A model of calcium-induced calcium release from the sarcoplasmic reticulum in the smooth muscle cell and its investigation by mathematical modeling

Abstract

AbstractA model of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum was developed, simulating the behavior of the smooth muscle cell under conditions of its agonist stimulation. The mathematical model is a system of thirteen differential equations. In the initial (basal) state, the parameters of active and passive transport of Ca2+through both the plasma membrane and the sarcoplasmic reticulum membrane are adjusted.A study of the model showed that, depending on the model parameters, the cell system can demonstrate two types of calcium concentration changes in the cytosol: a single Ca2+transient and an oscillatory mode.After stimulation is completed, the cell system returns to the basal state (underin vivoconditions) or goes to a new steady-state level (underin vitroconditions), except when the cell system is in oscillatory mode. It is shown that the sarcoplasmic reticulum can act both as a passive participant in the process of Ca2+accumulation in the smooth muscle cell, acting as a buffer, and play a major role in this process by significantly increasing the Ca2+concentration in the cytosol, which is initiated by Ca2+entry from the extracellular space.It was found that after stimulation of the smooth muscle cell, the net Ca2+flux from the cytosol increases due to an increase in Ca2+concentration in the cytosol, while the net Ca2+flux into the cytosol first increases due to an increase in the number of open calcium channels located on the membrane of the sarcoplasmic reticulum. It then begins to decrease due to a decrease in the Ca2+concentration gradient across the membrane of the sarcoplasmic reticulum. Therefore, at a certain time point these fluxes become equal and the process of Ca2+accumulation in the cytosol is terminated. Thus, calcium-induced calcium release is terminated spontaneously, resulting in the formation of a single cytosolic Ca2+transient. As a result of calcium-induced calcium release, the sarcoplasmic reticulum is not completely emptied, but retains quite significant amounts of Ca2+.The possibility of Ca2+redistribution between the three compartments (extracellular space, cytosol and sarcoplasmic reticulum) creates the possibility of oscillation of cytosolic Ca2+concentration. The oscillation amplitude and frequency can remain practically unchanged for a considerable period.The developed model qualitatively reproduces the results of experimental studies conducted to identify store-operated calcium channels using the inhibitors of the calcium pump of the sarcoplasmic reticulum in a calcium-free medium.