Calcium oscillation on homogeneous and heterogeneous networks of ryanodine receptor

Calcium oscillation is an important calcium homeostasis, imbalance of which is the key mechanism of initiation and progression of many major diseases. The formation and maintenance of calcium homeostasis are closely related to the spatial distribution of calcium channels on endoplasmic reticulum, whose complex structure was unveiled by recent observations with superresolution imaging techniques. In the current paper, a theoretical framework is established by abstracting the spatial distribution of the calcium channels as a nonlinear biological complex network with calcium channels as nodes and Ca2+ as edges. A dynamical model for a ryanodine receptor (RyR) is adopted to investigate the effect of spatial distribution on calcium oscillation. The mean-field model can be well reproduced from the complete graph and dense Erdos-Renyi network. The synchronization of RyRs is found important to generate a global calcium oscillation. Below a critical density of the Erdos-Renyi or BaraBasi-Albert network, the amplitude and interspike interval decrease rapidly with the end of disappearance of oscillation due to the desynchronization. The clique graph with a cluster structure cannot produce a global oscillation due to the failure of synchronization between clusters. A more realistic geometric network is constructed in a two-dimensional plane based on the experimental information about the RyR arrangement of clusters and the frequency distribution of cluster sizes. Different from the clique graph, the global oscillation can be generated with reasonable parameters on the geometric network. The simulation also suggests that existence of small clusters and rogue RyRs plays an important role in the maintenance of global calcium oscillation through keeping synchronization between large clusters. Such results support the heterogeneous distribution of RyRs with different-size clusters, which is helpful to understand recent observations with superresolution nanoscale imaging techniques. The current theoretical framework can also be extent to investigate other phenomena in calcium signal transduction.

Automated summary

Calcium oscillation is crucial for calcium homeostasis and its imbalance is involved in the development of major diseases. The spatial distribution of calcium channels on the endoplasmic reticulum is linked to the formation and maintenance of calcium homeostasis, and recent observations have revealed their complex structure. In this study, a theoretical framework is established to investigate the effect of spatial distribution on calcium oscillation. The synchronization of ryanodine receptors (RyRs) is found to be essential for generating global calcium oscillation. Different network structures, such as Erdos-Renyi and BaraBasi-Albert networks, have different impacts on the amplitude and interval of the oscillation. A geometric network model based on experimental information is shown to generate global oscillation. The presence of small clusters and rogue RyRs plays a crucial role in maintaining global calcium oscillation.