Orai3--the 'exceptional' Orai?

The field of agonist-activated Ca(2+) entry in non-excitable cells underwent a revolution some 5 years ago with the discovery of the Orai proteins as the essential pore-forming components of the low-conductance, highly Ca(2+)-selective CRAC channels whose activation is dependent on depletion of intracellular stores. Mammals possess three distinct Orai proteins (Orai1, 2 and 3) of which Orai3 is unique to this class, apparently evolving from Orai1. However, the sequence of Orai3 shows marked differences from that of Orai1, particularly in those regions of the protein outside of the essential pore-forming domains. Correspondingly, studies from several different groups have indicated that the inclusion of Orai3 is associated with the appearance of conductances that display unique features in their gating, selectivity, regulation and mode of activation. In this Topical Review, these features are discussed with the purpose of proposing that the evolutionary appearance of Orai3 in mammals, and the consequent development of conductances displaying novel properties - whether formed by Orai3 alone or in conjunction with the other Orai proteins - is associated with the specific role of this member of the Orai family in a unique range of distinct cellular activities.