Activation of the Liver Glycogen Phosphorylase by Ca2+Oscillations: a Theoretical Study

Cytosolic calcium plays a crucial role as a second messenger in cellular signalling. Various cell types, including hepatocytes, display Ca2+oscillations when stimulated by an extracellular signal. However, the biological relevance of this temporal organization remains unclear. In this paper, we investigate theoretically the effect of Ca2+oscillations on a particular example of cell regulation: the phosphorylation–dephosphorylation cycle controlling the activation of glycogen phosphorylase in hepatocytes. By modelling periodic sinusoidal variations in the intracellular Ca2+concentration, we show that Ca2+oscillations reduce the threshold for the activation of the enzyme. Furthermore, as the activation of a given enzyme depends on the kinetics of its phosphorylation–dephosphorylation cycle, specificity can be encoded by the oscillation frequency. Finally, using a model for signal-induced Ca2+oscillations based on Ca2+-induced Ca2+release, we show that realistic Ca2+oscillations can potentiate the response to a hormonal stimulation. These results indicate that Ca2+oscillations in hepatocytes could contribute to increase the efficiency and specificity of cellular signalling, as shown experimentally for gene expression in lymphocytes (Dolmetsch et al., 1998).