**5. ORAI3 and calcium signaling**

Shortly after the molecular description of ORAI1 as the CRAC channel, it was revealed the essential role of other ORAI proteins in cell signaling. The involvement of ORAI3, together with ORAI1, in arachidonic acid-regulated Ca2+ (ARC) channels was early proposed [88, 89]. In contrast to SOC channels, the activation of ARC channels depends on the pool of STIM1 resident in the plasma membrane [90]. More interestingly, ORAI1 and ORAI3 show a differential sensitivity to reactive oxygen species, due to the extracellularly located Cys195 residue which is found in ORAI1, but not in ORAI3. The differential redox sensitivity underlies the differential responses between naïve and T helper lymphocytes, an event that lets T(H) cells proliferate and secrete cytokines in oxidative environments [91].

ORAI3, but not ORAI1, was also involved in the activation of PLCδ in response to arachidonic acid, an activation that controls oscillation frequency of Ca2+ spikes triggered by carbachol [92]. ORAI3 channels are overexpressed in estrogen receptor-positive breast cancer cells [93], and it was later demonstrated, using the MCF-7 cancer cell line, that silencing ORAI3 slows down cell cycle and triggers arrest at G1 phase [94]. EGF triggers Ca2+ entry through ORAI3, and the channel is transcriptionally upregulated by the estrogen receptor alpha (ERα) [95]. It is now accepted that cancer cells show a remodeling of ORAI proteins, with an enhanced participation of ORAI3 compared to noncancerous cells, suggesting that heteromerization of ORAI3 and ORAI1 is a common feature in malignant transformation [96].
