Modeling local and global intracellular calcium responses mediated by diffusely distributed inositol 1,4,5-trisphosphate receptors

Considerable insight into intracellular Ca2+Ca2+ responses has been obtained through the development of whole cell models that are based on molecular mechanisms, e.g., single channel kinetics of the inositol 1,4,5-trisphosphate (IP3IP3) receptor Ca2+Ca2+ channel. However, a limitation of most whole cell models to date is the assumption that IP3IP3 receptor Ca2+Ca2+ channels (IP3RIP3Rs) are globally coupled by a “continuously stirred” bulk cytosolic [Ca2+Ca2+], when in fact open IP3RIP3Rs experience elevated “domain” Ca2+Ca2+ concentrations. Here we present a 2N+22N+2-compartment whole cell model of local and global Ca2+Ca2+ responses mediated by N=100,000N=100,000 diffusely distributed IP3RIP3Rs, each represented by a four-state Markov chain. Two of these compartments correspond to bulk cytosolic and luminal Ca2+Ca2+ concentrations, and the remaining 2N2N compartments represent time-dependent cytosolic and luminal Ca2+Ca2+ domains associated with each IP3RIP3R. Using this Monte Carlo model as a starting point, we present an alternative formulation that solves a system of advection–reaction equations for the probability density of cytosolic and luminal domain [Ca2+Ca2+] jointly distributed with IP3RIP3R state. When these equations are coupled to ordinary differential equations for the bulk cytosolic and luminal [Ca2+Ca2+], a realistic but minimal model of whole cell Ca2+Ca2+ dynamics is produced that accounts for the influence of local Ca2+Ca2+ signaling on channel gating and global Ca2+Ca2+ responses. The probability density approach is benchmarked and validated by comparison to Monte Carlo simulations, and the two methods are shown to agree when the number of Ca2+Ca2+ channels is large (i.e., physiologically realistic). Using the probability density approach, we show that the time scale of Ca2+Ca2+ domain formation and collapse (both cytosolic and luminal) may influence global Ca2+Ca2+ oscillations, and we derive two reduced models of global Ca2+Ca2+ dynamics that account for the influence of local Ca2+Ca2+ signaling on global Ca2+Ca2+ dynamics when there is a separation of time scales between the stochastic gating of IP3RIP3Rs and the dynamics of domain Ca2+Ca2+.