STIM is a Ca²⁺ sensor essential for Ca²⁺-store- depletion-triggered Ca²⁺ influx

Ca²⁺ signaling in nonexcitable cells is typically initiated by receptor-triggered production of inositol-1,4,5-trisphosphate and the release of Ca²⁺ from intracellular stores [1]. An elusive signaling process senses the Ca²⁺ store depletion and triggers the opening of plasma membrane Ca²⁺ channels [2-5]. The resulting sustained Ca²⁺ signals are required for many physiological responses, such as T cell activation and differentiation [6]. Here, we monitored receptor-triggered Ca²⁺ signals in cells transfected with siRNAs against 2,304 human signaling proteins, and we identified two proteins required for Ca ²⁺-store-depletion-mediated Ca²⁺ influx, STIM1 and STIM2 [7-9]. These proteins have a single transmembrane region with a putative Ca ²⁺ binding domain in the lumen of the endoplasmic reticulum. Ca ²⁺ store depletion led to a rapid translocation of STIM1 into puncta that accumulated near the plasma membrane. Introducing a point mutation in the STIM1 Ca²⁺ binding domain resulted in prelocalization of the protein in puncta, and this mutant failed to respond to store depletion. Our study suggests that STIM proteins function as Ca²⁺ store sensors in the signaling pathway connecting Ca²⁺ store depletion to Ca²⁺ influx.