Fig 1. Reaction scheme and IP₃R model.

The biochemical processes included in the model are illustrated in (A). Cytosolic calcium can exit the cytosol to the extracellular space or the endoplasmic reticulum (ER) at a (total) rate α, lumping together the effects of ER and plasma membrane pumps. Likewise, Ca²⁺ can enter the cytosol from the extracellular space or from the ER via IP₃R-independent flow, with (total) rate γ, emulating calcium channels from the plasma membrane. When an IP₃R channel opens, calcium enters the cytosol through the channel at rate μ. Phospholipase Cδ (PLCδ), once activated by calcium binding, produces IP₃ at rate δ. Like Ca²⁺, IP₃ can bind the IP₃R channel and is removed with rate β. (B) Our model of the kinetics of the IP₃R channel is an 8-state Markov model adapted from [46, 56]. Each IP₃R channel monomer is associated with 3 binding sites, two calcium binding sites and one IP₃ binding site. Occupancy states are designated by a triplet {i, j, k} where i stands for the occupation of the first Ca binding site (i = 1 if bound, 0 else), j for that of the IP₃ binding site and k for the second Ca site. The first calcium binding site has higher affinity than the second. The open state is state {110}, where the first Ca and the IP₃ sites are bound but not the second Ca site. (C) Spatial parameters for the particle-based model. The $N_{{\text{IP}}_{\text{3}}\text{R}}I{P}_{\text{3}}R$ molecules are positioned within uniformly distributed clusters, with η IP₃R in each cluster. Hence η = 1 corresponds to uniformly distributed IP₃R (no clustering), while the degree of clustering increases with η (for constant total IP₃R number). To account for potential co-localization between IP₃R-dependent and IP₃R-independent calcium sources, the influx of IP₃R-independent calcium (at rate γ) occurs within distance R_γ of an IP₃R. Thus, low values of R_γ emulate co-localization between IP₃R-dependent and IP₃R-independent Ca²⁺ influx sources.