Modulation of Elementary Calcium Release Mediates a Transition from Puffs to Waves in an IP3R Cluster Model

The oscillating concentration of intracellular calcium is one of the most important examples for collective dynamics in cell biology. Localized releases of calcium through clusters of inositol 1,4,5-trisphosphate receptor channels constitute elementary signals called calcium puffs. Coupling by diffusing calcium leads to global releases and waves, but the exact mechanism of inter-cluster coupling and triggering of waves is unknown. To elucidate the relation of puffs and waves, we here model a cluster of IP3R channels using a gating scheme with variable non-equilibrium IP3 binding. Hybrid stochastic and deterministic simulations show that puffs are not stereotyped events of constant duration but are sensitive to stimulation strength and residual calcium. For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs. This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval. Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell.Author Summary: Intracellular calcium oscillations and waves are paramount cellular signals. The frequency of global release events regulates, for example, expression of genes. Knowledge about the mechanism of oscillations and the factors that determine their frequency is crucial when aiming at the control of downstream processes. Many experimental and modeling studies have demonstrated that a calcium cycle consists of both deterministic and stochastic components, but the respective mechanisms are under debate. Here we aim to clarify both components by analyzing calcium release in Xenopus oocytes and a computational model for a cluster of IP3 receptor channels. Just as in calcium fluorescence traces, in the computed sequences some of the events are prolonged releases lasting for several seconds. We find that synchronized unbinding and rebinding of IP3 cause this modulation in time. Our experimental and computational data show agreement in many properties including wave period, extended refractoriness, and release amplitude. Our analysis suggests that global calcium concentrations are stochastically oscillating because of a modulated but random appearance of high-release events. Thus our approach integrates both deterministic properties and stochasticity of waves, and reveals key control parameters of calcium oscillations.