate of spiral waves. This work suggests new pharmaceutical targets for the long QT syndrome and potentially other cardiac disorders.
KW - Cardiac action potential
KW - Glycosylation
KW - In-silico model
KW - Long-QT syndrome
KW - hERG channel
UR - http://www.scopus.com/inward/record.url?scp=84892413601&partnerID=8YFLogxK
U2 - 10.1109/JBHI.2013.2260864
DO - 10.1109/JBHI.2013.2260864
M3 - Article
C2 - 24403418
AN - SCOPUS:84892413601
VL - 18
SP - 205
EP - 214
JO - IEEE Journal of Biomedical and Health Informatics
JF - IEEE Journal of Biomedical and Health Informatics
SN - 2168-2194
IS - 1
M1 - 6510434
ER -