A basic model of calcium homeostasis in non-excitable cells

Abstract

The level of cytosolic calcium (Ca2+) in cells is tightly regulated to about 100 nM (pCa ≈ 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 indicatingthat 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.

Homeostasis at different backgrounds: The roles of overlayed feedback structures in vertebrate photoadaptation

“…There is evidence that intracellular Ca stores leak Ca into the cytosol [39–42]. Analyzing the data by Camello et al [41] and Luik et al [42], we observed (S4 Text and [43]) that the kinetics of the two recorded leaks were surprisingly different. While Camello et al [41] found practically zero-order kinetics with respect to ER calcium and leak rates at around 0.25 μ M/s, the data by Luik et al [42] show clean first-order kinetics with respect to ER calcium.…”

Homeostasis at different backgrounds: The roles of overlayed feedback structures in vertebrate photoadaptation

“…There is evidence that intracellular Ca stores leak Ca into the cytosol [43][44][45][46]. Analyzing the data by Camello et al [45] and Luik et al [46], we observed (S4 Text and [47]) that the kinetics of the two recorded leaks were surprisingly different. While Camello et al [45] found practically zero-order kinetics with respect to ER calcium and leak rates at around 0.25 μM/s, the data by Luik et al [46] show clean first-order kinetics with respect to ER calcium.…”

Platelet rich plasma mitigates silver nanoparticles induced - pulmonary fibrosis in Wister rats via CASPASE -3 &TWIST-1genes downregulation

“…Additionally, AgNPs may cause apoptosis via the caspase-dependent mitochondrial pathway, which has been shown to alter cell dynamics, harm the cell membrane, inactivate ATPase activity to suppress Ca 2+ -ATPase, Na+/K+-ATPase and Ca 2+ /Mg 2+− ATP as produce excessive amounts of ROS and MDA, sensitize cell signaling to the release of cytochrome C and pro-apoptotic protein into the cytoplasm, and activate the caspase cascade as reported by 100 ; 101 . Clearance of Ca 2+ and cell homeostasis maintenance are controlled by the calmodulin (CaM)-dependent enzyme Ca 2+ -ATPase, which can prevent cells from going through apoptosis 102 .…”