IP 3 receptors and Ca 2+ entry.

Inositol 1,4,5-trisphosphate receptors (IP ₃ R) are the most widely expressed intracellular Ca ²⁺ release channels. Their activation by IP ₃ and Ca ²⁺ allows Ca ²⁺ to pass rapidly from the ER lumen to the cytosol. The resulting increase in cytosolic [Ca ²⁺ ] may directly regulate cytosolic effectors or fuel Ca ²⁺ uptake by other organelles, while the decrease in ER luminal [Ca ²⁺ ] stimulates store-operated Ca ²⁺ entry (SOCE). We are close to understanding the structural basis of both IP ₃ R activation, and the interactions between the ER Ca ²⁺ -sensor, STIM, and the plasma membrane Ca ²⁺ channel, Orai, that lead to SOCE. IP ₃ Rs are the usual means through which extracellular stimuli, through ER Ca ²⁺ release, stimulate SOCE. Here, we review evidence that the IP ₃ Rs most likely to respond to IP ₃ are optimally placed to allow regulation of SOCE. We also consider evidence that IP ₃ Rs may regulate SOCE downstream of their ability to deplete ER Ca ²⁺ stores. Finally, we review evidence that IP ₃ Rs in the plasma membrane can also directly mediate Ca ²⁺ entry in some cells.
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