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J Mol Cell Cardiol. 2019 Mar;128:145-157. doi: 10.1016/j.yjmcc.2019.02.001. Epub 2019 Feb 5.

Na+ microdomains and sparks: Role in cardiac excitation-contraction coupling and arrhythmias in ankyrin-B deficiency.

Author information

1
Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD 21218, USA. Electronic address: lulu.chu1@astrazeneca.com.
2
Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD 21218, USA. Electronic address: jgreenst@jhu.edu.
3
Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD 21218, USA. Electronic address: rwinslow@jhu.edu.

Abstract

Cardiac sodium (Na+) potassium ATPase (NaK) pumps, neuronal sodium channels (INa), and sodium calcium (Ca2+) exchangers (NCX1) may co-localize to form a Na+ microdomain. It remains controversial as to whether neuronal INa contributes to local Na+ accumulation, resulting in reversal of nearby NCX1 and influx of Ca2+ into the cell. Therefore, there has been great interest in the possible roles of a Na+ microdomain in cardiac Ca2+-induced Ca2+ release (CICR). In addition, the important role of co-localization of NaK and NCX1 in regulating localized Na+ and Ca2+ levels and CICR in ankyrin-B deficient (ankyrin-B+/-) cardiomyocytes has been examined in many recent studies. Altered Na+ dynamics may contribute to the appearance of arrhythmias, but the mechanisms underlying this relationship remain unclear. In order to investigate this, we present a mechanistic canine cardiomyocyte model which reproduces independent local dyadic junctional SR (JSR) Ca2+ release events underlying cell-wide excitation-contraction coupling, as well as a three-dimensional super-resolution model of the Ca2+ spark that describes local Na+ dynamics as governed by NaK pumps, neuronal INa, and NCX1. The model predicts the existence of Na+ sparks, which are generated by NCX1 and exhibit significantly slower dynamics as compared to Ca2+ sparks. Moreover, whole-cell simulations indicate that neuronal INa in the cardiac dyad plays a key role during the systolic phase. Rapid inward neuronal INa can elevate dyadic [Na+] to 35-40 mM, which drives reverse-mode NCX1 transport, and therefore promotes Ca2+ entry into the dyad, enhancing the trigger for JSR Ca2+ release. The specific role of decreased co-localization of NaK and NCX1 in ankyrin-B+/- cardiomyocytes was examined. Model results demonstrate that a reduction in the local NCX1- and NaK-mediated regulation of dyadic [Ca2+] and [Na+] results in an increase in Ca2+ spark activity during isoproterenol stimulation, which in turn stochastically activates NCX1 in the dyad. This alteration in NCX1/NaK co-localization interrupts the balance between NCX1 and NaK currents in a way that leads to enhanced depolarizing inward current during the action potential plateau, which ultimately leads to a higher probability of L-type Ca2+ channel reopening and arrhythmogenic early-afterdepolarizations.

KEYWORDS:

Cardiac myocyte; Computational model; Neuronal sodium channels; Sodium microdomains; Sodium potassium ATPase pump; Sodium sparks; Sodium‑calcium exchanger

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