The ARC channel--an endogenous store-independent Orai channel

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.