STIM1 Is a Calcium Sensor Specialized for Digital Signaling

Abstract

Summary When cells are activated by calcium-mobilizing agonists at low, physiological concentrations, the resulting calcium signals generally take the form of repetitive regenerative discharges of stored calcium, termed calcium oscillations [1]. These intracellular calcium oscillations have long fascinated biologists as representing a mode of digitized intracellular signaling. Recent work has highlighted the role of calcium influx as an essential component of calcium oscillations [2]. This influx occurs through a process known as store-operated calcium entry which is initiated by calcium sensor proteins in the endoplasmic reticulum, STIM1 and STIM2 [3]. STIM2 is activated by changes in endoplasmic reticulum calcium near the resting level, while a threshold of calcium depletion is required to activate STIM1 [4]. In this study, we show that, surprisingly, it is STIM1 and not STIM2 that is exclusively involved in calcium entry during calcium oscillations. The implication is that each oscillation produces a transient drop in endoplasmic reticulum calcium that is sufficient to transiently activate STIM1. This transient activation of STIM1 can be observed in some cells by total internal reflection fluorescence microscopy. This arrangement nicely provides a clearly defined and unambiguous signaling system, translating a digital calcium release signal into calcium influx that can signal to downstream effectors.

Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels

“…Although STIM2α was initially described as a SOCE inhibitor (Soboloff et al, 2006), this was later determined to be an artifact of overexpression (Parvez et al, 2008). STIM2α activates Orai channels less effectively than STIM1 (Bird et al, 2009;Wang et al, 2014); thus, in the presence of STIM1 and limiting amounts of Orai1, overexpressed STIM2α can reduce SOCE by competing with STIM1 for binding to Orai1 channels. When this competition is eliminated, e.g., by the simultaneous overexpression of Orai1, STIM2α robustly acti- vates SOCE (Fig.…”

“…When this competition is eliminated, e.g., by the simultaneous overexpression of Orai1, STIM2α robustly acti- vates SOCE (Fig. 2 E; Parvez et al, 2008;Bird et al, 2009). In contrast, STIM2β cannot effectively bind or activate Orai channels by itself, and it inhibits SOCE even when Orai1 is overexpressed, ruling out a simple competitive mechanism as an explanation for its inhibitory effect.…”

Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca 2+ oscillations and gene expression

“…Because of its lower affinity for ER Ca 2+ levels, STIM2 will be recruited preferentially after modest store depletion (14), but its impact will be countered by its lower intrinsic ability to open CRAC channels (11)(12)(13). More robust Ca 2+ release is required to lower store Ca 2+ content sufficiently for STIM1 to activate (26).…”

“…First, they differ in their respective abilities to activate Orai1. STIM2 activates Ca 2+ entry less well than STIM1, for similar levels of Orai1 expression (11). This divergence has been attributed to differences within the amino-terminal domain of the STIM proteins (12) as well as inhibition of STIM2-Orai1 coupling by cytoplasmic calmodulin (13).…”

“…STIM2 has therefore been proposed both to fulfill a housekeeping role, ensuring that the stores are topped up with calcium in the absence of stimulation, and to activate Ca 2+ entry through Orai1 after moderate store depletion (14). By contrast, STIM1 requires a substantial fall in stored Ca 2+ for activation and is thought to gate CRAC channels after strong stimulation (11).…”