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. 2018 Sep 19;9:1306. doi: 10.3389/fphys.2018.01306

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Copyright © 2018 Tomek, Tomková, Zhou, Bub and Rodriguez.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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A diagram of the HeRd model of ventricular cardiomyocyte and an overview of calcium handling. Shown are transmembrane currents, compartmentalized sarcoplasmic reticulum and the associated fluxes, and CaMKII signaling. β-adrenergic signaling components in the model were not used in this study. The calcium handling components relevant for alternans are highlighted in orange font. Green arrows indicate which components are regulated by CaMKII, an important regulator of calcium handling. Within an action potential, calcium handling in the model works as follows: L-type calcium current (I_CaL) induces an influx of calcium which is sensed by ryanodine receptors (RyR). This induces a large-magnitude release of calcium, J_rel, via RyR (this process is termed CICR: calcium-induced calcium release). The amount of calcium released via RyR depends mainly on the calcium stimulus via I_CaL and the load–release relationship of junctional sarcoplasmic reticulum containing RyR (JSR): the fuller the JSR is, the more calcium it releases (Shannon et al., 2000). This relationship is steep, as shown in a previous study of the Hund-Rudy model (Livshitz and Rudy, 2007) and experiments (Shannon et al., 2000), i.e., a relatively small increase in JSR contents may increase fractional release considerably. The released calcium then diffuses to the intracellular space (J_diff) and eventually to SERCA pumps, which reuptake the calcium back to network sarcoplasmic reticulum containing SERCA pumps (NSR). Ultimately, within sarcoplasmic reticulum, calcium diffuses from NSR to JSR along the concentration gradient (J_tr), from where it may be released in the next action potential. SS codes the junctional calcium subspace where the calcium influx via ICaL stimulates ryanodine receptors. The figure is based on Heijman et al. (2011).