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

07:00 EST 4th February 2019 | BioPortfolio

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

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This article was published in the following journal.

Name: Journal of molecular and cellular cardiology
ISSN: 1095-8584
Pages:

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A tetrameric calcium release channel in the SARCOPLASMIC RETICULUM membrane of SMOOTH MUSCLE CELLS, acting oppositely to SARCOPLASMIC RETICULUM CALCIUM-TRANSPORTING ATPASES. It is important in skeletal and cardiac excitation-contraction coupling and studied by using RYANODINE. Abnormalities are implicated in CARDIAC ARRHYTHMIAS and MUSCULAR DISEASES.

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