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Inositol 1,4,5-trisphosphate (IP(3)R) receptor channels control release of Ca(2+) from the endoplasmic reticulum into the cytosol of a cell. The binding of both 1,4,5-trisphosphate (IP(3)) and activating Ca(2+) is required for the channel to open. At high Ca(2+) concentrations, IP(3)Rs are inhibited. IP(3)Rs are composed of four identical subunits and form in clusters. Many models have been proposed to describe how the binding of IP(3) and Ca(2+) to subunits results in the opening and closing of IP(3)Rs. Here we compare the opening and closing probability distributions for clusters of IP(3)Rs, resulting from three different models. The distributions are calculated both analytically, using a method we have developed, and with simulations. We found significant differences in the behavior of the three models as the Ca(2+) and IP(3) concentrations are varied.

Microdomains of calcium (i.e., areas on the nanometer scale that have qualitatively different calcium concentrations from that in the bulk cytosol) are known to be important in many situations. In cardiac cells, for instance, a calcium microdomain between the L-type channels and the ryanodine receptors, the so-called diadic cleft, is where the majority of the control of calcium release occurs. In other cell types that exhibit calcium oscillations and waves, the importance of microdomains in the vicinity of clusters of inositol trisphosphate receptors, or between the endoplasmic reticulum (ER) and other internal organelles or the plasma membrane, is clear. Given the limits of computational power, it is not currently realistic to model an entire cellular cytoplasm by incorporating detailed structural information about the ER throughout the entire cytoplasm. Hence, most models use a homogenised approach, assuming that both cytoplasm and ER coexist at each point of the domain. Conversely, microdomain models can be constructed, in which detailed structural information can be incorporated, but, until now, methods have not been developed for linking such a microdomain model to a model at the level of the entire cell. Using the homogenisation approach we developed in an earlier paper [Goel, P., Friedman, A., Sneyd, J., 2006. Homogenization of the cell cytoplasm: the calcium bidomain equations. SIAM J. Multiscale Modeling Simulation, in press] we show how a multiscale model of a calcium microdomain can be constructed. In this model a detailed model of the microdomain (in which the ER and the cytoplasm are separate compartments) is coupled to a homogenised model of the entire cell in a rigorous way. Our method is illustrated by a simple model of the diadic cleft of a cardiac half-sarcomere.