Abstract
Calcium (Ca2+) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca2+ store and then activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration, which is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca2+ signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca2+ is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca2+-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca2+-calcineurin–NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases.
Highlights
Calcium (Ca2+) is a second messenger that performs various functions, including cell division, activation, proliferation, and apoptosis in many cells [1] (Table 1)
We have discussed recent advances in understanding the role played by the Ca2+ signaling pathway in the function of diverse immune cells, especially lymphocytes
stromal interaction molecule 1 (STIM1), which can translocate to the membrane, and binds to Orai1
Summary
Calcium (Ca2+) is a second messenger that performs various functions, including cell division, activation, proliferation, and apoptosis in many cells [1] (Table 1). Ca2+ levels in the extracellular fluid (ECF) and endoplasmic reticulum (ER) lumen are maintained in the several millimolar (mM) range. The cytosolic Ca2+ levels are approximately in the range of 100 nM, which is 10,000 times lower than ECF Ca2+ concentrations [2]. The resulting Ca2+ gradient is kept by intracellular Ca2+ stores, various types of Ca2+ channels, Ca2+/H+ ATPase, and Na+/Ca2+ exchangers. The cytosolic Ca2+ level is low in resting cells, but Ca2+-mobilizing agonists, such as hormones
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