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| Signalling: The ins and outs of Ca2+ signalling in mast cells
The ER Ca2+ sensor STIM1 (stromal interaction molecule 1) and the calcium-release-activated calcium (CRAC) channel component CRACM1 are required for mast-cell function, revealing a key role for store-operated Ca2+ influx in mediating allergic reactions. The influx of calcium ions (Ca2+) through calcium-release-activated calcium (CRAC) channels following the engagement of immunoreceptors on lymphocytes is widely recognized as being crucial for the proper functioning of these cells. Ca2+ influx is understood to be triggered by the depletion of Ca2+ stores in the endoplasmic reticulum (ER), a process that is referred to as store-operated Ca2+ (SOC) influx. Recently, two key regulators of Ca2+ influx have been identified – stromal interaction molecule 1 (STIM1), which is a sensor of ER Ca2+ stores that couples depletion of Ca2+ from ER stores with SOC influx, and ORAI1 (also known as CRACM1), which is a component of the CRAC channel. Now, two studies report for the first time on the role of these molecules in regulating mast-cell function.
Baba et al. generated Stim1-/- mice and found that the mice died perinatally but that day 18.5 embryos showed no obvious abnormalities and mast-cell differentiation was normal. Primary mast cells were generated from these embryos by culturing fetal liver cells in the presence of interleukin-3 (IL-3). These fetal liver derived mast cells were stimulated artificially (using thapsigargin to block the ER Ca2+ pump and EGTA to deplete Ca2+ stores) and physiologically (using IgE and cognate antigen to engage the high-affinity Fc receptor for IgE). In both cases, Ca2+ influx was impaired. The authors next looked at the requirement for STIM1 in mast-cell degranulation and cytokine production. Stim1-/- mast cells showed significant impairment in degranulation following antigen stimulation, as measured by the release of So, how does defective SOC influx lead to impaired mast-cell function? The authors looked at how STIM1 deficiency affects intracellular signalling events and found that the activation of both nuclear factor- In a second study, Vig and colleagues generated Cracm1-/- mice to address the role of CRAC channels in mast-cell function. As in the study by Baba and colleagues, the authors observed inhibition of degranulation (of both preformed and newly generated granules), significantly impaired secretion of some, but not all, of the key mast-cell cytokines, and defective allergic reactions in vivo in the absence of CRACM1. Humans with mutations in CRACM1 have a severe combined immunodeficiency disorder, indicating that CRACM1 is crucial for T-cell proliferation and cytokine secretion. However, one surprising aspect of the study by Vig et al. was the fact that CRACM1-deficient mice had normal thymi and showed normal T-cell development and proliferation but defective cytokine secretion. T cells from wild-type mice were found to express much higher levels of CRACM2 than CRACM1 or CRACM3, suggesting that CRACM2 rather than CRACM1 is a key component of CRAC channels in mouse T cells. Together these studies reveal a key role for SOC influx in mediating mast-cell function and allergic reactions. Elaine Bell References
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-hexosaminidase from preformed mast-cell granules. The secretion of the cytokines IL-6, tumour-necrosis factor (TNF) and IL-13 was also significantly impaired compared with that of wild-type mast cells.
B (NF-