Breaking down calcium timing in heterogenous cells populations (original) (raw)
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Calcium Dynamics: Spatio‐Temporal Organization from the Subcellular to the Organ Level
International Review of Cytology, 2007
Many essential physiological processes are controlled by calcium. To ensure reliability and specificity, calcium signals are highly organized in time and space in the form of oscillations and waves. Interesting findings have been obtained at various scales, ranging from the stochastic opening of a single calcium channel to the intercellular calcium wave spreading through an entire organ. A detailed understanding of calcium dynamics thus requires a link between observations at different scales. It appears that some regulations such as calcium-induced calcium release or PLC activation by calcium, as well as the weak diffusibility of calcium ions play a role at all levels of organization in most cell types. To comprehend how calcium waves spread from one cell to another, specific gap-junctional coupling and paracrine signaling must also be taken into account. On the basis of a pluridisciplinar approach ranging from physics to physiology, a unified description of calcium dynamics is emerging, which could help understanding how such a small ion can mediate so many vital functions in living systems.
Oscillations and waves in single- and multi-cellular systems with free calcium
2003
Calcium ions are an important second messenger in living cells. Indeed calcium signals in the form of waves have been the subject of much recent experimental interest. A fundamental approach for studying cellular signalling is the combination of state-of-the-art experimental techniques, in particular high-resolution fluorescence imaging, with spatio-temporal mathematical models of intracellular calcium regulation. Experimental findings can be incorporated into mathematical models and, vice versa, model predictions can be directly tested in experiments. This approach provides a powerful tool to clarify the very complex mechanisms involved in cellular Ca2+ signalling. The aim of this thesis is to provide insight into oscillations and waves of cytosolic Ca2+ in both single- and multi-cellular systems from a mathematical perspective. [Continues.]
Complex intracellular calcium oscillations A theoretical exploration of possible mechanisms
Biophysical Chemistry, 1997
Intracellular Ca'+ oscillations are commonly observed in a large number of cell types in response to stimulation by an extracellular agonist. In most cell types the mechanism of regular spiking is well understood and models based on Ca2+-induced Ca*+ release (CICR) can account for many experimental observations. However, cells do not always exhibit simple Ca*+ oscillations. In response to given agonists, some cells show more complex behaviour in the form of bursting, i.e. trains of Ca2+ spikes separated by silent phases. Here we develop several theoretical models, based on physiologically plausible assumptions, that could account for complex intracellular Ca'+ oscillations. The models are all based on one-or two-pool models based on CICR. We extend these models by (i) considering the inhibition of the Ca*+-release channel on a unique intracellular store at high cytosolic Ca2+ concentrations, (ii> taking into account the Ca*+-activated degradation of inositol 1,4,5trisphosphate (IP& or (iii) considering explicitly the evolution of the Ca2' concentration in two different pools, one sensitive and the other one insensitive to IP,. Besides simple periodic oscillations, these three models can all account for more complex oscillatory behaviour in the form of bursting. Moreover, the model that takes the kinetics of IP, into account shows chaotic behaviour.
Causality Analysis and Cell Network Modeling of Spatial Calcium Signaling Patterns in Liver Lobules
Frontiers in physiology, 2018
Dynamics as well as localization of Ca transients plays a vital role in liver function under homeostatic conditions, repair, and disease. In response to circulating hormonal stimuli, hepatocytes exhibit intracellular Ca responses that propagate through liver lobules in a wave-like fashion. Although intracellular processes that control cell autonomous Ca spiking behavior have been studied extensively, the intra- and inter-cellular signaling factors that regulate lobular scale spatial patterns and wave-like propagation of Ca remain to be determined. To address this need, we acquired images of cytosolic Ca transients in 1300 hepatocytes situated across several mouse liver lobules over a period of 1600 s. We analyzed this time series data using correlation network analysis, causal network analysis, and computational modeling, to characterize the spatial distribution of heterogeneity in intracellular Ca signaling components as well as intercellular interactions that control lobular scale...
Biophysical Journal, 2007
This article addresses how quantitative models such as the one proposed in the companion article can be used to study cellular network perturbations such as knockdowns and pharmacological perturbations in a predictive manner. Using the kinetic model for cytosolic calcium dynamics in RAW 264.7 cells developed in the companion article, the calcium response to complement 5a (C5a) for the knockdown of seven proteins (C5a receptor; G-b-2; G-a,i-2,3; regulator of G-protein signaling-10; G-protein coupled receptor kinase-2; phospholipase C b-3; arrestin) is predicted and validated against the data from the Alliance for Cellular Signaling. The knockdown responses provide insights into how altered expressions of important proteins in disease states result in intermediate measurable phenotypes. Long-term response and long-term dose response have also been predicted, providing insights into how the receptor desensitization, internalization, and recycle result in tolerance. Sensitivity analysis of longterm response shows that the mechanisms and parameters in the receptor recycle path are important for long-term calcium dynamics.
Bulletin of Mathematical Biology, 2011
In the present paper we address the nature of synchronization properties found in populations of mesenteric artery smooth muscle cells. We present a minimal model of the onset of synchronization in the individual smooth muscle cell that is manifested as a transition from calcium waves to whole-cell calcium oscillations. We discuss how different types of ion currents may influence both amplitude and frequency in the regime of whole-cell oscillations. The model may also explain the occurrence of mixed-mode oscillations and chaotic oscillations frequently observed in the experimental system.
Calcium Oscillations in a Triplet of Pancreatic Acinar Cells
Biophysical Journal, 2005
We use a mathematical model of calcium dynamics in pancreatic acinar cells to investigate calcium oscillations in a ring of three coupled cells. A connected group of cells is modeled in two different ways: 1), as coupled point oscillators, each oscillator being described by a spatially homogeneous model; and 2), as spatially distributed cells coupled along their common boundaries by gap-junctional diffusion of inositol trisphosphate and/or calcium. We show that, although the point-oscillator model gives a reasonably accurate general picture, the behavior of the spatially distributed cells cannot always be predicted from the simpler analysis; spatially distributed diffusion and cell geometry both play important roles in determining behavior. In particular, oscillations in which two cells are in synchrony, with the third phase-locked but not synchronous, appears to be more dominant in the spatially distributed model than in the point-oscillator model. In both types of model, intercellular coupling leads to a variety of synchronous, phase-locked, or asynchronous behaviors. For some parameter values there are multiple, simultaneous stable types of oscillation. We predict 1), that intercellular calcium diffusion is necessary and sufficient to coordinate the responses in neighboring cells; 2), that the function of intercellular inositol trisphosphate diffusion is to smooth out any concentration differences between the cells, thus making it easier for the diffusion of calcium to synchronize the oscillations; 3), that groups of coupled cells will tend to respond in a clumped manner, with groups of synchronized cells, rather than with regular phase-locked periodic intercellular waves; and 4), that enzyme secretion is maximized by the presence of a pacemaker cell in each cluster which drives the other cells at a frequency greater than their intrinsic frequency.
How Does Intracellular Ca2+ Oscillate: By Chance or by the Clock?
Biophysical Journal, 2008
Ca 21 oscillations have been considered to obey deterministic dynamics for almost two decades. We show for four cell types that Ca 21 oscillations are instead a sequence of random spikes. The standard deviation of the interspike intervals (ISIs) of individual spike trains is similar to the average ISI; it increases approximately linearly with the average ISI; and consecutive ISIs are uncorrelated. Decreasing the effective diffusion coefficient of free Ca 21 using Ca 21 buffers increases the average ISI and the standard deviation in agreement with the idea that individual spikes are caused by random wave nucleation. Array-enhanced coherence resonance leads to regular Ca 21 oscillations with small standard deviation of ISIs.