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Modeling IP(3) induced Ca(2+) signaling based on its interspike interval statistics

Item Type:Preprint
Title:Modeling IP(3) induced Ca(2+) signaling based on its interspike interval statistics
Creators Name:Friedhoff, V.N. and Falcke, M.
Abstract:Inositol 1,4,5-trisphosphate (IP(3)) induced Ca(2+) signaling is a second messenger system used by almost all eukaryotic cells. Recent research identified 8 general properties of Ca(2+) spiking common to all cell types investigated and demonstrated randomness of Ca(2+) signaling on all structural levels. We suggest a theory of Ca(2+) spiking starting from the random behaviour of IP(3) receptor channel clusters mediating the release of Ca(2+) from the endoplasmic reticulum. Spike generation begins after the absolute refractory period of the previous spike. According to its hierarchical spreading from initiating channel openings to cell level, we describe it as a first passage process from none to all clusters open while the cell recovers from the inhibition which terminated the previous spike. Our theory reproduces quantitatively all general properties for different IP(3) pathways including the exponential stimulation response relation of the average interspike interval (ISI) T(av) and its robustness properties, random spike timing with a linear moment relation between T(av) and the ISI standard deviation and its robustness properties, sensitive dependency of T(av) on diffusion properties, and non-oscillatory local dynamics. We explain large cell variability of T(av) observed in experiments by variability of channel cluster coupling by Ca(2+) induced Ca(2+) release, the number of clusters and IP(3) pathway components expression levels. We predict the relation between puff probability and agonist concentration, and [IP(3)] and agonist concentration. Differences of spike behaviour between cell types and stimulating agonists are explained by the different types of negative feedback terminating spikes. In summary, the hierarchical random character of spike generation explains all of the identified general properties.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2022.12.20.521161
Date:20 December 2022
Official Publication:https://doi.org/10.1101/2022.12.20.521161
Related to:
https://edoc.mdc-berlin.de/23531/Final version

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