[Frontiers in Bioscience 17, 847-860, January 1, 2012]

STIM and Orai proteins and the non-capacitative ARC channels

Trevor J. Shuttleworth1

1Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY


1. Abstract
2. Importance and role of store-independent calcium entry
3. Properties of ARC channels
4. STIM11 and the regulation of ARC channel activity
5. Orai proteins and the molecular make-up of ARC channels
6. Functional role of ARC channels
7. Conclusions
8. Acknowledgments
9. References


The ARC channel is a small conductance, highly Ca2+-selective ion channel whose activation is specifically dependent on low concentrations of arachidonic acid acting at an intracellular site. They are widely distributed in diverse cell types where they provide an alternative, store-independent pathway for agonist-activated Ca2+ entry. Although biophysically similar to the store-operated CRAC channels, these two conductances function under distinct conditions of agonist stimulation, with the ARC channels providing the predominant route of Ca2+ entry during the oscillatory signals generated at low agonist concentrations. Despite these differences in function, like the CRAC channel, activation of the ARC channels is dependent on STIM1, but it is the pool of STIM1 that constitutively resides in the plasma membrane that is responsible. Similarly, both channels are formed by Orai proteins but, whilst the CRAC channel pore is a tetrameric assembly of Orai1 subunits, the ARC channel pore is formed by a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits. There is increasing evidence that the activity of these channels plays a critical role a variety of different