Physiology of intracellular calcium buffering

Calcium signaling underlies much of physiology. Almost all the Ca²⁺ in the cytoplasm is bound to buffers, with typically only ∼1% being freely ionized at resting levels in most cells. Physiological Ca²⁺ buffers include small molecules and proteins, and experimentally Ca²⁺ indicators will also buffer calcium. The chemistry of interactions between Ca²⁺ and buffers determines the extent and speed of Ca²⁺ binding. The physiological effects of Ca²⁺ buffers are determined by the kinetics with which they bind Ca²⁺ and their mobility within the cell. The degree of buffering depends on factors such as the affinity for Ca²⁺, the Ca²⁺ concentration, and whether Ca²⁺ ions bind cooperatively. Buffering affects both the amplitude and time course of cytoplasmic Ca²⁺ signals as well as changes of Ca²⁺ concentration in organelles. It can also facilitate Ca²⁺ diffusion inside the cell. Ca²⁺ buffering affects synaptic transmission, muscle contraction, Ca²⁺ transport across epithelia, and the killing of bacteria. Saturation of buffers leads to synaptic facilitation and tetanic contraction in skeletal muscle and may play a role in inotropy in the heart. This review focuses on the link between buffer chemistry and function and how Ca²⁺ buffering affects normal physiology and the consequences of changes in disease. As well as summarizing what is known, we point out the many areas where further work is required.