ORAI Calcium Channels

Abstract

In this review article, we discuss the different gene products and translational variants of ORAI proteins and their contribution to the makeup of different native calcium-conducting channels with distinct compositions and modes of activation. We also review the different modes of regulation of these distinct calcium channels and their impact on downstream cellular signaling controlling important physiological functions.

FIGURE 1.

Evolution of ORAI genes Invertebrates have a single ORAI gene. Vertebrates possess two genes: ORAI1 and ORAI2. ORAI3 appeared in mammals, likely duplicating from ORAI1. Alternative translation-initiation of mRNA generates ORAI1α only in mammals. A shorter ORAI1β exists in all species.

FIGURE 2.

Schematic representation of various consensus regions unique to ORAI1α Within the 63 amino acids exclusive to human ORAI1α, the two PKC phosphorylation sites at serine 27 and serine 30 are labeled in blue, and the overlapping PIP₂ and AC8 binding domains are in gray and purple, respectively. The caveolin-binding region is labeled in green. Methionine 1 and methionine 64 are labeled in red. E106 is the selectivity filter in human ORAI1.

FIGURE 3.

ORAI protein contributions to distinct native Ca²⁺-conducting channels ORAI channel genes and translational variants contribute to at least four distinct conductances. Both ORAI1α and ORAI1β form different populations of I_CRAC that differ in their fast CDI. In addition, both ORAI1α and ORAI1β generate Ca²⁺ signals that cause either Ca²⁺ activation of TRPC4/5 channels or membrane insertion of TRPC1-containing vesicles and generation of TRPC1-mediated I_SOC. However, only ORAI1α can form I_ARC through heteromeric association with ORAI3.

FIGURE 4.

Different ORAI-mediated channels couple to distinct downstream pathways ORAI1-mediated I_CRAC is known to cause NFAT activation through calcineurin. I_CRAC channels mediated by homohexamers of either ORAI1α or ORAI1β are expected to couple equally well to NFAT. Furthermore, I_CRAC mediated by ORAI1α is likely to induce CREB activation through AC8/AKAP79/PKA. ORAI1α/β- and TRPC1-mediated I_SOC activates NF-κB, whereas receptor activation of Ca²⁺ entry through ORAI1α/3-mediated I_ARC failed to activate NFAT but instead coupled to AKT signaling.