STIM1 (red) in the ER approaches Orai1 (green) in the plasma membrane upon loss of ER Ca2+ stores (bottom).

An ER protein scoots around to a site next to the plasma membrane (PM) to trigger calcium signaling, as shown by Wu et al. (page 803) and Luik et al. (page 815).

Cytoplasmic Ca2+ signals often come in two waves—a burst from the ER followed by a longer influx of extracellular Ca2+ through the PM's Ca2+ release–activated Ca2+ (CRAC) channels. The influx is triggered by the depletion of ER Ca2+ stores, which is sensed by a transmembrane ER Ca2+ sensor called STIM1. The new results reveal how STIM1 conveys the Ca2+ drop all the way from the ER to the PM.

Wu et al. show that Ca2+ store depletion causes STIM1 to relocate to ER regions that are just 10-25 nm from the PM. STIM1 accumulates at these sites several seconds before CRAC channels open.

In the second report, Luik et al. show that store depletion causes a CRAC channel subunit called Orai1 to accumulate in the PM opposite STIM1 puncta. They also find that Ca2+ influx through CRAC channels is limited to a small percentage of the cell surface in the immediate vicinity of these STIM1-Orai1 units.

The localized Ca2+ entry may restrict downstream responses to those mediated by nearby Ca2+-sensitive proteins. All the membrane and protein movements involved offer plenty of regulatory opportunities to enhance or dampen channel opening.

With such little space between them, STIM1 might activate Orai1 through physical interactions, perhaps through their predicted facing coiled-coil domains, but activation by a diffusible factor is also possible. Physical contact between STIM1 and a PM protein might explain why Wu et al. found about 50% more ER–PM junctions after Ca2+ store depletion. The group is now trying to determine how STIM1 and Orai1 find each other at these ER–PM junctions.