In our model systems, the RyR conductance was expressed as a sum a Ca2+ independent and a Ca2+ dependent component. Even when we varied the relative contributions of these components, as well as increased or decreased the sensitivity of the RyRs’ Ca2+ conductance to cytosolic Ca2+, our model simulations always indicated that the ER Ca2+ stores behaved as net Ca2+ sinks during simulated Ca2+ transients evoked by single or multiple APs. These results agree well with existing data in mammalian sympathetic neurons (Hernández-Cruz et al., 1997; Wanaverbecq et al., 2003), but disagrees with earlier findings by ourselves and others in frog sympathetic ganglion neurons, where CICR was shown to produce a net increase of cytosolic Ca2+, both in experimental studies (Akita and Kuba, 2000; Cseresnyés and Schneider, 2004) and, more recently, in a model system as well (Patterson et al, 2007). This disagreement may simply be caused by species differences. Our results indicate that the fluorescence signal recorded from the central regions of a cell in any XY plane could be a combination of “pure” signals from more than one theoretical domain: the domain sampled in the focal plane and one or more domains above or below the focal plane. Our examinations show that it is possible, using confocal data and applying our 6-domain model, to un-mix the contaminated optical signals and thus to estimate what the “pure” signals would be in an ideal confocal section. Conclusions: From these results we concluded that spatial non-uniformity of Ca2+ responses to APs is an inherent property of frog SGNs and rat SCG neurons, and that the non-uniformity is maintained in primary cell cultures, even though the hot spots may not always be directly observable in all cultured SGNs. The hot spots possibly serve as information transmitters that signal the arrival of the AP-induced calcium signals to the cell nucleus and the axon. Our computer simulations proved to be successful in reproducing our experimental characterization of the dynamics of the intracellular local Ca2+ signals initiated by AP-induced Ca2+ entry in a multi-compartmental model. The model provided a characterization of the SCG and SGN neuronal systems in terms of Ca2+ fluxes underlying the spatio-temporal properties of local Ca2+ signals during and after single AP induced by electrical field stimulation.