Long-Lasting Sparks: Multi-Metastability and Release Competition in the Calcium Release Unit Network

Calcium (Ca) sparks are elementary events of biological Ca signaling. A normal Ca spark has a brief duration in the range of 10 to 100 ms, but long-lasting sparks with durations of several hundred milliseconds to seconds are also widely observed. Experiments have shown that the transition from normal to long-lasting sparks can occur when ryanodine receptor (RyR) open probability is either increased or decreased. Here, we demonstrate theoretically and computationally that long-lasting sparks emerge as a collective dynamical behavior of the network of diffusively coupled Ca release units (CRUs). We show that normal sparks occur when the CRU network is monostable and excitable, while long-lasting sparks occur when the network dynamics possesses multiple metastable attractors, each attractor corresponding to a different spatial firing pattern of sparks. We further highlight the mechanisms and conditions that produce long-lasting sparks, demonstrating the existence of an optimal range of RyR open probability favoring long-lasting sparks. We find that when CRU firings are sparse and sarcoplasmic reticulum (SR) Ca load is high, increasing RyR open probability promotes long-lasting sparks by potentiating Ca-induced Ca release (CICR). In contrast, when CICR is already strong enough to produce frequent firings, decreasing RyR open probability counter-intuitively promotes long-lasting sparks by decreasing spark frequency. The decrease in spark frequency promotes intra-SR Ca diffusion from neighboring non-firing CRUs to the firing CRUs, which helps to maintain the local SR Ca concentration of the firing CRUs above a critical level to sustain firing. In this setting, decreasing RyR open probability further suppresses long-lasting sparks by weakening CICR. Since a long-lasting spark terminates via the Kramers’ escape process over a potential barrier, its duration exhibits an exponential distribution determined by the barrier height and noise strength, which is modulated differently by different ways of altering the Ca release flux strength.Author Summary: Calcium (Ca) sparks, resulting from Ca-induced Ca release, are elementary events of biological Ca signaling. Sparks are normally brief, but long-lasting sparks have been widely observed experimentally under various conditions. The underlying mechanisms of spark duration or termination and the corresponding determinants remain a topic of debate. In this study, we demonstrate theoretically and computationally that normal brief sparks are excitable transients, while long-lasting sparks are multiple metastable states emerging in the diffusively coupled Ca release unit network, as a result of cooperativity and release competition among the Ca release units. Termination of a long-lasting spark is a Kramers’ escape process over a potential barrier, and the spark duration is the first-passage time, exhibiting an exponential distribution.