Ca2+ Leak and Ca2+ Sparks in Mammalian Heart: Insights from a Computational Model

Calcium (Ca2+) signaling in muscle, neuronal, and non-excitable cells has benefited significantly from advances in biological tools and imaging technology, however, the molecular interactions of nanoscopic molecules, structures and compartments has been challenging to study under physiological conditions. Here, we exploit novel computational modeling techniques to examine real-time molecular and cellular physiology in cardiac ventricular myocytes. The model focuses on local and cell-wide Ca2+ signaling phenomena related to calcium induced calcium release from intracellular calcium channels, ryanodine receptors (RyR2s), located on the sarcoplasmic reticulum (SR) membrane. This work is informed by the latest molecular investigations and recent characterizations of channels, transporters, and buffers located in mammalian heart. We have created a detailed, whole-cell model of Ca2+ signaling using a realistic number of calcium release units (CRU) each containing a cluster of stochastically gating RyR2s. During systole the opening of these RyR2s is triggered by Ca2+ entry via voltage gated L-type Ca2+ channels. The synchronized opening of the RyR2 cluster leads to localized elevations of [Ca2+]i known as Ca2+ sparks. During diastole Ca2+ sparks are still observed and are attributed to the finite opening rate of the RyR2. RyR2s are also believed to display unsynchronized or non-spark openings where only a few channels in the CRU open without triggering the remainder of the RyR2 cluster. This non-spark Ca2+ release would be below current experimental detection thresholds and therefore “invisible.” These spark and non-spark openings of RyR2s constitute a molecular basis for Ca2+ leak from the SR. The computational model suggests that a significant fraction of SR Ca2+ leak is due to RyR2s openings that fail to trigger a “visible” Ca2+ spark. Additionally, the fraction of non-spark or “invisible” SR Ca2+ leak increases as SR Ca2+ content declines.