Abstract
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.
Highlights
Transient and repetitive increases in the concentration of cytosolic Ca2+ are ubiquitous chemical cues in a cell
The small number of IP3 receptor (IP3R) channels involved in a puff (*10) and the random appearance of puffs suggest their spontaneous generation by microscopic fluctuations, which has been related to classical excitability in activator-inhibitor systems [8,9]
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
Summary
Transient and repetitive increases in the concentration of cytosolic Ca2+ are ubiquitous chemical cues in a cell. The formation of complex intracellular release patterns plays an important role in cell communication, since Ca2+ achieves its functional specificity by differential signaling in space, time, and amplitude [1]. It is a purpose of numerous research studies to understand the systemic generation of cytosolic Ca2+ signals [2]. Ca2+ diffusion coupling is responsible for communication between clusters [11,22,23], mediating the synchronization of clusters into oscillations and the propagation of waves, but it is less clear what are the respective roles of increased IP3 stimulation and Ca2+ diffusion in the puff-to-wave transition. In a first scenario (i) the excitability of clusters grows with [IP3] so that a given amount of Ca2+, e.g. diffusing from an active cluster, triggers puffs more frequently
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