Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Adv Exp Med Biol. 2011;716:62-90. doi: 10.1007/978-1-4419-9533-9_5.
A calcium signal is essential for degranulation, generation of eicosanoids and optimal production of cytokines in mast cells in response to antigen and other stimulants. The signal is initiated by phospholipase C-mediated production of inositol1,4,5-trisphosphate resulting in release of stored Ca(2+) from the endoplasmic reticulum (ER) and Golgi. Depletion of these stores activates influx of extracellular Ca(2+), usually referred to as store-operated calcium entry (SOCE), through the interaction of the Ca(2+)-sensor, stromal interacting molecule-1 (STIM1 ), in ER with Orai1(CRACM1) and transient receptor potential canonical (TRPC) channel proteins in the plasma membrane (PM). This interaction is enabled by microtubular-directed reorganization of ER to form ER/PM contact points or "punctae" in which STIM1 and channel proteins colocalize. The ensuing influx of Ca(2+) replenishes Ca(2+) stores and sustains elevated levels of cytosolic Ca(2+) ions-the obligatory signal for mast-cell activation. In addition, the signal can acquire spatial and dynamic characteristics (e.g., calcium puffs, waves, oscillations) that encode signals for specific functional outputs. This is achieved by coordinated regulation of Ca(2+) fluxes through ATP-dependent Ca(2+)-pumps and ion exchangers in mitochondria, ER and PM. As discussed in this chapter, studies in mast cells revealed much about the mechanisms described above but little about allergic and autoimmune diseases although studies in other types of cells have exposed genetic defects that lead to aberrant calcium signaling in immune diseases. Pharmacologic agents that inhibit or activate the regulatory components of calcium signaling in mast cells are also discussed along with the prospects for development of novel SOCE inhibitors that may prove beneficial in the treatment inflammatory mast-cell related diseases.
钙信号对于肥大细胞脱颗粒、类花生酸生成和细胞因子的最佳产生是必需的，这些反应是对抗原和其他刺激物的应答。该信号由磷脂酶 C 介导的肌醇 1,4,5-三磷酸的产生起始，导致内质网（ER）和高尔基体中储存的 Ca(2+)释放。这些储存的耗竭激活了细胞外 Ca(2+)的流入，通常称为储存操作的钙进入（SOCE），通过 ER 中的 Ca(2+)传感器基质相互作用分子-1（STIM1）与质膜（PM）中的 Orai1（CRACM1）和瞬时受体电位经典（TRPC）通道蛋白的相互作用。这种相互作用是通过微管定向的 ER 重组形成 ER/PM 接触点或“点状结构”来实现的，在这些点状结构中，STIM1 和通道蛋白共定位。随后 Ca(2+)的流入补充了 Ca(2+)储存并维持了胞质 Ca(2+)离子的升高水平——这是肥大细胞激活的必需信号。此外，该信号可以获得空间和动态特征（例如，钙峰、波、振荡），这些特征编码特定功能输出的信号。这是通过在线粒体、ER 和 PM 中通过 ATP 依赖性 Ca(2+)泵和离子交换器来协调调节 Ca(2+)通量来实现的。正如本章所讨论的，在肥大细胞中的研究揭示了上述机制的许多信息，但对过敏和自身免疫性疾病的了解甚少，尽管在其他类型的细胞中的研究已经揭示了导致免疫疾病中异常钙信号的遗传缺陷。还讨论了抑制或激活肥大细胞中钙信号调节成分的药理学试剂，以及开发新型 SOCE 抑制剂的前景，这些抑制剂可能在治疗炎症性肥大细胞相关疾病方面具有有益作用。
