The Many Faces of Orai

Abstract

Three decades ago, Putney1 forwarded the idea of store-operated Ca2+ entry in mammalian cells. He rationalized that after the discharge of Ca2+ from an intracellular pool, an undefined signaling pathway would enhance extracellular Ca2+ influx and promote store refilling. Using concurrent advancements in pharmacology, biochemistry, and Ca2+ measurement techniques, the endoplasmic reticulum was readily identified as the intracellular Ca2+ pool and inositol triphosphate receptor activation as central to the depletion process. The molecular identity of store-operated Ca2+ channels remained unclear till 2005 when unbiased screening arrays first identified stromal interacting molecule-1 (STIM1). This single transmembrane spanning protein resides primarily, although not exclusively in the endoplasmic reticulum, and it retains a luminal EF-hand motif. On internal store depletion, it has been argued that Ca2+ dissociates from this motif and initiates a response that promotes STIM1 aggregation and the direct physical gating to the pore (Figure). The pore-forming subunits of the store-operated Ca2+ channel were later isolated by …