NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes

Biophysical Journal
Mingwang ZhongAlain Karma

Abstract

Long QT syndrome type 2 (LQT2) is a congenital disease characterized by loss of function mutations in hERG potassium channels (IKr). LQT2 is associated with fatal ventricular arrhythmias promoted by triggered activity in the form of early afterdepolarizations (EADs). We previously demonstrated that intracellular Ca2+ handling is remodeled in LQT2 myocytes. Remodeling leads to aberrant late RyR-mediated Ca2+ releases that drive forward-mode Na+-Ca2+ exchanger (NCX) current and slow repolarization to promote reopening of L-type calcium channels and EADs. Forward-mode NCX was found to be enhanced despite the fact that these late releases do not significantly alter the whole-cell cytosolic calcium concentration during a vulnerable period of phase 2 of the action potential corresponding to the onset of EADs. Here, we use a multiscale ventricular myocyte model to explain this finding. We show that because the local NCX current is a saturating nonlinear function of the local submembrane calcium concentration, a larger number of smaller-amplitude discrete Ca2+ release events can produce a large increase in whole-cell forward-mode NCX current without increasing significantly the whole-cell cytosolic calcium concentration. Furthermore, w...Continue Reading

Citations

Feb 23, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Lijuan JiaoHong Sun
Oct 6, 2020·Frontiers in Physiology·Alexandra NjegicElizabeth J Cartwright
Nov 15, 2018·Frontiers in Physiology·Shanna Hamilton, Dmitry Terentyev
Jul 7, 2020·Circulation. Arrhythmia and Electrophysiology·Jungmin HwangBum-Rak Choi
Jan 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ewan D FowlerMark B Cannell
Oct 24, 2020·The Journal of Biological Chemistry·Nilüfer N TuranGideon Koren
Jan 18, 2021·The Journal of Biological Chemistry·Nilüfer N TuranGideon Koren

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