Inositol 1,4,5-trisphosphate receptors (IP3Rs) are widely expressed intracellular Ca2+ channels that evoke large local increases in cytosolic Ca2+ concentration. By depleting the ER of Ca2+, IP3Rs also activate store-operated Ca2+ entry (SOCE). Immobile IP3Rs close to the plasma membrane (PM) are the only IP3Rs that respond to physiological stimuli. The association of these ‘licensed’ IP3Rs with the ER-PM junctions where STIM interacts with Orai PM Ca2+ channels may define the autonomous functional unit for SOCE. Ca2+ entering cells through SOCE can be delivered directly to specific effectors, or it may reach them only after the Ca2+ has been sequestered by the ER and then released through IP3Rs. This ‘tunnelling’ of Ca2+ through the ER to IP3Rs selectively delivers Ca2+ to different effectors.
