One of the "Breakthroughs of the Year" noted in last year’s compendium at STKE was the discovery of the role of STIM proteins, particularly STIM1, in coupling stimulus-induced depletion of intracellular calcium stores to influx of extracellular calcium through the plasma membrane calcium channel Orai1. Brandman et al. have now capped off 2007 with a paper describing a key role of STIM2 in regulation of basal concentrations of calcium in the cytoplasm and endoplasmic reticulum (ER) in unstimulated cells. The authors used an siRNA screen to find proteins that regulated basal calcium concentrations in cultured human HeLa cells. They sensitized the cells to depletion of calcium regulatory proteins by exposing them to low or high concentrations of extracellular calcium for 24 hours. The protein that stood out as a positive regulator of basal calcium concentrations was STIM2. Automated low-magnification imaging of fluorescently tagged STIM2 showed that, like STIM1, the protein translocated to the plasma membrane when intracellular stores of calcium were depleted. However, STIM2 was sensitive to smaller changes in the concentration of calcium in the ER and seemed to be tuned to provide a linear response to small changes in basal concentrations of calcium, whereas STIM1 has a switchlike response to large changes in the concentration of calcium after receptor stimulation. Thus, the authors propose that STIM2 may help maintain a constant basal concentration of calcium in the cytoplasm and ER, thus avoiding accidental activation of calcium signaling pathways. STIM2 may also provide a way for weak receptor stimuli to allow persistent changes in calcium concentrations, with STIM1 operating primarily to handle strong receptor stimuli.
O. Brandman, J. Liou, W. S. Park, T. Meyer, STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131, 1327-1339 (2007). [PubMed]