The elemental principles of calcium signaling

Complexity of Intracellular Caz+ Signals Ca2+ is a ubiquitous intracellular signaling molecule controlling a wide array of cellular processes, including secretion, contraction, and cell proliferation (Berridge, 1993; Clapham, 1995). In resting cells, the intracellular Ca2+ concentration ([Cap+],) is maintained at approximately 1 O-l 00 nM, and during stimulation the average [Ca2+li can rise up to several micromolar, depending on the cell type. Such Ca2+signals have acomplex temporal and spatial arrangement, although the mechanisms underlying the complexity are not entirely clear. Tonic [Ca”], increases do not occur in many cells. Instead, Ca2+ is frequently presented to the cytoplasm in a pulsatile manner, such as the repetitive Ca2+ spikes that drive the beating heart, the rapid subplasmalemmal [Ca2+li increases that occur during depolarization of excitable cells, and the regular Cd+ spikes (or oscillations) observed during hormonal stimulation of many nonexcitable cell types. The spatial correlate of a Ca2+ spike is a Ca2+ wave in which Ca*+ is initially elevated in a discrete region of the cell before spreading throughout the cell as a regenerative increase. Since information is encoded in the spatiotemporal patterns of these intracellular signals, much interest is now focused on how these complex Ca*+ signals are generated. Intracellular Ca2+ Release Channels Cells utilize two sources of Ca2+ for generating signals: Ca2+ release from intracellular stores and Ca*+ entry across the plasma membrane. Both Ca2+ release and entry mechanisms can give rise to highly localized Ca2+ signals, which may be considered as the elemental events of Ca2+ signaling (Table 1). Most of the elementary events described so far are associated with the release of Ca*+ from intracellular stores, which is controlled by two families of channel; Minireview