Multiple types of calcium channels arising from alternative translation initiation of the Orai1 message

Distinct Orai1 transcripts encode proteins that form Ca2+ channels with distinct properties. One gene for three currents Mammals produce alternative forms of the calcium channel pore-forming protein Orai1 using two different translation initiation start sites in the encoding transcripts. Desai et al. showed that these long and short forms produce calcium channels with distinct properties. Although both forms can participate in channels that respond to depletion of calcium from internal stores, only the long form contributes to a channel that is activated by arachidonic acid and leukotriene C4, lipids that promote inflammation. Their data suggest that characteristics of Orai1 genetic knockout may result from loss of any combination of these different calcium currents, not just loss of store-operated calcium entry. In mammals exclusively, the pore-forming Ca2+ release–activated Ca2+ (CRAC) channel subunit Orai1 occurs in two forms because of alternative translation initiation. The longer, mammal-specific Orai1α contains an additional 63 amino acids upstream of the conserved start site for Orai1β, which occurs at methionine 64 in Orai1α. Orai1 participates in the generation of three distinct Ca2+ currents, including two store-operated currents: Icrac, which involves activation of Orai1 channels by the Ca2+-sensing protein STIM1 (stromal interaction molecule 1), and Isoc, which involves an interaction among Orai1, the transient receptor potential (TRP) family member TRPC1 (TRP canonical 1), and STIM1. Orai1 is also a pore-forming subunit of an arachidonic acid (or leukotriene C4)–regulated current Iarc that involves interactions among Orai1, Orai3, and STIM1. We evaluated the roles of the two Orai1 forms in the Ca2+ currents Icrac, Isoc, and Iarc. We found that Orai1α and Orai1β were largely interchangeable for Icrac and Isoc, although Orai1α exhibited stronger inhibition by Ca2+. Only the mammalian-specific Orai1α functioned in the arachidonic acid–regulated current Iarc. Thus, alternative translation initiation of the Orai1 message produces at least three types of Ca2+ channels with distinct signaling and regulatory properties.