Store-operated Ca²⁺ entry (SOCE) is a ubiquitous Ca²⁺ signaling pathway that is evolutionarily conserved across eukaryotes. SOCE is triggered physiologically when the endoplasmic reticulum (ER) Ca²⁺ stores are emptied through activation of inositol 1,4,5-trisphosphate receptors. SOCE is mediated by the Ca²⁺ release-activated Ca²⁺ (CRAC) channels, which are highly Ca²⁺ selective. Upon store depletion, the ER Ca²⁺-sensing STIM proteins aggregate and gain extended conformations spanning the ER–plasma membrane junctional space to bind and activate Orai, the pore-forming proteins of hexameric CRAC channels. In recent years, studies on STIM and Orai tissue-specific knockout mice and gain- and loss-of-function mutations in humans have shed light on the physiological functions of SOCE in various tissues. Here, we describe recent findings on the composition of native CRAC channels and their physiological functions in immune, muscle, secretory, and neuronal systems to draw lessons from transgenic mice and human diseases caused by altered CRAC channel activity.

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