Diffusive spatio-temporal noise in a first-passage time model for intracellular calcium release


Flegg, Mark B.
Rüdiger, Sten
Erban, Radek

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The intracellular release of calcium from the endoplasmic reticulum is controlled by ion channels. The resulting calcium signals exhibit a rich spatio-temporal signature, which originates at least partly from microscopic fluctuations. While stochasticity in the gating transition of ion channels has been incorporated into many models, the distribution of calcium is usually described by deterministic reaction-diffusion equations. Here we test the validity of the latter modeling approach by using two different models to calculate the frequency of localized calcium signals (calcium puffs) from clustered IP3 receptor channels. The complexity of the full calcium system is here limited to the basic opening mechanism of the ion channels and, in the mathematical reduction simplifies to the calculation of a first passage time. Two models are then studied: (i) a hybrid model, where channel gating is treated stochastically, while calcium concentration is deterministic and (ii) a fully stochastic model with noisy channel gating and Brownian calcium ion motion. The second model utilises the recently developed two-regime method [M. B. Flegg, S. J. Chapman, and R. Erban, "The two-regime method for optimizing stochastic reaction-diffusion simulations," J. R. Soc., Interface 9, 859-868 (2012)] in order to simulate a large domain with precision required only near the Ca2+ absorbing channels. The expected time for a first channel opening that results in a calcium puff event is calculated. It is found that for a large diffusion constant, predictions of the interpuff time are significantly overestimated using the model (i) with a deterministic non-spatial calcium variable. It is thus demonstrated that the presence of diffusive noise in local concentrations of intracellular Ca2+ ions can substantially influence the occurrence of calcium signals. The presented approach and results may also be relevant for other cell-physiological first-passage time problems with small ligand concentration and high cooperativity. © 2013 American Institute of Physics.

Flegg MB, Rüdiger S, Erban R (2013) Diffusive spatio-temporal noise in a first-passage time model for intracellular calcium release. J Chem Phys 138: 154103. Available: http://dx.doi.org/10.1063/1.4796417.

The research leading to these results has received funding from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement No. 239870. This publication was based on the work supported in part by Award No. KUK-C1-013-04, made by King Abdullah University of Science and Technology (KAUST). Radek Erban would also like to thank Somerville College, University of Oxford, for a Fulford Junior Research Fellowship; Brasenose College, University of Oxford, for a Nicholas Kurti Junior Fellowship; the Royal Society for a University Research Fellowship; and the Leverhulme Trust for a Philip Leverhulme Prize. This prize money was used to support research visits of Sten Rudiger in Oxford. Sten Rudiger also acknowledges support from the Deutsche Forschungsgemeinschaft.

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The Journal of Chemical Physics


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