Stochastic contribution for the coding of agonist induced calcium oscillation in hepatocytes

The influence of stochastic inositol-1,4,5-trisphosphate receptor (IP₃R) dynamics and their clustering have been extensively investigated to explore the mechanism through which the stochastic molecular event finally shape the intracellular calcium signaling. Most of the previous works employed simplified models which take the concentration of IP₃ instead of that of the agonist as the stimulation intensity. However, the IP₃ level is not linearly dependent on the agonist concentration in stimulus induced signaling systems because there are feedback links in the transduction network. In this work, we include both the IP₃R dynamics and the typical agonist induced signaling transduction cascade in the model to investigate the essential influence of stochastic IP₃R dynamics on the coding of the stimulus induced calcium signal. Simulation results reveal two distinct oscillation areas under different stimulation levels. The signal is optimally modulate by the IP₃R cluster number in the weak stimulated area while affected by the stimulus intensity in the strong stimulated area. Different dependences of coefficient of variance (CV) on the number of clusters are obtained in these two areas, which explains the disagreement in the previous reported results. Besides, the transition between these areas explains the significant CV reduction observed in experiments.