Stimulus-dependent control of inositol 1,4,5-trisphosphate-induced Ca2+ oscillation frequency by the endoplasmic reticulum Ca2+-ATPase

In many cell types, receptor stimulation evokes cytosolic calcium oscillati ons with a frequency that depends on agonist dose. Previous studies demonst rated controversial effects of changing the activity of the endoplasmic ret iculum Ca2+-ATPase upon the frequency of oscillations. By numerical simulat ions, we found that the model of De Young and Keizer (J. Keizer and G. W. D e Young, 1994, J. Theor. Biol. 166:431-442), unlike other models, can expla in the observed discrepancies, assuming that the different experiments were performed at different stimulus levels. According to model predictions, pa rtial inhibition of internal calcium pumps is expected to increase frequenc y at low stimulus strength and should have an opposite effect at strong sti muli. Similar results were obtained using an analytical estimation of oscil lation period, based on calcium-dependent channel activation and inactivati on. In experiments on HeLa cells, 4 nM thapsigargin increased the frequency of calcium oscillations induced by 1 and 2.5 muM histamine but had no effe ct on supramaximally stimulated cells. In HEp-2 cells, 2 nM thapsigargin sl owed down the rapid, ATP-incluced oscillations. Our results suggest that in the investigated cell types, the De Young-Keizer model based on inositol 1 ,4,5-trisphosphate-dependent calcium-induced calcium release can properly d escribe intracellular calcium oscillations.