Mitochondrial outer membrane permeabilization and inner membrane permeabilization in regulating apoptosis and inflammation.

Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization remains elusive. Here, we construct a mathematical model consisting of four functional modules. Bifurcation analysis reveals that bistability stems from Bcl-2 family member interaction and time series shows that the time difference between Cyt c and mtDNA release is around 30 min, which are consistent with previous works. The model predicts that Bax aggregation kinetic determines cells to undergo apoptosis or inflammation, and that modulating the inhibitory effect of caspase 3 on IFN-ß production allows the concurrent occurrence of apoptosis and inflammation. This work provides a theoretical framework for exploring the mechanism of mitochondrial membrane permeabilization in controlling cell fate.

Isoprenaline: a potential contributor in sick sinus syndrome--insights from a mathematical model of the rabbit sinoatrial node.

The mechanism of isoprenaline exerting its effects on cardiac pacemaking and driving in sick sinus syndrome is controversial and unresolved. In this paper, mathematical models for rabbit sinoatrial node cells were modified by incorporating equations for the known dose-dependent actions of isoprenaline on various ionic channel currents, the intracellular Ca²âº transient, and i(Na) changes induced by SCN5A gene mutations; the cell models were also incorporated into an intact SAN-atrium model of the rabbit heart that is based on both heterogeneities of the SAN electrophysiology and histological structure. Our results show that, in both central and peripheral cell models, isoprenaline could not only shorten the action potential duration, but also increase the amplitude of action potential. The mutation impaired the SAN pacemaking. Simulated vagal nerve activity amplified the bradycardic effects of the mutation. However, in tissue case, the pacemaker activity may show temporal, spatial, or even spatiotemporal cessation caused by the mutation. Addition of isoprenaline could significantly diminish the bradycardic effect of the mutation and the SAN could restart pacing and driving the surrounding tissue. Positive effects of isoprenaline may primarily be attributable to an increase in i(Na) and i(Ca,T) which were reduced by the mutation.

Termination of Ca²+ release for clustered IP3R channels.

In many cell types, release of calcium ions is controlled by inositol 1,4,5-trisphosphate (IP3) receptor channels. Elevations in Ca²âº concentration after intracellular release through IP3 receptors (IP3R) can either propagate in the form of waves spreading through the entire cell or produce spatially localized puffs. The appearance of waves and puffs is thought to implicate random initial openings of one or a few channels and subsequent activation of neighboring channels because of an "autocatalytic" feedback. It is much less clear, however, what determines the further time course of release, particularly since the lifetime is very different for waves (several seconds) and puffs (around 100 ms). Here we study the lifetime of Ca²âº signals and their dependence on residual Ca²âº microdomains. Our general idea is that Ca²âº microdomains are dynamical and mediate the effect of other physiological processes. Specifically, we focus on the mechanism by which Ca²âº binding proteins (buffers) alter the lifetime of Ca²âº signals. We use stochastic simulations of channel gating coupled to a coarse-grained description for the Ca²âº concentration. To describe the Ca²âº concentration in a phenomenological way, we here introduce a differential equation, which reflects the buffer characteristics by a few effective parameters. This non-stationary model for microdomains gives deep insight into the dynamical differences between puffs and waves. It provides a novel explanation for the different lifetimes of puffs and waves and suggests that puffs are terminated by Ca²âº inhibition while IP3 unbinding is responsible for termination of waves. Thus our analysis hints at an additional role of IP3 and shows how cells can make use of the full complexity in IP3R gating behavior to achieve different signals.

Neuronal modeling with intracellular calcium signaling.

Cytosolic Ca(2+) ions play an important role in the regulation of numerous aspects of cellular activity in virtually all cell types. There is a complex interaction between the neuronal electrical signals on plasma membrane and the chemical signals of intracellular calcium. Each neuron can be considered as a binary membrane system with plasma membrane and endoplasmic reticulum membrane, and the neuronal endoplasmic reticulum can be regarded as a neuron-within-a-neuron. This review explores the simulation modeling of neuronal dynamics mutually coupled with the intracellular calcium signaling released from endoplasmic reticulum through the inositol 1,4,5-trisphosphate receptor calcium channels. We show that a current trend is to include the intracellular calcium dynamics into the neuronal models, and the frontier of this research is now shifting to spatial neuronal models with diffusing intracellular calcium. It is expected that more important results will be obtained with the neuronal models incorporating the intracellular calcium dynamics, especially the spatial models considering the calcium diffusion both in soma and dendritic branches.

Induced dipoles incorporated into all-atom Zn protein simulations with multiscale modeling.

Zinc is found saturated in the deposited Amyloid-beta (Aß) peptide plaques in Alzheimer's disease (AD) patients' brains. Binding of zinc promotes aggregation of Aß, including the pathogenic aggregates. Up to now, only the region 1-16 of Aß complexed with zinc (Aß(1-16)-Zn) is defined structurally in experiment. In order to explore the induced polarization effect of zinc on the global fluctuations and the experimentally observed coordination mode of Aß(1-16)-Zn, we consider an all-atom molecular dynamics (MD) of Aß(1-16)-Zn solvated in implicit water. In our model, the zinc polarization affects the whole peptide. The induced dipoles are divided into three distinct scales according to their distances from zinc. Besides, the atomistic polarizability on the coordinating side chains is rescaled to describe the electron redistribution effect. We show that, associated with proper van der Waals (vdW) parameters, our model not only obtains the reasonable coordinating configuration of zinc binding site but also retains the global stabilization, especially the N-terminal region, of the Aß(1-16)-Zn. We suggest that it is the induced polarization effect that promotes reasonable solvent exposures of hydrophobic/hydrophilic residues regarding zinc-induced Aß aggregation.

Stochastic properties of Ca(2+) release of inositol 1,4,5-trisphosphate receptor clusters.

Intracellular Ca(2+) release is controlled by inositol 1,4,5-trisphosphate (IP(3)) receptors or ryanodine receptors. These receptors are typically distributed in clusters with several or tens of channels. The random opening and closing of these channels introduces stochasticity into the elementary calcium release mechanism. Stochastic release events have been experimentally observed in a variety of cell types and have been termed sparks and puffs. We put forward a stochastic version of the Li-Rinzel model (the deactivation binding process is described by a Markovian scheme) and a computationally more efficient Langevin approach to model the stochastic Ca(2+) oscillation of single clusters. Statistical properties such as Ca(2+) puff amplitudes, lifetimes, and interpuff intervals are studied with both models and compared with experimental observations. For clusters with tens of channels, a simply decaying amplitude distribution is typically observed at low IP(3) concentration, while a single peak distribution appears at high IP(3) concentration.