Browsing by Author "Schaeffer, DG"

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    BIFURCATIONS IN A MODULATION EQUATION FOR ALTERNANS IN A CARDIAC FIBER
    (ESAIM-MATHEMATICAL MODELLING AND NUMERICAL ANALYSIS-MODELISATION MATHEMATIQUE ET ANALYSE NUMERIQUE, 2010) Dai, S; Schaeffer, DG
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    Modeling mutant phenotypes and oscillatory dynamics in the \emph{Saccharomyces cerevisiae} cAMP-PKA pathway
    (PLoS Computational Biology, 2010-12) Gonzales, K; Kayikci, Omur; Schaeffer, DG; Magwene, P

    Background

    The cyclic AMP-Protein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. We present a mathematical model that recapitulates the short-term and long-term dynamics of this pathway in the budding yeast, Saccharomyces cerevisiae. Our model is aimed at recapitulating the dynamics of cAMP signaling for wild-type cells as well as single (pde1Δ and pde2Δ) and double (pde1Δpde2Δ) phosphodiesterase mutants.

    Results

    Our model focuses on PKA-mediated negative feedback on the activity of phosphodiesterases and the Ras branch of the cAMP-PKA pathway. We show that both of these types of negative feedback are required to reproduce the wild-type signaling behavior that occurs on both short and long time scales, as well as the the observed responses of phosphodiesterase mutants. A novel feature of our model is that, for a wide range of parameters, it predicts that intracellular cAMP concentrations should exhibit decaying oscillatory dynamics in their approach to steady state following glucose stimulation. Experimental measurements of cAMP levels in two genetic backgrounds of S. cerevisiae confirmed the presence of decaying cAMP oscillations as predicted by the model.

    Conclusions

    Our model of the cAMP-PKA pathway provides new insights into how yeast respond to alterations in their nutrient environment. Because the model has both predictive and explanatory power it will serve as a foundation for future mathematical and experimental studies of this important signaling network.
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    ItemOpen Access
    Spectrum of a linearized amplitude equation for alternans in a cardiac fiber
    (SIAM Journal on Applied Mathematics, 2008-12-01) Dai, S; Schaeffer, DG
    Under rapid periodic pacing, cardiac cells typically undergo a period-doubling bifurcation in which action potentials of short and long duration alternate with one another. If these action potentials propagate in a fiber, the short-long alternation may suffer reversals of phase at various points along the fiber, a phenomenon called (spatially) discordant alternans. Either stationary or moving patterns are possible. Using a weak approximation, Echebarria and Karma proposed an equation to describe the spatiotemporal dynamics of small-amplitude alternans in a class of simple cardiac models, and they showed that an instability in this equation predicts the spontaneous formation of discordant alternans. To study the bifurcation, they computed the spectrum of the relevant linearized operator numerically, supplemented with partial analytical results. In the present paper we calculate this spectrum with purely analytical methods in two cases where a small parameter may be exploited: (i) small dispersion or (ii) a long fiber. From this analysis we estimate the parameter ranges in which the phase reversals of discordant alternans are stationary or moving. © 2008 Society for Industrial and Applied Mathematics.