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

Cardiac sodium (Na⁺) potassium ATPase (NaK) pumps, neuronal sodium channels (I_Na), and sodium calcium (Ca²⁺) 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 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 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 Ca²⁺ 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 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: {{ getKeywords(articleDetailText.words) }}