STIMulating store-operated Ca(2+) entry

Abstract

Calcium influx through plasma membrane store-operated Ca(2+) (SOC) channels is triggered when the endoplasmic reticulum (ER) Ca(2+) store is depleted - a homeostatic Ca(2+) signalling mechanism that remained enigmatic for more than two decades. RNA-interference (RNAi) screening and molecular and cellular physiological analysis recently identified STIM1 as the mechanistic 'missing link' between the ER and the plasma membrane. STIM proteins sense the depletion of Ca(2+) from the ER, oligomerize, translocate to junctions adjacent to the plasma membrane, organize Orai or TRPC (transient receptor potential cation) channels into clusters and open these channels to bring about SOC entry.

Figure 1

Domains of STIM proteins. Drosophila and human STIM proteins are situated in the ER membrane. Modules of STIM1, STIM2 and Stim include: the signal peptide, the predicted EF-hand and SAM domains, the transmembrane region and two regions predicted to form coiled-coil structures comprising the ERM domain. Proline-rich domains (P) and the lysine-rich C-terminal regions are unique to the mammalian STIM family members. Drosophila Stim contains an N-terminal sequence in the ER that is not present in either STIM1 or STIM2. The N-linked glycosylation sites at the SAM domain, experimentally verified for STIM1 (refs 11, 85), are also indicated. Background colours represent basal Ca²⁺ concentrations of ~50 nM in the cytosol and > 400 µM in the ER lumen. Ca²⁺ ions are shown as red dots, including Ca²⁺ bound to the EF-hand domain.

Figure 2

STIM Ca²⁺ sensor, signal initiation and messenger functions. STIM molecules are shown in the basal state as dimers (left); the Ca²⁺ sensor EF-hand domain has bound Ca²⁺ (red dots) when the ER Ca²⁺ store is filled. Background colours represent basal Ca²⁺ concentrations of ~50 nM in the cytosol and > 400 µM in the ER lumen. ER Ca²⁺ store depletion causes Ca²⁺ to unbind from the low affinity EF-hand of STIM; this is the molecular switch that leads to STIM oligomerization and translocation (dashed arrows) to ER–plasma membrane junctions. Non-conducting Orai channel subunits are shown as dimers.

Figure 3

STIM-mediated organization of the elementary unit and activation of Orai channels. STIM accumulation induces Orai channels to cluster in the adjacent plasma membrane. The C-terminal effector domain of STIM induces Orai channels to open by direct binding of the distal coiled-coil domain, and Ca²⁺ enters the cell (red arrows). Two STIMs can activate a single CRAC channel consisting of an Orai tetramer; channel activation of Orai may involve a preliminary step of assembling Orai dimers into a functional tetramer. Background colours represent changes in cytosolic Ca²⁺ concentration (from that in the basal state as represented in Fig 2 and Fig 3) to > 1 µM due to Ca²⁺ entry, and ER luminal Ca²⁺ to < 300 µM.