Orai channels – New insights, new ideas

Abstract

The basic mechanism of agonist-activated Ca2+ entry in non-excitable cells was first defined by Jim Putney some 25 years ago (Putney, 1986). This mechanism of ‘capacitative’, or store-operated, Ca2+ entry described how such entry was strictly a consequence of the depletion of intracellular Ca2+ stores, typically those formed by the endoplasmic reticulum (ER). During agonist action such depletion would normally result from the generation of InsP3, and the resulting release of ER Ca2+, but the essential dependence on store depletion per se was demonstrated by the fact that the same entry could be induced by any means that resulted in a corresponding decline in the concentration of free Ca2+ in the ER, including inhibition of SERCA pumps, or increasing Ca2+ buffer levels in the ER. Subsequently, a highly Ca2+-selective conductance representing such an entry pathway was identified, initially in mast cells and T lymphocytes, and its essential biophysical properties described and defined (Hoth & Penner, 1992; Zweifach & Lewis, 1993). This was the CRAC channel (Ca2+ release-activated Ca2+ channel). However, despite extensive analysis of the properties and behaviour of these channels, their molecular identity and the actual processes that link the depletion of intracellular Ca2+ stores with activation of the channels remained unknown for almost 15 years. All of this changed dramatically with a series of papers that appeared in 2005 and 2006. First, the protein STIM1 was identified as the molecule linking the detection of Ca2+ store depletion with the subsequent activation of the CRAC channels (Liou et al. 2005; Roos et al. 2005). Then, a year later, a novel family of proteins named Orai proteins were shown to form the channels themselves (Feske et al. 2006; Vig et al. 2006; Zhang et al. 2006). The resulting surge of new findings that resulted from this identification of the molecular basis of store-operated Ca2+ entry was nicely summarized in a symposium organized by Anant Parekh and sponsored by The Journal of Physiology, which was held at the 52nd Annual Biophysical Society meeting at Long Beach, California in 2008.