STIM Is a Ca2+ Sensor Essential for Ca2+-Store-Depletion-Triggered Ca2+ Influx

Abstract

Ca(2+) signaling in nonexcitable cells is typically initiated by receptor-triggered production of inositol-1,4,5-trisphosphate and the release of Ca(2+) from intracellular stores. An elusive signaling process senses the Ca(2+) store depletion and triggers the opening of plasma membrane Ca(2+) channels. The resulting sustained Ca(2+) signals are required for many physiological responses, such as T cell activation and differentiation. Here, we monitored receptor-triggered Ca(2+) signals in cells transfected with siRNAs against 2,304 human signaling proteins, and we identified two proteins required for Ca(2+)-store-depletion-mediated Ca(2+) influx, STIM1 and STIM2. 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 Ca(2+) 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 Ca(2+) store sensors in the signaling pathway connecting Ca(2+) store depletion to Ca(2+) influx.

Attenuated mesangial cell proliferation related to store-operated Ca2+ entry in aged rat: the role of STIM 1 and Orai 1

“…STIM 1 and Orai 1 puncta formation directly correlates to SOCE activity (Liou et al 2005). Similar to the glomerulus, immunofluorescence images also indicate that the expression level of STIM 1 and Orai 1 decreased in aged rat GMCs (Fig.…”

“…The N-terminus of STIM 1 is located in the lumen of the endoplasmic reticulum (ER) and functions as a Ca 2+ sensor. The C-terminus of STIM 1 is located in the cytosol and activates SOCE upon store depletion by interacting with the plasma membrane Orai 1 Liou et al 2005;Roos et al 2005). Knockdown of STIM 1 expression using specific small interfering RNA (siRNA) significantly reduced SOCE in a number of cell types, whereas STIM 1 overexpression modestly enhanced SOCE (Feske et al 2006;Roos et al 2005;Williams et al 2002;Liou et al 2005).…”

Thapsigargin activates Ca2+ entry both by store-dependent, STIM1/Orai1-mediated, and store-independent, TRPC3/PLC/PKC-mediated pathways in human endothelial cells

“…More recently, two major SOCE components have been identified: the Stromal Interacting Molecule 1 (STIM1) [20][21][22] predominantly located in the ER membrane and that senses the luminal Ca 2+ concentration, and the Ca 2+ channel Orai1 (also known as CRACM; [23][24][25]). Upon Ca 2+ store depletion, STIM1 oligomerizes, translocates close to the plasma membrane and aggregates into punctate structures [2,21,26].…”

“…Upon Ca 2+ store depletion, STIM1 oligomerizes, translocates close to the plasma membrane and aggregates into punctate structures [2,21,26]. The interaction between STIM1 and Orai1 leads to channel opening and Ca 2+ entry [23,25,27].…”

Calcium dependence of T cell proliferation following focal stimulation

“…A similar conclusion was independently reached by others [15][16][17][18], who in addition showed that ORAI1 increased CRAC currents if expressed with the CRAC activator STIM1. STIM1 has been previously shown to mediate CRAC activation after Ca 2+ store depletion [19][20][21][22].…”