MODELING OSCILLATIONS OF CALCIUM AND ENDOPLASMIC-RETICULUM TRANSMEMBRANE POTENTIAL - ROLE OF THE SIGNALING AND BUFFERING PROTEINS AND OF THE SIZE OF THE CA2+ SEQUESTERING ER SUBCOMPARTMENTS

Intracellular calcium oscillations provide a natural clock that may be of crucial importance for the timing of many cellular processes. Eluc idating of the mechanisms underlying these oscillations is of particul ar interest. The theoretical description presented here extends existi ng models of calcium oscillations by allowing for two types of protein s differing in their calcium-binding properties. This model reflects e xperimental findings by considering both a fast calcium-binding proces s to low-affinity protein binding sites such as found in the N-domains of calmodulin or troponin C and a class of high-affinity calcium bind ing proteins with slow binding kinetics (e.g., parvalbumin or the C-do mains of calmodulin and troponin C). Furthermore, recalling that calci um is mainly stored in small subcompartments of the ER, it is argued t hat only a small fraction of its overall volume participates in the ra pid release and uptake of calcium. The effect of the size of this frac tion is studied. The hypothesis saying that any electric potential dif ference across the ER membrane would be dissipated by the highly perme ant ions is critically examined by an analytical estimation based on t he electroneutrality condition and by numerical integration of the com plete model equations. It is predicted theoretically that the transmem brane potential of the ER calcium stores, which is up to now virtually impossible to determine in experiment, builds up in the millivolt ran ge at physiological concentrations of monovalent ions. The phenomenolo gy of oscillations is studied by numerical integration. The model repr oduces experimentally observed values of frequency and amplitude as we ll as the typical spike-like shape of oscillations. The model reveals also the time course of a shift of the bound Ca2+ population from the low-affinity binding sites to the high-affinity binding sites. (C) 199 8 Elsevier Science S.A. All rights reserved.