Research

Abstract: The behavior of calcium oscillations near bifurcations is analyzed for three different models. For the model developed by Somogyi and Stucki [42], it is shown that the range of oscillations is bounded by supercritical and subcritical Hopf bifurcations. Near the latter, canard orbits arise, that is, quasi-harmonic oscillations with a very small amplitude grow very fast to become pulsed oscillations. The potential biological significance of this behavior is discussed. A time-scale analysis of this model is performed and an approximation formula for the oscillation period is derived. For two models that we presented earlier [30, 31], it is shown that a homoclinic bifurcation and an infinite period bifurcation, respectively, occur. These imply that the oscillation period can reach arbitrarily high values. This behavior is discussed in the light of frequency encoding, and the scaling laws of the oscillation period are given.

World Scientific	S. Schuster and M. Marhl Bifurcation analysis of calcium oscillations. Time-scale separation, canards, and frequency lowering Journal of Biological Systems 9 (2001) 291-314	Abstract: The behavior of calcium oscillations near bifurcations is analyzed for three different models. For the model developed by Somogyi and Stucki [42], it is shown that the range of oscillations is bounded by supercritical and subcritical Hopf bifurcations. Near the latter, canard orbits arise, that is, quasi-harmonic oscillations with a very small amplitude grow very fast to become pulsed oscillations. The potential biological significance of this behavior is discussed. A time-scale analysis of this model is performed and an approximation formula for the oscillation period is derived. For two models that we presented earlier [30, 31], it is shown that a homoclinic bifurcation and an infinite period bifurcation, respectively, occur. These imply that the oscillation period can reach arbitrarily high values. This behavior is discussed in the light of frequency encoding, and the scaling laws of the oscillation period are given.

Elsevier	*T. Haberichter, M. Marhl, R. Heinrich* Birhythmicity, trirhythmicity and chaos in bursting calcium oscillations Biophysical Chemistry 90 (2001) 17-30	Abstract: We have analyzed various types of complex calcium oscillations. The oscillations are explained with a model based on calcium-induced calcium release (CICR). In addition to the endoplasmic reticulum as the main intracellular Ca2+ store, mitochondrial and cytosolic Ca2+ binding proteins are also taken into account. This model was previously proposed for the study of the physiological role of mitochondria and the cytosolic proteins in gene rating complex Ca2+ oscillations [1]. Here, we investigated the occurrence of different types of Ca2+ oscillations obtained by the model, i.e. simple oscillations, bursting, and chaos. In a bifurcation diagram, we have shown that all these various modes of oscillatory behavior are obtained by a change of only one model parameter, which corresponds to the physiological variability of an agonist. Bursting oscillations were studied in more detail because they express birhythmicity, trirhythmicity and chaotic behavior. Two different routes to chaos are observed in the model: in addition to the usual period doubling cascade, we also show intermittency. For the characterization of the chaotic behavior, we made use of return maps and Lyapunov exponents. The potential biological role of chaos in intracellular signaling is discussed.

Elsevier	*M. Marhl, S. Schuster, M. Brumen, R. Heinrich* Modelling the interrelations between calcium oscillations and ER membrane potential oscillations Biophysical Chemistry 63 (1997) 221-239	Abstract: A refined electrochemical model accounting for intracellular calcium oscillations and their interrelations with oscillations of the potential difference across the membrane of the endoplasmic reticulum (ER) or other intracellular calcium stores is established. The ATP dependent uptake of Ca2+ from the cytosol into the ER, the Ca2+ release from the ER through channels following a calcium-induced calcium release mechanism, and a potential-dependent Ca2+ leak flux out of the ER are included in the model and described by plausible rate laws. The binding of calcium to specific proteins such as calmodulin is taken into account. The quasi-electroneutrality condition allows us to express the transmembrane potential in terms of the concentrations of cytosolic calcium and free binding sites on proteins, which are the two independent variables of the model. We include monovalent ions in the model, because they make up a considerable portion in the balance of electroneutrality. As the permeability of the endoplasmic membrane for these ions is much higher than that for calcium ions, we assume the former to be in Nernst equilibrium. A stability analysis of the steady-state solutions (which are unique or multiple depending on parameter values) is carried out and the Hopf bifurcation leading from stable steady states to self-sustained oscillations is analysed with the help of appropriate mathematical techniques. The oscillations obtained by numerical integration exhibit the typical spike-like shape found in experiments and reasonable values of frequency and amplitude. The model describes the process of switching between stationary and pulsatile regimes as well as changes in oscillation frequency upon parameter changes. It turns out that calcium oscillations can arise without a permanent influx of calcium into the cell, when a calcium-buffering system such as calmodulin is included.