Activation and regulation of store‐operated calcium entry

The process of store-operated Ca²⁺ entry (SOCE), whereby Ca²⁺ influx across the plasma membrane is activated in response to depletion of intracellular Ca²⁺ stores in the endoplasmic reticulum (ER), has been under investigation for greater than 25 years; however, only in the past 5 years have we come to understand this mechanism at the molecular level. A surge of recent experimentation indicates that STIM molecules function as Ca²⁺ sensors within the ER that, upon Ca²⁺ store depletion, rearrange to sites very near to the plasma membrane. At these plasma membrane-ER junctions, STIM interacts with and activates SOCE channels of the Orai family. The molecular and biophysical data that have led to these findings are discussed in this review, as are several controversies within this rapidly expanding field.