Orai and STIM are the basic components of a highly complex and regulated mechanism for Ca2+ entry into the cell, known as store-operated calcium entry (SOCE). The activation of plasma membrane G-protein-coupled receptors associated with the phospholipase C cascade results in the rapid and massive production of inositol 1,4,5-triphosphate (IP3). This second messenger triggers the massive efflux of Ca2+ from the endoplasmic reticulum and into the cytosol, resulting in the oligomerization of the stromal interacting molecule (STIM1), a sensor of ER Ca2+. STIM1 oligomers (the so-called puncta) activate Orai channels at the plasma membrane, triggering the influx of Ca2+ into the cytosol. Several microscopy techniques have been implemented to study SOCE, resulting in stunning images of protein complexes assembling in real time. However, little attention has been paid to the findings about this complex mechanism from the imaging point of view, some of which appear to produce contradictory results. In the present review we gathered all the information about SOCE obtained with imaging techniques and contrast these findings with those obtained with alternative methods. 1. Introduction Calcium (Ca2+) is a key and ubiquitous second messenger, controlling a wide variety of cellular functions from cell proliferation to apoptosis [1]. Hence, Ca2+ signaling has to be highly regulated both in time and space [2]. To accomplish this task, cells rely on numerous pumps and channels, comprising the machinery to generate and regulate spatial-temporal Ca2+ signals [3]. There are two principal Ca2+ sources in the cell: (i) the extracellular medium and (ii) the intracellular stores, most notably the endoplasmic reticulum (ER), which plays a central role in Ca2+ homeostasis, not only as the major intracellular store, but also as the controller of the cytosolic entry of Ca2+ across the plasma membrane (PM). The modulation of calcium entry from the ER begins when phospholipase C (PLC) is activated by G-protein-coupled receptors on the cell surface, leading to the generation of the second messenger inositol 1,4,5-trisphosphate (IP3), which releases Ca2+ from the ER after binding the IP3 receptor (IP3R) located at the ER membrane [4, 5]. IP3R activation results in the massive efflux of Ca2+ from the ER and into the cytosol. This decrease of ER-Ca2+ content triggers the influx of extracellular Ca2+ via plasma membrane Ca2+ channels in a process known as store operated calcium entry (SOCE) [4]. The importance of SOCE in the immune system has been well established, where it plays a
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