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Calcium signals in lymphocyte activation and disease

Calcium ions function as universal second messengers in virtually all eukaryotic cells including cells of the immune system where they are crucial for the function of T and B cells, mast cells and dendritic cells. The predominant mechanism regulating intracellular Ca2+ levels in cells of the adaptive immune system is store-operated Ca2+ influx through so-called Ca2+-release activated Ca2+ (CRAC) channels. We identified ORAI1 (also named CRACM1) as a pore subunit of the CRAC channel essential for the function of T cells and mast cells. ORAI1/CRAC channels are activated when intracellular Ca2+ stores are depleted. The resulting decrease in the ER Ca2+ concentration is sensed by stromal interaction molecule 1 (STIM1) that is required for activation of ORAI1/CRAC channels. We showed that murine T cells lacking STIM1 exhibit severely impaired store-operated Ca2+ influx. T cells from mice lacking STIM1 or its paralogue STIM2 both showed significantly reduced cytokine production in vitro and a defect in regulatory T cell development as well as lympho- and myeloproliferation in vivo. Mutation of ORAI1 in humans is associated with severe combined immunodeficiency (SCID), increased susceptibility to infections and a failure to thrive. A similar defect is found in mice transgenic for the equivalent R93W mutation in murine ORAI1, which all but abrogates CRAC channel function and T cell activation. Taken together STIM1, STIM2 and ORAI1 are essential regulators of store-operated Ca2+ entry in cells of the immune system and other tissues.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Feske, S. Calcium signals in lymphocyte activation and disease. Cell Commun Signal 7 (Suppl 1), A76 (2009).

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