Calcium signals driven by single channel noise.

Alexander Skupin,Helmut Kettenmann,Martin Falcke,Jorg Stelling

doi:10.1371/journal.pcbi.1000870

Abstract

Usually, the occurrence of random cell behavior is appointed to small copy numbers of molecules involved in the stochastic process. Recently, we demonstrated for a variety of cell types that intracellular Ca2+ oscillations are sequences of random spikes despite the involvement of many molecules in spike generation. This randomness arises from the stochastic state transitions of individual Ca2+ release channels and does not average out due to the existence of steep concentration gradients. The system is hierarchical due to the structural levels channel - channel cluster - cell and a corresponding strength of coupling. Concentration gradients introduce microdomains which couple channels of a cluster strongly. But they couple clusters only weakly; too weak to establish deterministic behavior on cell level. Here, we present a multi-scale modelling concept for stochastic hierarchical systems. It simulates active molecules individually as Markov chains and their coupling by deterministic diffusion. Thus, we are able to follow the consequences of random single molecule state changes up to the signal on cell level. To demonstrate the potential of the method, we simulate a variety of experiments. Comparisons of simulated and experimental data of spontaneous oscillations in astrocytes emphasize the role of spatial concentration gradients in Ca2+ signalling. Analysis of extensive simulations indicates that frequency encoding described by the relation between average and standard deviation of interspike intervals is surprisingly robust. This robustness is a property of the random spiking mechanism and not a result of control.

Highlights

Cellular behavior is the dynamics emerging out of molecular properties and molecular interactions
While noise in gene expression can be attributed to small molecule numbers, we consider here noise in signalling pathways which occurs even in systems with large molecule numbers
The challenge for systems biology is to connect the properties of all these proteins to cellular behavior

Summary

Introduction

Cellular behavior is the dynamics emerging out of molecular properties and molecular interactions. Cells are indispensably subject to intrinsic noise due to the randomness of diffusion and molecule state transitions in gene expression [1,2], signaling pathways and control mechanisms It drives noise induced cell differentiation [3], cell-to-cell variability of cloned cells [4] or second messenger dynamics [5]. Molecular interactions create nonlinear feedback like substrate depletion and allosteric regulation in enzyme kinetics or mutual activation of ion channels in membrane potential dynamics. They couple active molecules inside cells spatially by diffusion of product and substrate or electric currents. These structures are often called microdomains [6,7,8,9]

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