Evolutionary origins of STIM1 and STIM2 within ancient Ca2+ signaling systems

Human stromal interaction molecule (STIM) proteins are parts of elaborate eukaryotic Ca2+ signaling systems that include numerous plasma membrane (PM), endoplasmic reticulum (ER), and mitochondrial Ca2+ transporters, channels and regulators. STIM2 and STIM1 function as Ca2+ sensors with different sensitivities for ER Ca2+. They translocate to ER–PM junctions and open PM Orai Ca2+ influx channels when receptor-mediated Ca2+ release lowers ER Ca2+ levels. The resulting increase in cytosolic Ca2+ leads to the activation of numerous Ca2+ effector proteins that in turn regulate differentiation, cell contraction, secretion and other cell functions. In this review, we use an evolutionary perspective to survey molecular activation mechanisms in the Ca2+ signaling system, with a particular focus on regulatory motifs and functions of the two STIM proteins. We discuss the presence and absence of STIM genes in different species, the order of appearance of STIM versus Orai, and the evolutionary addition of new signaling domains to STIM proteins.