In non-excitable cells, Ca²⁺ signaling plays a most important role in important cellular functions such as migration, proliferation and differentiation¹. In such cells, Ca²⁺ enters via either non-selective cation channels such as TRPCs or through highly selective Ca²⁺ such as Ca²⁺ release-activated Ca²⁺ channels (CRAC channels) or store-operated Ca²⁺ entry channels (SOC channels), and the arachidonic acid-regulated Ca²⁺ channels (ARC channels)².

Orai channels are part of the molecular components involved in the Ca²⁺ entry described above. Three Orai channels have been described in mammalian cells: Orai1-3. These channels make up the pore forming unit of CRAC channels³. They are membrane proteins with four transmembrane domains and intracellular N- and C-termini. Orai1 and Orai3 share similar distribution and are expressed in the heart, brain, liver, spleen, lung, intestine, lymphoid organs, skin, and skeletal muscle. Expression of Orai2 is more limited and is found mainly in the brain and lower expression is detected in the lung, spleen and intestine³.

CRAC channels have been for the most part identified as homotetramers of Orai1 interacting with endoplasmic reticulum located STIM1 that are activated by a depletion of intracellular Ca^2+ 4. Orai3 was shown to emit store-operated Ca²⁺ entry (SOCE) currents along with STIM1/2 in breast cancer cells which are Estrogen Receptor positive (ER⁺), whereas Orai1/STIM1 are responsible for these currents in Estrogen Receptor negative (ER^-) cells¹. Furthermore, inhibition of Orai3 in these cells elicits cell cycle arrest and ultimately apoptosis (normal cells do not undergo apoptosis)⁵. ARC channels are composed of a heteropentameric organization of Orai1/Orai3 (in a 3:2 ratio) which interacts with the small fraction of plasma membrane localized STIM1. These channels are activated by low concentrations of arachidonic acid localized at the inner face of the plasma membrane⁶.