Exploring the unique features of the ARC channel, a Store-independent Orai channel

The discovery of the Orai proteins, and the identification of STIM1 as the molecule that regulates them, was based on their role in the agonist-activated store-operated entry of calcium via the CRAC channels. However, these same proteins are also essential components of the ARC channels responsible for a similar agonist-activated, but store-independent, arachidonic acid-regulated entry of calcium. The fact that these 2 biophysically similar calcium entry pathways frequently co-exist in the same cells suggests that they must each possess different features that allow them to function in distinct ways to regulate specific cellular activities. This review begins to address this question by describing recent findings characterizing the unique features of the ARC channelstheir molecular composition, STIM1-dependent activation, and physiological activitiesand the importance of defining such features for the accurate therapeutic targeting of these 2 Orai channel subtypes.