Stochastic Aspects of Oscillatory Ca 2+ Dynamics in Hepatocytes

Abstract

Signal-induced Ca 2+ oscillations have been observed in many cell types and play a primary role in cell physiology. Although it is the regular character of these oscillations that first catches the attention, a closer look at time series of Ca 2+ increases reveals that the fluctuations on the period during individual spike trains are far from negligible. Here, we perform a statistical analysis of the regularity of Ca 2+ oscillations in norepinephrine-stimulated hepatocytes and find that the coefficient of variation lies between 10% and 15%. Stochastic simulations based on Gillespie's algorithm and considering realistic numbers of Ca 2+ ions and inositol trisphosphate (InsP 3) receptors account for this variability if the receptors are assumed to be grouped in clusters of a few tens of channels. Given the relatively small number of clusters (∼200), the model predicts the existence of repetitive spikes induced by fluctuations (stochastic resonance). Oscillations of this type are found in hepatocytes at subthreshold concentrations of norepinephrine. We next predict with the model that the isoforms of the InsP 3 receptor can affect the variability of the oscillations. In contrast, possible accompanying InsP 3 oscillations have no impact on the robustness of signal-induced repetitive Ca 2+ spikes.