Spatial and temporal aspects of cellular calcium signaling

Cytosolic Ca²⁺ signals are often organized in complex temporal and spatial patterns, even under conditions of sustained stimulation. In this review we discuss the mechanisms and physiological significance of this behavior in nonexcitable cells, in which the primary mechanism of Ca²⁺ mobilization is through (1,4,5)IP₃-dependent Ca²⁺ release from intracellular stores. Oscillations of cytosolic free Ca²⁺ ([Ca²⁺](i)) are a common form of temporal organization; in the spatial domain, these [Ca²⁺](i) oscillations may take the form of [Ca²⁺](i) waves that propagate throughout the cell or they may be restricted to specific subcellular regions. These patterns of Ca²⁺ signaling result from the limited range of cytoplasmic Ca²⁺ diffusion and the feedback regulation of the pathways responsible for Ca²⁺ mobilization. In addition, the spatial organization of [Ca²⁺](i) changes appears to depend on the strategic distribution[Ca²⁺](i) of Ca²⁺ stores within the cell. One type of [Ca²⁺](i) oscillation is baseline spiking, in which discrete [Ca²⁺](i) spikes occur with a frequency, but not amplitude, that is determined by agonist dose. Most current evidence favors a model in which baseline [Ca²⁺](i) spiking results from the complex inter-play between [Ca²⁺](i) and (1,4,5)IP₃ in regulating the gating of (1,4,5)IP₃-sensitive intracellular Ca²⁺ channels. Sinusoidal [Ca²⁺](i) oscillations represent a mechanistically distinct type of temporal organization, in which agonist dose regulates the amplitude but has no effect on oscillation frequency. Sinusoidal [Ca²⁺](i) oscillations can be explained by a negative feedback effect of protein kinase C on the generation of (1,4,5)IP₃ at the level of phospholipase C or its activating G-protein. The physiological significance of [Ca²⁺](i) oscillations and waves is becoming more established with the observation of this behavior in intact tissues and by the recognition of Ca²⁺-dependent processes that are adapted to respond to frequency- modulated oscillatory [Ca²⁺](i) signals. In some cells, these [Ca²⁺](i) signals are targeted to control processes in limited cytoplasmic domains, and in other systems [Ca²⁺](i) waves can be propagated through gap junctions to coordinate the function of multicellular systems.