Figure 2. Actions of the key SOCE mediators, STIM1 and Orai1.

Signaling is generally initiated by agonist (Ag) acting through a receptor (R) and G-protein (G) to activate phospholipase C (PLC) and produce the Ca²⁺-mobilizing messenger, inositol 1,4,5-trisphosphate (IP₃). IP₃ in turn activates the IP₃ receptor (IP3R) in the endoplasmic reticulum. The fall in Ca²⁺ in the endoplasmic reticulum activates STIM1 to aggregate and migrate to specific sites near the plasma membrane where Orai1 channels are activated resulting in SOCE. Channels composed of Orai1 and Orai3 (not shown) subunits can also be activated in a non-store-operated mode by arachidonic acid or a metabolite, leukotriene C4. Calcium entering through Orai1 channels can recruit and together with STIM1 activated certain members of the TRPC cation channel family. Some members of the TRPC cation family can also be activated more directly by products of phospholipase C. Calcium entering the cytoplasm through all of these routes regulates and activates a myriad of cell responses, some of which were discussed in the current review.