Pathogenic Role of Store-Operated and Receptor-Operated Ca^𝟐+ Channels in Pulmonary Arterial Hypertension

Figure 6

IP₃ activates voltage-independent Ca²⁺ SOC channels on the plasma membrane, resulting in Ca²⁺ influx into the cell (SOCE). When the SE/ER is filled with Ca²⁺, STIM is evenly dispersed along the membrane and Ca²⁺ is bound to the low-affinity EF hand domain near the N-terminal. Once the IP₃R is activated by IP₃, Ca²⁺ levels in the SR/ER decrease. Following detection of Ca²⁺ depletion from the SR/ER store, by the Ca²⁺ binding domain on the N-terminal of STIM found on the SR/ER membrane, Ca²⁺ will dissociate from STIM causing a conformational change that allows for the dimerization and formation of oligomers through interaction of their sterile 𝛼-motifs (SAMs). Oligomers then translocate to ER/SR-plasma membrane junction where they induce the clustering of SOC channels (e.g., Orai) and stimulate opening of the channel by interaction of the STIM-Orai activating region (SOAR) near the C-terminus on STIM, resulting in an influx of Ca²⁺ [36].