Stromal interaction molecule 1 (STIM1) is responsible for activating the Ca 2+ release-activated Ca 2+ (CRAC) channel by first sensing the changes in Ca 2+ concentration in the endoplasmic reticulum ([Ca 2+ ]ER) via its luminal canonical EF-hand motif and subsequently oligomerizing to inter-act with the CRAC channel pore-forming subunit Orai1.