Combining a realistic model of inositol 1,4,5-trisphosphate (1P3)-induced Ca2+ oscillations with the diffusion of IP3 and buffered diffusion of Ca2+, we have found that diffusion of Ca2+ plays only a minor role in a class of agonistinduced Ca2+ wave trains. These waves are primarily kinematic in nature, with variable wavelengths and speeds that depend primarily on the phase differences between oscillators at different spatial points. The period is set by the steady-state value of EP3, while the wave speed approximately equals the wavelength/period. Ca2+ diffusion, which is much slower than that ofIP3 because of endogenous buffers, is shown to have only a small effect on the wave trains and not to be necessary for the apparent wave propagation. Diffusion of IP3 sets the phase gradient responsible for these wave trains, which consist primarily of localized cycles of Ca2+ uptake and release. Our results imply a possible previously undisclosed role for 1P3 in cell signaling.Repetitive Ca2+ waves have been observed with fluorescent dye microscopy in a number of cell types (1,2 (7,8) suggest that similar mechanisms also may be functioning in these secretory cells.Although the biological function of Ca2+ waves is not known, their ubiquity in certain cell types, including fertilized egg cells (5), makes understanding their mode (or modes) of propagation an important problem. Because the effective diffusion constant for Ca2+ is much smaller than that of IP3 (9), it has been argued that diffusion of Ca2+ can explain the speed of the wave (10), and recently mathematical models have been used to explore the role of diffusion in these waves (4,11,12). Here we report calculations with a realistic model of IP3-induced Ca2+ oscillations (13), which when combined with the diffusion of Ca2+ and IP3 can generate wave trains that are primarily kinematic in nature-i.e., they do not require bulk movement of Ca2+ (14-16). As we describe in the following sections, the reason for this, perhaps surprising, result is the slow rate of Ca2+ diffusion caused by endogenous Ca2+ buffers.
The ModelWe have based our computer simulations on a kinetic model of the biphasic Ca2+-activation and -inhibition of the IP3R (13). When combined with a sarcoplasmic or endoplasmic reticulum Ca2+-ATPase (SERCA-type Ca2+-ATPase) and a slow leak from the endoplasmic reticulum (ER), the model gives rises to spontaneous cytoplasmic Ca2+ oscillations at fixed, physiological levels of IP3 (13). We use a simplified version of that model (17) [along with buffered diffusion of cytoplasmic Ca2+ (18) and the diffusion, generation, and removal of IP3] to explore the behavior of planar Ca2+ waves. It is known that buffers greatly reduce the rate of diffusion of Ca2+ in the cytoplasm (9), and our model includes the effect of buffers in both the cytoplasm and ER (18). Fig. 1 shows a diagram ofthe model ofCa2+ handling by the ER. Ca2+ enters the cytosol from the ER via IP3Rs and a leak flux, with the ER being refilled by SERCA-type Ca2+-ATPases. In addition to these ...