General scheme of the distribution and movement of intracellular calcium (Ca). In contrast to magnesium, Ca has a particularly adaptable coordination sphere that facilitates its binding to the irregular geometry of proteins, a binding that is readily reversible. Low intracellular Ca concentrations can function as either a first or second messenger. The extremely low concentrations of intracellular Ca are necessary to avoid Ca-phosphate microprecipitation and make Ca an extremely sensitive cellular messenger. Less than 1% of the total intracellular Ca exists in the free ionized form, with a concentration of approximately 0.1 ^mol/L. Technical methods available to investigate intracel-lular free Ca concentration include Ca-selective microelectrodes, bioluminescent indicators, metallochromic dyes, Ca-sensitive fluorescent indicators, electron-probe radiographic microanaly-sis, and fluorine-19 nuclear magnetic resonance imaging. Intracellular Ca is predominantly sequestered within the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR). Some sequestration of Ca occurs within mitochondria and the nucleus. Ca can be bound to proteins such as calmodulin and calbindin, and Ca can be complexed to phosphate, citrate, and other anions. Intracellular Ca is closely regulated by balancing Ca entry by way of voltage-operated channels (VOC), receptor-operated channels (ROC), and store-operated channels (SOC), with active Ca efflux by way of plasma membrane-associated Ca-adenosine triphosphatase (ATPase) and a Na-Ca exchanger. Intracellular Ca also is closely regulated by balancing Ca movement into the SR (SR Ca-ATPase) and efflux from the SR by an inositol 1,4,5-trisphosphate (InsP3) receptor [1-7].

The highest concentration of intracellular Ca is found in the brush border of epithelial cells, where there is also the highest concentration of Ca-binding proteins such as actin-myosin and calbindin. Intracellular Ca messages are closely modulated by the phospholipase C-InsP3 pathway and also the phospholipase A2-arachidonic acid pathway, along with intracellular Ca, which itself modulates the InsP3 receptor.

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