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

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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 e!ect 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, speciality 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 speciality of cellular signalling, as shown experimentally for gene expression in lymphocytes (Dolmetsch et al., 1998).

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Mathieu Deneux <mathieu.deneux@gmail.com>

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