SPATIAL AND TEMPORAL ASPECTS OF CELLULAR CALCIUM SIGNALING

Cytosolic Ca2+ signals are often organized in complex temporal and spa tial patterns, even under conditions of sustained stimulation. In this review we discuss the mechanisms and physiological significance of th is behavior in nonexcitable cells, in which the primary mechanism of C a2+ mobilization is through (1,4,5)IP3-dependent Ca2+ release from int racellular 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 propa gate throughout the cell or they may be restricted to specific subcell ular regions. These patterns of Ca2+ signaling result from the limited range of cytoplasmic Ca2+ diffusion and the feedback regulation of th e pathways responsible for Ca2+ mobilization. In addition, the spatial organization of [Ca2+](i) changes appears to depend on the strategic distribution of Ca2+ stores within the cell. One type of [Ca2+](i) osc illation is baseline spiking, in which discrete [Ca2+](i) spikes occur with a frequency, but not amplitude, that is determined by agonist do se. Most current evidence favors a model in which baseline [Ca2+](i) s piking results from the complex interplay between [Ca2+](i) and (1,4,5 )IP3 in regulating the gating of (1,4,5)IP3-sensitive intracellular Ca 2+ channels. Sinusoidal [Ca2+](i) oscillations represent a mechanistic ally distinct type of temporal organization, in which agonist dose reg ulates the amplitude but has no effect on oscillation frequency. Sinus oidal [Ca2+](i) oscillations can be explained by a negative feedback e ffect 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 sig nificance of [Ca2+](i) oscillations and waves is becoming more establi shed with the observation of this behavior in intact tissues and by th e recognition of Ca2+-dependent processes that are adapted to respond to frequency-modulated oscillatory [Ca2+](i) signals. In some cells, t hese [Ca2+](i) signals are targeted to control processes in limited cy toplasmic domains, and in other systems [Ca2+](i) waves can be propaga ted through gap junctions to coordinate the function of multicellular systems.