Although Orai channels and their regulator stromal interacting molecule 1 (STIM1) were originally identified and described as the key components of the store-operated highly
calcium-selective
CRAC channels, it is now clear that these
proteins are equally essential components of the agonist-activated, store-independent
calcium entry pathway mediated by the
arachidonic acid-regulated
calcium-selective (
ARC) channel. Correspondingly,
ARC channels display biophysical properties that closely resemble those of
CRAC channels but, whereas the latter is formed exclusively by Orai1 subunits, the
ARC channel is formed by a combination of Orai1 and Orai3 subunits. Moreover, while STIM1 in the membrane of the endoplasmic reticulum is the critical sensor of intracellular
calcium store depletion that results in the activation of the
CRAC channels, it is the pool of STIM1 resident in the plasma membrane that regulates the activity of the store-independent
ARC channels. Here, we describe the unique features of the
ARC channels and their activation and discuss recent evidence indicating how these two coexisting, and biophysically very similar, Orai channels act to play entirely distinct roles in the regulation of various important cellular activities.