Calcium release-activated calcium (CRAC) channels, characterized for their activation by depletion of the endoplasmic reticulum (ER) Ca2+ stores, are a prominent route for Ca2+ entry in many cells. The ensuing calcium signals mediate short-term cellular functions such as refilling of stores, as well as long-term functions, such as gene transcription, cell proliferation, and cell migration.
CRAC channels are formed from the Orai proteins (Orai1–3) of which Orai1 is the best studied member that forms the highly Ca2+ selective pore of the channel. Activation of Orai1 occurs in response to binding of the ER Ca2+ sensing proteins, STIM1 and STIM2, that detect changes in the ER Ca2+ concentration via their luminal EF-hand domains and migrate to the junctional ER to interact with and activate the Orai1 channel to stimulate Ca2+ influx. Mutations in Orai1 and STIM1 are associated with a variety of pathologies such as severe combined immunodeficiency syndrome, myopathies, and bleeding disorders, highlighting their importance for human physiology.