Periodic forcing of intracellular calcium oscillators - Theoretical studies of the effects of low frequency fields on the magnitude of oscillations

In many types of cell the signal transduction from plasmalemma to intracellular targets is linked to the oscillatory behaviour of intracellular Ca2+. Experimental investigations of the effects of low frequency electromagnetic fields on living systems seem to indicate that calcium signaling pathways, and a cytosolic calcium oscillator in particular, may be the processes which are affected by external fields. In accordance with these findings the external forcing of a cytosolic calcium oscillator was studied numerically on two models of intracellular Ca2+ oscillations: the 'minimal' model suggested by Goldbeter et al. [A. Goldbeter, G. Dupont, M.J. Berridge, Minimal model for signal-induced Ca2+ oscillations and for their frequency encoding through protein phosphorylation, Proc. Natl. Acad. Sci. USA 87 (1990) 1461-1465.], and a three-dimensional model with chaos [P. Shen, R. Larter, Chaos in intracellular Ca2+ oscillations in a new model for non-excitable cells, Cell Calcium 17 (1995) 225-232]. The results obtained previously [J. Galvanovskis, J. Sandblom, B. Bergqvist, S. Galt, Y. Hamnerius, Cytoplasmic Ca2+ oscillations in human leukemia T-cells are reduced by 50 Hz magnetic fields, Bioelectromagnetics, in press.] in experiments on periodic forcing by 50 Hz magnetic fields of Ca2+ oscillations in Jurkat cells were qualitatively reproduced with simulations on the 'minimal' model. Simulations revealed that the most sensitive part in the chain of reactions involved in Ca2+ oscillations was the Ca2+ release from internal stores by calcium induced calcium release. The analysis further showed that the effect of forcing depends on the level of cell stimulation by the external application of agonist depending on the strength of this stimulus opposite field effects could be achieved. A multitude of frequency and amplitude 'windows' was also demonstrated in the response of a cytosolic oscillator quantified by the use of the total spectral power of Ca2+ oscillations. The occurrence of maxima in the forcing effect at the basic Ca2+ oscillator frequency and its higher harmonics shows that it may be possible to explain the experimentally observed resonance effects on a basis of non-linear dynamics. Simulations on the three-dimensional model revealed the extreme sensitivity of a chaotic state to periodic forcing, suggesting a possible role of chaotic processes in detection of weak signals within cells. (C) 1998 Elsevier Science S.A. All rights reserved.