Protein phosphorylation driven by intracellular calcium oscillations: a kinetic analysis

Given the ubiquitous nature of signal-induced Ca2+ oscillations, the question arises as to how cellular responses are affected by repetitive Ca2+ spikes. Among these responses, we focus on those involving protein phosphorylation. We examine, by numerical simulations of a theoretical model, the situation where a protein is phosphorylated by a Ca(2+)-activated kinase and dephosphorylated by a phosphatase. This reversible phosphorylation system is coupled to a mechanism generating cytosolic Ca2+ oscillations; for definiteness, this oscillatory mechanism is based on the process of Ca(2+)-induced Ca2+ release. The analysis shows that the average fraction of phosphorylated protein increases with the frequency of repetitive Ca2+ spikes; the latter frequency generally rises with the extent of external stimulation. Protein phosphorylation therefore provides a mechanism for the encoding of the external stimulation in terms of the frequency of signal-induced Ca2+ oscillations. Such a frequency encoding requires precise kinetic conditions on the Michaelis-Menten constants of the kinase and phosphatase, their maximal rates, and the degree of cooperativity in kinase activation by Ca2+. In particular, the most efficient encoding of Ca2+ oscillations based on protein phosphorylation occurs in conditions of zero-order ultrasensitivity, when the kinase and phosphatase are saturated by their protein substrate. The kinetic analysis uncovers a wide variety of temporal patterns of phosphorylation that could be driven by signal-induced Ca2+ oscillations.