Protein phosphorylation driven by intracellular calcium oscillations: A kinetic analysis (Model B)

Model Status

This model has been built with the differential expressions in Dupont and Goldbeter's 1992 paper. This file is known to run in PCEnv and COR, and variables for constants (vMK) can be altered to produce figure4b, c and figure5b and c (the ratio vMK/vP is held constant at vMK/vP = 20/0.89). The current parameterization is set to reproduce 4b with vMK=100 (note the erratum received in 1995: wT=10 not 1, to replicate figure 5. Initial conditions for Z, Y and Wstar were set by letting the model settle into a steady state.

Model Structure

Abstract: 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 Ca2+-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 Ca2+-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.

Schematic diagram of the cell model.

The original paper reference is cited below:

Protein phosphorylation driven by intracellular calcium oscillations: A kinetic analysis, Dupont G, Goldbeter A 1992, Biophysical Chemistry 41, 257-270. PubMedID: 1316185