Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling

Calcium-induced calcium release is the principal mechanism that triggers the cell-wide [Ca2 +]i transient that activates muscle contraction during cardiac excitation-contraction coupling (ECC). Here, we characterize this process in mouse cardiac myocytes with a novel mathematical action potential (AP) model that incorporates realistic stochastic gating of voltage-dependent L-type calcium (Ca2 +) channels (LCCs) and sarcoplasmic reticulum (SR) Ca2 + release channels (the ryanodine receptors, RyR2s). Depolarization of the sarcolemma during an AP stochastically activates the LCCs elevating subspace [Ca2 +] within each of the cell's 20,000 independent calcium release units (CRUs) to trigger local RyR2 opening and initiate Ca2 + sparks, the fundamental unit of triggered Ca2 + release. Synchronization of Ca2 + sparks during systole depends on the nearly uniform cellular activation of LCCs and the likelihood of local LCC openings triggering local Ca2 + sparks (ECC fidelity). The detailed design and true SR Ca2 + pump/leak balance displayed by our model permits investigation of ECC fidelity and Ca2 + spark fidelity, the balance between visible (Ca2 + spark) and invisible (Ca2 + quark/sub-spark) SR Ca2 + release events. Excess SR Ca2 + leak is examined as a disease mechanism in the context of “catecholaminergic polymorphic ventricular tachycardia (CPVT)”, a Ca2 +-dependent arrhythmia. We find that that RyR2s (and therefore Ca2 + sparks) are relatively insensitive to LCC openings across a wide range of membrane potentials; and that key differences exist between Ca2 + sparks evoked during quiescence, diastole, and systole. The enhanced RyR2 [Ca2 +]i sensitivity during CPVT leads to increased Ca2 + spark fidelity resulting in asynchronous systolic Ca2 + spark activity. It also produces increased diastolic SR Ca2 + leak with some prolonged Ca2 + sparks that at times become “metastable” and fail to efficiently terminate. There is a huge margin of safety for stable Ca2 + handling within the cell and this novel mechanistic model provides insight into the molecular signaling characteristics that help maintain overall Ca2 + stability even under the conditions of high SR Ca2 + leak during CPVT. Finally, this model should provide tools for investigators to examine normal and pathological Ca2 + signaling characteristics in the heart.