  Plasma membrane calcium influx through ion channels is crucial for many
events in cellular physiology. Cell surface stimuli lead to the production of
inositol 1,4,5-trisphosphate (IP3), which binds to IP3 receptors in the
endoplasmic reticulum (ER) to release calcium pools from the ER lumen. This
leads to depletion of ER calcium pools which has been termed store-depletion.
Store-depletion leads the dissociation of calcium ions from the EF-hand motif
of the ER calcium sensor Stromal Interaction Molecule 1 (STIM1). This leads to
a conformational change in STIM1 which helps it to interact with a plasma
membrane (PM) at ER:PM junctions. At these ER:PM junctions, STIM1 binds to and
activates a calcium channel known as Orai1 to form calcium-release activated
calcium (CRAC) channels. Activation of Orai1 leads to calcium influx, known as
store-operated calcium entry (SOCE). In addition to Orai1 and STIM1, the
homologs of Orai1 and STIM1, such as Orai2/3 and STIM2 also play a crucial role
in calcium homeostasis. The influx of calcium through the Orai channel
activates a calcium current that has been termed CRAC currents. CRAC channels
form multimers and cluster together in large macromolecular assemblies termed
puncta. How these CRAC channels form puncta has been contentious since their
discovery. In this review, we will outline the history of SOCE, the molecular
players involved in this process (Orai and STIM proteins, TRP channels,
SOCE-associated regulatory factor etc.), as well as the models that have been
proposed to explain this important mechanism in cellular physiology.
