STIM1 has a plasma membrane role in the activation of store-operated Ca²⁺ channels

Receptor-induced Ca²⁺ signals are key to the function of all cells and involve release of Ca²⁺ from endoplasmic reticulum (ER) stores, triggering Ca²⁺ entry through plasma membrane (PM) "store-operated channels" (SOCs). The identity of SOCs and their coupling to store depletion remain molecular and mechanistic mysteries. The single transmembrane-spanning Ca²⁺-binding protein, STIM1, is necessary in this coupling process and is proposed to function as an ER Ca ²⁺ sensor to provide the trigger for SOC activation. Here we reveal that, in addition to being an ER Ca²⁺ sensor, STIM1 functions within the PM to control operation of the Ca²⁺ entry channel itself. Increased expression levels of STIM1 correlate with a gain in function of Ca²⁺ release-activated Ca²⁺ (CRAC) channel activity. Point mutation of the N-terminal EF hand transforms the CRAC channel current (I _CRAC) into a constitutively active, Ca²⁺ store-independent mode. Mutants in the EF hand and cytoplasmic C terminus of STIM1 alter operational parameters of CRAC channels, including pharmacological profile and inactivation properties. Last, Ab externally applied to the STIM1 N-terminal EF hand blocks both I_CRAC in hematopoietic cells and SOC-mediated Ca²⁺ entry in HEK293 cells, revealing that STIM1 has an important functional presence within the PM. The results reveal that, in addition to being an ER Ca²⁺ sensor, STIM1 functions within the PM to exert control over the operation of SOCs. As a cell surface signaling protein, STIM1 represents a key pharmacological target to control fundamental Ca ²⁺-regulated processes including secretion, contraction, metabolism, cell division, and apoptosis.