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bioRxiv · 10.1101/2022.12.28.522077

A basic model of calcium homeostasis in non-excitable cells

Selsto, C. H.·Ruoff, P.
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Abstract

The level of cytosolic calcium (Ca2+) in cells is tightly regulated to about 100 nM (pCa {approx} 7). Due to external stimuli, the basal cytosolic Ca2+ level can temporarily be raised to much higher values. The resulting Ca2+ transients take part in cell-intrinsic signals, which result in cellular responses. Because of its signaling importance and that high levels of Ca2+ can lead to apoptosis, regulation and homeostatic control of cytosolic Ca2+ is essential. Based on experimentally known molecular interactions and kinetic data together with control theoretic concepts (integral feedback) we developed a basic computational model describing robust cytosolic Ca2+ homeostasis. The aim of the model is to describe the integrative mechanisms involved in cytosolic Ca2+ homeostasis in non-excitable cells. From a model perspective, the cytosolic steady state value (set point) of 100 nM is determined by negative feedback loops (outflow controllers), one of these represented by the plasma membrane Ca2+ ATPase (PMCA) - calmodulin (CaM) pump and its activation by cytosolic Ca2+. Hysteretic behaviors of the Ca pumps and transporters have been added leading to improved kinetic behaviors indicating that hysteretic properties of the Ca2+ pumps appear important how cytosolic Ca2+ transients are formed. Supported by experimental data the model contains new findings that the activation of the inositol 1,4,5,-tris-phosphate receptor by cytosolic Ca2+ has a cooperativity of 1, while increased Ca2+ leads to a pronounced inhibition with a cooperativity of 2. The model further suggests that the capacitative inflow of Ca2+ into the cytosol at low Ca2+ storage levels in the ER undergoes a successive change in the cooperativity of the Store Operated calcium Channel (SOCC) as Ca2+ levels in the ER change. Integrating these aspects the model can show sustained oscillations with period lengths between 2 seconds and 30 hours. Author SummaryCytosolic calcium is subject to a general homeostatic regulation to about 100 nM against a ten thousand times larger extracellular calcium concentration. We investigated the conditions for robust cytosolic and luminal (endoplasmatic reticulum, ER) calcium homeostasis in non-excitable blood and epithelial cells and how external and internal calcium perturbations affect these homeostatic mechanisms. We found that gradual time-dependent (hysteretic) changes of calcium pumps and transporters and their associated cooperativities play an essential role in observed kinetics of the calcium flow in and out of the ER. Using a two-site calcium binding model we quantitatively describe the cytosolic calcium-induced calcium transport out of the ER with a cooperativity of 1, and its inhibition at higher cytosolic calcium concentrations with a cooperativity of 2. For the capacitative Ca entry by Store Operated Calcium Channels (SOCCs) when ER calcium needs to be refilled we find excellent agreement between experimental kinetic data and the model when the cooperativity of luminal calcium changes from 1.3 at 500 M to 0.8 at 20 M. Integrating these different aspects of cytosolic and store calcium regulation leads to a basic model for cellular calcium homeostasis, which can show oscillations with period lenths from a few seconds up to 30 hours!

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Selsto, C. H., Ruoff, P.. 2022-12-31. A basic model of calcium homeostasis in non-excitable cells. https://doi.org/10.1101/2022.12.28.522077

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