Regulation of Calcium Signaling by STIM1 and ORAI1

STIM1 and ORAI1 proteins are regulators of intracellular Ca2+ mobilization. This Ca2+ mobilization is essential to shape Ca2+ signaling in eukaryotic cells. STIM1 is a transmembrane protein located at the endoplasmic reticulum, where it acts as an intraluminal Ca2+ sensor. The transient drop of intraluminal Ca2+ concentration triggers STIM1 activation, which relocates to plasma membrane-endoplasmic reticulum junctions to bind and activate ORAI1, a plasma membrane Ca2+ channel. Thus, the Ca2+ influx pathway mediated by STIM1/ORAI1 is termed store-operated Ca2+ entry (SOCE). STIM and ORAI proteins are also involved in non-SOCE Ca2+ influx pathways, as we discuss here. In this chapter, we review the current knowledge regarding the role of SOCE, STIM1, and ORAI1 in cell signaling, with special focus on the modulation of the activity of kinases, phosphatases, and transcription factors that are strongly influenced by the extracellular Ca2+ influx mediated by these regulators.