STIM2

STIM2 (stromal interaction molecule 2) is a transmembrane protein located in the membrane of the endoplasmic reticulum (ER) that functions as a sensor of ER luminal calcium and a key component of store-operated calcium entry (SOCE). It is closely related to STIM1, and both participate in activating plasma membrane calcium channels such as Orai proteins to refill ER stores with Ca2+.

Structure and sensing: STIM2 contains an EF-hand calcium-binding domain in the ER lumen that binds Ca2+ when stores are full. In response to ER Ca2+ depletion, Ca2+ dissociates from the EF-hand, triggering a conformational change and oligomerization. STIM2 then relocates to ER-plasma membrane junctions, where it engages and gates Orai channels to allow Ca2+ influx.

Activation properties: Compared with STIM1, STIM2 has a higher affinity for Ca2+ and tends to respond to smaller decreases in ER Ca2+. It generally mediates slower or more sustained Ca2+ entry and contributes to maintaining basal cytosolic Ca2+ levels and long-term Ca2+ signaling rather than rapid spikes.

Interactions and function: STIM2 can gate Orai1, Orai2, and Orai3 channels at ER-PM contact sites and interacts with regulatory proteins that fine-tune SOCE. In various cell types, STIM2 works together with STIM1 to shape overall Ca2+ signaling and homeostasis, influencing processes such as gene expression, secretion, muscle contraction, and synaptic function.

Clinical relevance: Altered STIM2 expression or function has been investigated in the context of immune cell signaling and neurobiology; however, precise roles and disease associations require further study. See also STIM1 and Orai proteins for related components of SOCE.