Calcium signaling

Calcium ions are important for cellular signalling, as once they enter the cytosol of the cytoplasm they exert allosteric regulatory effects on many enzymes and proteins. Calcium can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.

The resting concentration of Ca²⁺ in the cytoplasm is normally maintained around 100 nM, variously reported as 20,000- to 100,000-fold lower than typical extracellular concentration. To maintain this low concentration, Ca²⁺ is actively pumped from the cytosol to the extracellular space, the endoplasmic reticulum (ER), and sometimes into the . Certain proteins of the cytoplasm and organelles act as buffers by binding Ca²⁺. Signaling occurs when the cell is stimulated to release calcium ions (Ca²⁺) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.

Specific signals can trigger a sudden increase in the cytoplasmic Ca²⁺ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C pathway.

Depletion of calcium from the endoplasmic reticulum will lead to Ca²⁺ entry from outside the cell by activation of "Store-Operated Channels" (SOCs). This inflowing calcium current that results after stored calcium reserves have been released is referred to as Ca²⁺-release-activated Ca²⁺ current (ICRAC). The mechanisms through which ICRAC occurs are currently still under investigation, although two candidate molecules, Orai1 and STIM1, have been linked by several studies, and a model of store-operated calcium influx, involving these molecules, has been proposed. Recent studies have cited the phospholipase A2 beta, nicotinic acid adenine dinucleotide phosphate (NAADP), and the protein STIM 1 as possible mediators of ICRAC.

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