Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses

Abstract

Mast cells have key functions as effectors of immunoglobulin E-mediated allergic inflammatory diseases. Allergen stimulation induces Ca2+ influx and elicits the secretion of inflammatory mediators from mast cells. Here we show that the Ca2+-binding endoplasmic reticulum protein STIM1 is critical to mast cell function. STIM1-deficient fetal liver-derived mast cells had impaired Ca2+ influx mediated by the high-affinity immunoglobulin E receptor FcepsilonRI and activation of the transcription factors NF-kappaB and NFAT. Mast cells lacking STIM1 also had much less degranulation and cytokine production after FcepsilonRI stimulation. In addition, alterations in STIM1 expression affected the sensitivity of immunoglobulin E-mediated immediate-phase anaphylactic responses in vivo. Thus, STIM1 is key in promoting the Ca2+ influx that is essential for FcepsilonRI-mediated mast cell activation and anaphylaxis.

Positive and Negative Regulation of High Affinity IgE Receptor Signaling by Src Homology Region 2 Domain-Containing Phosphatase 1

“…6B). This result is in strong contrast to the previous study (64) in which lack of STIM1 completely abrogates Ca 2ϩ influx following the treatment with TG or ionomycin, implying the relatively intact function of STIM1/Orai1 in me-derived BMMC. Because TG-induced Ca 2ϩ response is slightly decreased in me-BMMC (Fig.…”

“…However, the Ca 2ϩ response in Lyndeficient mast cells was impaired at early transient stage of the response and was almost intact at the later prolonged phase (48,50,51) with one exception in which Lyn deficiency caused a marked decrease in overall Ca 2ϩ response (49). It should be noted that Stim1-deficient mast cells showed severely impaired sustained Ca 2ϩ increase and degranulation (64). Consistent with these published evidences, me-BMMC had a decrease in later, sustained Ca 2ϩ response and degranulation when cells were stimulated with high dose of Ag (50 ng/ml) (Fig.…”

“…Once the ER Ca 2ϩ stores are depleted, STIM1 becomes redistributed into discrete spots under the plasma membrane and activates CRAC channels. The importance of STIM1 in mast cell function has been demonstrated that STIM1-deficient fetal liver-derived mast cells have impaired Fc RI-induced Ca 2ϩ influx, degranulation, and cytokine production (64). In addition, Orai1 colocalizes with STIM1 after store depletion and both proteins move in coordinated fashion to form closely apposed clusters in the ER and plasma membrane, thereby creating the elementary unit of store-operated Ca 2ϩ entry (65).…”

Thapsigargin activates Ca2+ entry both by store-dependent, STIM1/Orai1-mediated, and store-independent, TRPC3/PLC/PKC-mediated pathways in human endothelial cells

“…Interestingly, even though the silencing efficiency was of between 65 and 80% at the protein level, an important residual Ca 2+ entry persisted upon store depletion. Such a "partial" SOCE reduction was already observed, for instance in smooth muscle cells [52][53][54] or HEK cells [20], but in most cell types, the inhibition of SOCE upon STIM1 invalidation is very pronounced [3,39,55,56]. This finding prompted us to investigate the mechanism of the residual TG-induced Ca 2+ entry.…”

Mast cell activation: A complex interplay of positive and negative signaling pathways

“…IP 3 and DAG are second messengers that induce a series of complex modifications in the mast cell physiology. The binding of IP 3 to its receptor causes the "first wave" of calcium (Ca 2+ ) mobilization, which is the transient release of Ca 2+ from endoplasmic reticulum stores; this in turn induces a prolonged "second wave" of Ca 2+ through store-operated calcium entry (through the association of the proteins STIM-1 in the endoplasmic reticulum and Orai-1 on the plasma membrane [9]; Fig. 1A).…”