title: Decoding of calcium oscillations by phosphorylation cycles: analytic results.
abstract: Experimental studies have demonstrated that Ca(2+)-regulated proteins are sensitive to the frequency of Ca(2+) oscillations, and several mathematical models for specific proteins have provided insight into the mechanisms involved. Because of the large number of Ca(2+)-regulated proteins in signal transduction, metabolism and gene expression, it is desirable to establish in general terms which molecular properties shape the response to oscillatory Ca(2+) signals. Here we address this question by analyzing in detail a model of a prototypical Ca(2+)-decoding module, consisting of a target protein whose activity is controlled by a Ca(2+)-activated kinase and the counteracting phosphatase. We show that this module can decode the frequency of Ca(2+) oscillations, at constant average Ca(2+) signal, provided that the Ca(2+) spikes are narrow and the oscillation frequency is sufficiently low--of the order of the phosphatase rate constant or below. Moreover, Ca(2+) oscillations activate the target more efficiently than a constant signal when Ca(2+) is bound cooperatively and with low affinity. Thus, the rate constants and the Ca(2+) affinities of the target-modifying enzymes can be tuned in such a way that the module responds optimally to Ca(2+) spikes of a certain amplitude and frequency. Frequency sensitivity is further enhanced when the limited duration of the external stimulus driving Ca(2+) signaling is accounted for. Thus, our study identifies molecular parameters that may be involved in establishing the specificity of cellular responses downstream of Ca(2+) oscillations.
authors.affiliation: Research Group Modeling of Biological Systems, German Cancer Research Center, Heidelberg, Germany. c.salazar@dkfz-heidelberg.de
authors.forename: Carlos
authors.initials: C
authors.lastname: Salazar
authors.forename: Antonio Zaccaria
authors.initials: AZ
authors.lastname: Politi
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
mesh_terms: D001683:Biological Clocks / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D003198:Computer Simulation; D008954:Models, Biological; D009991:Oscillometry / Q000379:methods*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*
chemical_list: D010770:Phosphotransferases; D002118:Calcium