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Changes in the cytoplasm free Ca2+ concentration [Ca2+]in regulate a large number of relevant physiological processes and have a major impact on cell development and function. The identification of STIM, the endoplasmic reticulum (ER) Ca2+ sensor, and Orai, a key subunit of the Ca2+ release-activated Ca2+ (CRAC) channel pore, have provided the tools to illuminate the mechanisms of CRAC channel regulation, that play an important role in modulation of the free Ca2+ concentration in non-excitable cells. Store-operated Ca2+ entry (SOCE) is a common and ubiquitous mechanism for regulating Ca2+ influx into cells and is widely expressed in most tissues.