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 identified³. Orai1 (also known as CRACM1) acts as the store operated Ca²⁺ channel (SOC) and STIM1, which acts as the endoplasmic reticulum Ca²⁺ sensor^3,4. 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 reticulum^4-6. 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.