The discovery of stromal interaction molecules (STIM), STIM1 and STIM2, as signaling elements that govern Ca2+ entry by reversibly bridging the intermembrane gap between the cortical endoplasmic reticulum (ER) and plasma membrane (PM) has resulted in a considerable gain in knowledge of the molecular mechanisms underlying ER-PM junctional communication. Progress in understanding the structural basis of the Ca2+ entry pathway mediated by coupling of STIM1 to the PM Ca2+ channel Orai is paralleled by rapidly accumulating information on STIM-associated signaling events and on alternative (non-Orai) or auxiliary interaction partners of STIM (see Chapters 3 and 10). The highly divergent target molecules of STIMs reside within as well as outside of junctional ER structures and include cation channel effectors as well as junctional regulators and scaffolds. The signaling function of STIM embraces not only ER luminal Ca2+ sensing and the regulation of Ca2+ handling proteins but also dynamic architectural ER remodeling. Here we aim to provide an outline of the emerging picture of STIM proteins as multifunctional and highly versatile ER-resident molecular switches involved in cellular Ca2+ homeostasis and beyond.
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