Cytosolic calcium (Ca²⁺) has long been known to act as a key second messenger in many intracellular pathways including synaptic transmission, muscle contraction, hormonal secretion, cell growth and proliferation^1,2. Intracellular Ca²⁺ levels are controlled by either the influx of Ca²⁺ through the calcium-release-activated Ca²⁺ channels (CRAC), or from intracellular stores which gained much attention.

Recently, several key players of the store operated complex have been identified. Orai1 (also known as CRACM1) acts as the store operated Ca²⁺ channel (SOC) and STIM1, which acts as the endoplasmic reticulum Ca²⁺ sensor³. The formation of functional channels requires the presence of both Orai1 and STIM1 proteins working as a complex and involves the co-clustering of Orai1 on the plasma membrane with STIM1 on the endoplasmic reticulum⁶. TRPC1, a member of the transient receptor potential family was also suggested to act as a player in the SOC complex⁷. In T-cells, Ca²⁺ entry following activation by antigen-receptor engagement occurs solely through CRAC channels where Orai1 constitutes the pore forming subunit^3,8.

Orai1 is a plasma membrane protein with four potential transmembrane domains and intracellular N- and C-terminus. In addition, two mammalian homologs to Orai1 have been identified; Orai2 and Orai3^3,9. All three, Orai1 Orai2 and Orai3, are capable of forming store operated channels with different magnitudes⁹.