FIGURE 7. Model depicting the role of STIM2 in the clustering of STIM1 and activation of SOCE following intracellular Ca²⁺-store depletion.

In unstimulated cells, ER [Ca²⁺] is high (blue) and the STIM proteins reside and are diffusively distributed in the ER membrane. Stimulation with relatively low concentration of agonist results in minimal depletion of the ER-Ca²⁺ stores and mobilization of STIM2. These conditions promote the formation of STIM2-STIM1 heteromers, which translocate to the ER-PM junctions where STIM1 interacts with Orai1 and activates SOCE. Substantial depletion of the ER-Ca²⁺ stores following stimulation with high concentrations of agonist drives the formation of STIM1 homomers and their recruitment to the ER-PM junctions where STIM1 activates Orai1. Because both STIM2-STIM1 heteromers and STIM1 homomers would form in response to high concentrations of agonist, we predict that Ca²⁺ influx would be greater than at the lower levels of stimulation.