Figure 1. Current understanding of the roles of Stim1 and Orai.

Agonist (Ag) activation of a plasma membrane receptor (R) results in formation of IP₃, which activates the IP₃ receptor (IP3R) causing discharge of stored Ca²⁺ from a subcompartment of the endoplasmic reticulum. Within this subcompartment, Ca²⁺ binds reversibly to an EF hand motif in Stim1; depletion of Ca²⁺ results in Ca²⁺ dissociation from Stim1, which causes Stim1 to redistribute within the endoplasmic reticulum to areas near Orai channels that reside in the plasma membrane. Stim1 then activates Ca²⁺-selective Orai channels; the mechanism by which this activation is accomplished is unknown at present. Stim1 is also present in the plasma membrane, although its function there is unclear. TRPC channels can also be activated by phospholipase C (PLC) –dependent mechanisms. There is evidence that in some instances, perhaps when combined with other subunits, they can function as store-operated channels, perhaps also involving Stim1 as an activator.