Calcium oscillations

Abstract

Calcium signaling results from a complex interplay between activation and inactivation of intracellular and extracellular calcium permeable channels. This complexity is obvious from the pattern of calcium signals observed with modest, physiological concentrations of calcium-mobilizing agonists, which typically present as sequential regenerative discharges of stored calcium, a process referred to as calcium oscillations. In this review, we discuss recent advances in understanding the underlying mechanism of calcium oscillations through the power of mathematical modeling. We also summarize recent findings on the role of calcium entry through store-operated channels in sustaining calcium oscillations and in the mechanism by which calcium oscillations couple to downstream effectors.

Figure 1.

Schematic representation of the protocol proposed by Sneyd et al. (2006) to discriminate between an InsP₃R-based or an InsP₃ metabolism-based mechanism for Ca²⁺ oscillations. If phospholipase C (PLC) activity is stimulated by Ca²⁺ (left panel), oscillations in InsP₃ must accompany Ca²⁺ oscillations. If some InsP₃ is exogenously added during Ca²⁺ oscillations, it will delay the next Ca²⁺ spikes, without significant change in the frequency of Ca²⁺ oscillations. In contrast (right panel), if Ca²⁺ oscillations rely on successive cycles of activation/inhibition of the InsP₃ receptor (InsP₃R), Ca²⁺ oscillations can occur with a constant level of InsP₃. In this case, the addition of InsP₃ during oscillations will provoke a transient rise in the frequency of Ca²⁺ oscillations, with a progressive return to the original frequency. See text and Sneyd et al. (2006) for details.

Figure 2.

Comparison among Ca²⁺ oscillations observed in hepatocytes stimulated by noradrenaline (upper panels) and simulated by a stochastic Gillespie’s algorithm taking into account realistic numbers of clusters of InsP₃ receptors (lower panels). The model is based on the assumption that Ca²⁺ dynamics occur in a deterministic regime, in which fluctuations are visible because of the rather low number of clusters. Both in the model and in experiments, the variability decreases when the frequency increases. See Dupont et al. (2008) for details.

Figure 3.

Lanthanide insulation renders Ca²⁺ oscillations independent of extracellular Ca²⁺. (A) 5 µM methacholine (MCh) induces sustained oscillations in a HEK293 cell. (B) In the absence of extracellular Ca²⁺, oscillations are not sustained. (C) In the presence of 1 mM Gd³⁺, oscillations are sustained, even in the absence of extracellular Ca²⁺. These panels illustrate responses of single cells. The statistical evaluation of multiple cells analyzed with this procedure is summarized in Bird and Putney (2005).