Several features, taken together, make Ca2+ stand out among the physiologically important cations: first, the concentration of “free” Ca2+ ([Ca2+]) in the cytoplasm is only ∼100 nM; second, Ca2+ binds with high affinity (dissociation constants from ∼100 nM to ∼10 μM) to many intracellular proteins that activate/control a wide variety of biochemical/cell physiological events; and third, the extracellular [Ca2+] is four orders of magnitude larger than the cytoplasmic [Ca2+] with similar concentration ratios for organellar vs. cytoplasmic [Ca2+], which means that transient increases in the plasma or organelle membrane permeability to Ca2+ may produce large relative changes in cytoplasmic [Ca2+]. The spatial and temporal evolution of these [Ca2+] transients is determined by the magnitude and time course of Ca2+ release, Ca2+ influx, and the kinetics of Ca2+ buffering by diffusible...

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