Regulators of Ca2+ Signaling in Mast Cells: Potential Targets for Treatment of Mast Cell-Related Diseases?

Abstract

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.

Inhibitory effect of a new orally active cedrol-loaded nanostructured lipid carrier on compound 48/80-induced mast cell degranulation and anaphylactic shock in mice

“…87 As calcium movement across the membrane of mast cell is associated with stimulation and secretion of mediator, its immobilization is the target for a drug to be called as effective antiallergic drugs. 68 Data presented in this paper show that cedrol and CR-NLC pretreatment greatly affected compound 48/80-induced mast cell degranulation and histamine release from the mice peritoneal mast cells. A close correlation between the concentration of the histamine, β-hexosaminidase-releasing stimulus, calcium ion influx, and the amount of released histamine, β-hexosaminidase suggest a cause-and-effect relationship between the influx of Ca 2+ and the release of both histamine and β-hexosaminidase (Tables 5 and 6; Figures 7 and 8).…”

“…67 As a result of it, calcium movement across the membrane increases leading to rising in intracellular Ca 2+ level in mast cell. 68,69 The fact that the Ca 2+ chelator ethylenediaminetetraacetic acid abolishes the Ca 2+ mobilization and mast cell degranulation that follow FcεR1 cross-linking proves intracellular Ca 2+ concentration to be a potential target of regulation. [70][71][72] This report presents the first study of the effects of the natural sesquiterpene cedrol and its nanoformulation CR-NLC on the compound 48/80-induced mast cell degranulation inhibition in vitro as well as early-phase type I hypersensitivity studies in vivo.…”

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

“…2C). As with thapsigargin, IgE-mediated calcium influx is dependent upon store-operated calcium entry (27). Therefore, FceRIβ exon skipping appears to selectively target IgE-dependent activation without disrupting cell responses to other stimuli.…”

Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections

“…Consequently, inhibition of calcium binding by a phenothiazine inhibits calcium signalling processes and therefore the processes of post-phagocytosis should be affected. Calcium signalling pathways of eukaryotic cells are affected by inhibitors of calcium transport [41][42][43][44][45][46][47][48][49]. As would be expected, phenothiazines are potent inhibitors of calcium transport [50].…”