Activation of the liver glycogen phosphorylase by Ca2+ oscillations: a theoretical study

Cytosolic calcium plays a crucial role as a second messenger in cellular si gnalling. Various cell types, including hepatocytes, display Ca2+ oscillati ons when stimulated by an extracellular signal. However, the biological rel evance of this temporal organization remains unclear. In this paper, we inv estigate theoretically the effect of Ca2+ oscillations on a particular exam ple of cell regulation: the phosphorylation-dephosphorylation cycle control ling 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 kin etics of its phosphorylation-dephosphorylation cycle, specificity can be en coded by the oscillation frequency. Finally, using a model for signal-induc ed Ca2+ oscillations based on Ca2+-induced Ca2+ release, Lye show that real istic Ca2+ oscillations can potentiate the response to a hormonal stimulati on. These results indicate that Ca2+ oscillations in hepatocytes could cont ribute to increase the efficiency and specificity of cellular signalling, a s shown experimentally for gene expression in lymphocytes (Dolmetsch et al. , 1998). (C) 2000 Academic Press.