Ruediger Thul

Cardiac cell modelling: observations from the heart of the cardiac physiome project.

In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field.

Release Currents of IP3 Receptor Channel Clusters and Concentration Profiles

We simulate currents and concentration profiles generated by Ca(2+) release from the endoplasmic reticulum (ER) to the cytosol through IP(3) receptor channel clusters. Clusters are described as conducting pores in the lumenal membrane with a diameter from 6 nm to 36 nm. The endoplasmic reticulum is modeled as a disc with a radius of 1-12 microm and an inner height of 28 nm. We adapt the dependence of the currents on the trans Ca(2+) concentration (intralumenal) measured in lipid bilayer experiments to the cellular geometry. Simulated currents are compared with signal mass measurements in Xenopus oocytes. We find that release currents depend linearly on the concentration of free Ca(2+) in the lumen. The release current is approximately proportional to the square root of the number of open channels in a cluster. Cytosolic concentrations at the location of the cluster range from 25 microM to 170 microM. Concentration increase due to puffs in a distance of a few micrometers from the puff site is found to be in the nanomolar range. Release currents decay biexponentially with timescales of <1 s and a few seconds. Concentration profiles decay with timescales of 0.125-0.250 s upon termination of release.

Fundamental properties of Ca2+ signals.

BACKGROUND Ca2+ is a ubiquitous and versatile second messenger that transmits information through changes of the cytosolic Ca2+ concentration. Recent investigations changed basic ideas on the dynamic character of Ca2+ signals and challenge traditional ideas on information transmission. SCOPE OF REVIEW We present recent findings on key characteristics of the cytosolic Ca2+ dynamics and theoretical concepts that explain the wide range of experimentally observed Ca2+ signals. Further, we relate properties of the dynamical regulation of the cytosolic Ca2+ concentration to ideas about information transmission by stochastic signals. MAJOR CONCLUSIONS We demonstrate the importance of the hierarchal arrangement of Ca2+ release sites on the emergence of cellular Ca2+ spikes. Stochastic Ca2+ signals are functionally robust and adaptive to changing environmental conditions. Fluctuations of interspike intervals (ISIs) and the moment relation derived from ISI distributions contain information on the channel cluster open probability and on pathway properties. GENERAL SIGNIFICANCE Robust and reliable signal transduction pathways that entail Ca2+ dynamics are essential for eukaryotic organisms. Moreover, we expect that the design of a stochastic mechanism which provides robustness and adaptivity will be found also in other biological systems. Ca2+ dynamics demonstrate that the fluctuations of cellular signals contain information on molecular behavior. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling.

Subcellular calcium dynamics in a whole-cell model of an atrial myocyte

In this study, we present an innovative mathematical modeling approach that allows detailed characterization of Ca2+ movement within the three-dimensional volume of an atrial myocyte. Essential aspects of the model are the geometrically realistic representation of Ca2+ release sites and physiological Ca2+ flux parameters, coupled with a computationally inexpensive framework. By translating nonlinear Ca2+ excitability into threshold dynamics, we avoid the computationally demanding time stepping of the partial differential equations that are often used to model Ca2+ transport. Our approach successfully reproduces key features of atrial myocyte Ca2+ signaling observed using confocal imaging. In particular, the model displays the centripetal Ca2+ waves that occur within atrial myocytes during excitation–contraction coupling, and the effect of positive inotropic stimulation on the spatial profile of the Ca2+ signals. Beyond this validation of the model, our simulation reveals unexpected observations about the spread of Ca2+ within an atrial myocyte. In particular, the model describes the movement of Ca2+ between ryanodine receptor clusters within a specific z disk of an atrial myocyte. Furthermore, we demonstrate that altering the strength of Ca2+ release, ryanodine receptor refractoriness, the magnitude of initiating stimulus, or the introduction of stochastic Ca2+ channel activity can cause the nucleation of proarrhythmic traveling Ca2+ waves. The model provides clinically relevant insights into the initiation and propagation of subcellular Ca2+ signals that are currently beyond the scope of imaging technology.

Toward a predictive model of Ca2+ puffs

We investigate the key characteristics of Ca(2+) puffs in deterministic and stochastic frameworks that all incorporate the cellular morphology of IP(3) receptor channel clusters. In the first step, we numerically study the Ca(2+) liberation in a three-dimensional representation of a cluster environment with reaction-diffusion dynamics in both the cytosol and the lumen. These simulations reveal that Ca(2+) concentrations at a releasing cluster range from 80 to 170 microM and equilibrate almost instantaneously on the time scale of the release duration. These highly elevated Ca(2+) concentrations eliminate Ca(2+) oscillations in a deterministic model of an IP(3)R channel cluster at physiological parameter values as revealed by a linear stability analysis. The reason lies in the saturation of all feedback processes in the IP(3)R gating dynamics, so that only fluctuations can restore experimentally observed Ca(2+) oscillations. In this spirit, we derive master equations that allow us to analytically quantify the onset of Ca(2+) puffs and hence the stochastic time scale of intracellular Ca(2+) dynamics. Moving up the spatial scale, we suggest to formulate cellular dynamics in terms of waiting time distribution functions. This approach prevents the state space explosion that is typical for the description of cellular dynamics based on channel states and still contains information on molecular fluctuations. We illustrate this method by studying global Ca(2+) oscillations.

Phase-Amplitude Descriptions of Neural Oscillator Models

Phase oscillators are a common starting point for the reduced description of many single neuron models that exhibit a strongly attracting limit cycle. The framework for analysing such models in response to weak perturbations is now particularly well advanced, and has allowed for the development of a theory of weakly connected neural networks. However, the strong-attraction assumption may well not be the natural one for many neural oscillator models. For example, the popular conductance based Morris–Lecar model is known to respond to periodic pulsatile stimulation in a chaotic fashion that cannot be adequately described with a phase reduction. In this paper, we generalise the phase description that allows one to track the evolution of distance from the cycle as well as phase on cycle. We use a classical technique from the theory of ordinary differential equations that makes use of a moving coordinate system to analyse periodic orbits. The subsequent phase-amplitude description is shown to be very well suited to understanding the response of the oscillator to external stimuli (which are not necessarily weak). We consider a number of examples of neural oscillator models, ranging from planar through to high dimensional models, to illustrate the effectiveness of this approach in providing an improvement over the standard phase-reduction technique. As an explicit application of this phase-amplitude framework, we consider in some detail the response of a generic planar model where the strong-attraction assumption does not hold, and examine the response of the system to periodic pulsatile forcing. In addition, we explore how the presence of dynamical shear can lead to a chaotic response.

Waiting time distributions for clusters of complex molecules

Waiting time distributions are in the core of theories for a large variety of subjects ranging from the analysis of patch clamp records to stochastic excitable systems. Here, we present a novel exact method for the calculation of waiting time distributions for state transitions of complex molecules with independent subunit dynamics. The absorbing state is a specific set of subunit states, i.e. is defined on the molecule level. Consequently, we formulate the problem as a random walk in the molecule state space. The subunits can posses an arbitrary number of states and any topology of transitions between them. The method circumvents problems arising from combinatorial explosion due to subunit coupling and requires solutions of the subunit master equation only.

Landau-Gutzwiller quasiparticles

We define Landau quasiparticles within the Gutzwiller variational theory and derive their dispersion relation for general multiband Hubbard models in the limit of large spatial dimensions D. Thereby we reproduce our previous calculations which were based on a phenomenological effective single-particle Hamiltonian. For the one-band Hubbard model we calculate the frst-order corrections in 1/D and find that the corrections to the quasiparticle dispersions are small in three dimensions. They may be largely absorbed in a rescaling of the total bandwidth, unless the system is close to half band filling. Therefore, the Gutzwiller theory in the limit of large dimensions provides quasiparticle bands which are suitable for a comparison with real, three-dimensional Fermi liquids.

Translating Intracellular Calcium Signaling into Models

The rich experimental data on intracellular calcium has put theoreticians in an ideal position to derive models of intracellular calcium signaling. Over the last 25 years, a large number of modeling frameworks have been suggested. Here, I will review some of the milestones of intracellular calcium modeling with a special emphasis on calcium-induced calcium release (CICR) through inositol-1,4,5-trisphosphate and ryanodine receptors. I will highlight key features of CICR and how they are represented in models as well as the challenges that theoreticians face when translating our current understanding of calcium signals into equations. The selected examples demonstrate that a successful model provides mechanistic insights into the molecular machinery of the Ca²⁺ signaling toolbox and determines the contribution of local Ca²⁺ release to global Ca²⁺ patterns, which at the moment cannot be resolved experimentally.

Reactive clusters on a membrane

We investigate the reaction dynamics of diffusive molecules with immobile binding partners. The fixed reactants build clusters that are comprised of just a few tens of molecules, which leads to small cluster sizes. These molecules participate in the reaction only if they are activated. The dynamics of activation is mapped to a time-dependent size of an active region within the cluster. We focus on the deterministic description of the dynamics of a single cluster. The spatial setup accounts for one of the most important determinants of the dynamics of a cluster, i.e. diffusional transport of reaction partners towards or away from the active region of the cluster. We provide numerical and analytical evidence that diffusion influences decisively the dynamic regimes of the reactions. The application of our methods to intracellular Ca2+ dynamics shows that large local concentrations saturate the Ca2+ feedback to the channel state control. It eliminates oscillations depending on this feedback.