Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Many issues remain unresolved concerning how local, subcellular Ca ²⁺ signals interact with bulk cellular concentrations to maintain homeostasis in health and disease. To aid in the interpretation of data obtained in quiescent ventricular myocytes, we present here a minimal whole cell model that accounts for both localized (subcellular) and global (cellular) aspects of Ca²⁺ signaling. Using a minimal formulation of the distribution of local [Ca²⁺] associated with a large number of Ca²⁺- release sites, the model simulates both random spontaneous Ca²⁺ sparks and the changes in myoplasmic and sarcoplasmic reticulum (SR) [Ca ²⁺] that result from the balance between stochastic release and reuptake into the SR. Ca²⁺-release sites are composed of clusters of two-state ryanodine receptors (RyRs) that exhibit activation by local cytosolic [Ca²⁺] but no inactivation or regulation by luminal Ca²⁺. Decreasing RyR open probability in the model causes a decrease in aggregate release flux and an increase in SR [Ca²⁺], regardless of whether RyR inhibition is mediated by a decrease in RyR open dwell time or an increase in RyR closed dwell time. The same balance of stochastic release and reuptake can be achieved, however, by either high-frequency/short-duration or low-frequency/long-duration Ca²⁺ sparks. The results are well correlated with recent experimental observations using pharmacological RyR inhibitors and clarify those aspects of the release-reuptake balance that are inherent to the coupling between local and global Ca²⁺ signals and those aspects that depend on molecular-level details. The model of Ca ²⁺ sparks and homeostasis presented here can be a useful tool for understanding changes in cardiac Ca²⁺ release resulting from drugs, mutations, or acquired diseases.