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

Lulu Chu, Joseph L. Greenstein, Raimond L. Winslow

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiac sodium (Na + ) potassium ATPase (NaK) pumps, neuronal sodium channels (I Na ), and sodium calcium (Ca 2+ ) exchangers (NCX1) may co-localize to form a Na + microdomain. It remains controversial as to whether neuronal I Na contributes to local Na + accumulation, resulting in reversal of nearby NCX1 and influx of Ca 2+ into the cell. Therefore, there has been great interest in the possible roles of a Na + microdomain in cardiac Ca 2+ -induced Ca 2+ release (CICR). In addition, the important role of co-localization of NaK and NCX1 in regulating localized Na + and Ca 2+ 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) Ca 2+ release events underlying cell-wide excitation-contraction coupling, as well as a three-dimensional super-resolution model of the Ca 2+ spark that describes local Na + dynamics as governed by NaK pumps, neuronal I Na , and NCX1. The model predicts the existence of Na + sparks, which are generated by NCX1 and exhibit significantly slower dynamics as compared to Ca 2+ sparks. Moreover, whole-cell simulations indicate that neuronal I Na in the cardiac dyad plays a key role during the systolic phase. Rapid inward neuronal I Na can elevate dyadic [Na + ] to 35–40 mM, which drives reverse-mode NCX1 transport, and therefore promotes Ca 2+ entry into the dyad, enhancing the trigger for JSR Ca 2+ 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 [Ca 2+ ] and [Na + ] results in an increase in Ca 2+ 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 Ca 2+ channel reopening and arrhythmogenic early-afterdepolarizations.

Original languageEnglish (US)
Pages (from-to)145-157
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume128
DOIs
StatePublished - Mar 2019

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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