Abstract
Store-operated Ca2+ entry is a major Ca2+ entry mechanism that is present in most cell types. In immune cells, store-operated Ca2+ entry is almost exclusively mediated by Ca2+ release-activated Ca2+ (CRAC) channels. Ca2+ entry through these channels and the corresponding cytosolic Ca2+ signals are required for many immune cell functions, including all aspects of T-cell activation. ORAI proteins are the molecular correlates for the CRAC channels. The three human members, ORAI1, ORAI2 and ORAI3, are activated through the stromal interaction molecules (STIM)1 and 2 following depletion of endoplasmic reticulum Ca2+ stores. Different combinations of STIM and ORAI can form different CRAC channels with distinct biophysical properties. In this article, we review and discuss mechanistic and functional implications of two important CRAC/ORAI inhibitors, 2-APB and BTP2, and the antibiotic G418 that has also been reported to interfere with ORAI channel function. The use of pharmacological tools should help to assign distinct physiological and pathophysiological functions to different STIM–ORAI protein complexes.
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