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Calcium signals driven by single channel noise.

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.

SUBMITTER: Skupin A

PROVIDER: S-EPMC2917103 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Calcium signals driven by single channel noise.

Skupin Alexander A Kettenmann Helmut H Falcke Martin M

PLoS computational biology 20100805 8

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 sy ...[more]

PMID: 20700497

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Project description:In pancreatic α-cells, intracellular Ca2+ ([Ca2+]i) acts as a trigger for secretion of glucagon, a hormone that plays a key role in blood glucose homeostasis. Intracellular Ca2+ dynamics in these cells are governed by the electrical activity of voltage-gated ion channels, among which ATP-sensitive K+ (KATP) channels play a crucial role. In the majority of α-cells, the global Ca2+ response to lowering external glucose occurs in the form of oscillations that are much slower than electrical activity. These Ca2+ oscillations are highly variable as far as inter-spike intervals, shapes and amplitudes are concerned. Such observations suggest that Ca2+ dynamics in α-cells are much influenced by noise. Actually, each Ca2+ increase corresponds to multiple cycles of opening/closing of voltage gated Ca2+ channels that abruptly become silent, before the occurrence of another burst of activity a few tens of seconds later. The mechanism responsible for this intermittent activity is currently unknown. In this work, we used computational modeling to investigate the mechanism of cytosolic Ca2+ oscillations in α-cells. Given the limited population of KATP channels in this cell type, we hypothesized that the stochastic activity of these channels could play a key role in the sporadic character of the action potentials. To test this assumption, we extended a previously proposed model of the α-cells electrical activity (Diderichsen and Göpel, 2006) to take Ca2+ dynamics into account. Including molecular noise on the basis of a Langevin type description as well as realistic dynamics of opening and closing of KATP channels, we found that stochasticity at the level of the activity of this channel is on its own not able to produce Ca2+ oscillations with a time scale of a few tens of seconds. However, when taking into account the intimate relation between Ca2+ and ATP changes together with the intrinsic noise at the level of the KATP channels, simulations displayed Ca2+ oscillations that are compatible with experimental observations. We analyzed the detailed mechanism and used computational simulations to identify the factors that can affect Ca2+ oscillations in α-cells.

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Calcium signals driven by single channel noise.

Publications

Calcium signals driven by single channel noise.

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