Regulation of Ca2+ Signaling with Particular Focus on Mast Cells

Abstract

Calcium signals mediate diverse cellular functions in immunological cells. Early studies with mast cells, then a preeminent model for studying Ca 2+ -dependent exocytosis, revealed several basic features of calcium signaling in non-electrically excitable cells. Subsequent studies in these and other cells further defined the basic processes such as inositol 1,4,5-trisphosphate-mediated release of Ca 2+ from Ca 2+ stores in the endoplasmic reticulum (ER); coupling of ER store depletion to influx of external Ca 2+ through a calcium-release activated calcium (CRAC) channel now attributed to the interaction of the ER Ca 2+ sensor, stromal interacting molecule-1 (STIM1), with a unique Ca 2+ -channel protein, Orai1/CRACM1, and subsequent uptake of excess Ca 2+ into ER and mitochondria through ATP-dependent Ca 2+ pumps. In addition, transient receptor potential channels and ion exchangers also contribute to the generation of calcium signals that may be global or have dynamic (e.g., waves and oscillations) and spatial resolution for specific functional readouts. This review discusses past and recent developments in this field of research, the pharmacologic agents that have assisted in these endeavors, and the mast cell as an exemplar for sorting out how calcium signals may regulate multiple outputs in a single cell.

Aryl hydrocarbon receptor controls murine mast cell homeostasis

“…29,30 Further, mitochondrial calcium uptake is required for STIM1-Orai1-dependent store-operated calcium influx. [25][26][27][28] In this study, the levels of STIM1 and Orai1 were similar in AhR-WT and AhR-null mast cells (supplemental Figure 12). It is thus likely that the reduction in mitochondrial membrane potential noted in AKO mast cells may influence its calcium uptake and subsequent activation of calcium entry.…”

“…Since store-operated Ca 21 entry depends on mitochondrial Ca 21 uptake and increased mitochondrial depolarization suppresses storeoperated Ca 21 influx, [25][26][27][28] mitochondrial membrane potentials were analyzed by the use of a dual-wavelength fluorescent probe, JC-1, which as a monomer emits green fluorescence and in a reaction driven by the mitochondrial membrane potential converts to a red-fluorescence-emitting dimer. As seen in Figure 6A-B, the ratio of red/green JC-1 fluorescence was significantly lower in AKO mast cells relative to the WT cells, suggesting functional mitochondrial alterations.…”

Btk-dependent Rac activation and actin rearrangement following FcεRI aggregation promotes enhanced chemotactic responses of mast cells

“…In several cell types, increased cytosolic Ca 2+ levels and cytoskeletal reorganization associated with actin polymerization and depolymerization are crucial events for cell migration (Allen et al, 2009;Jung et al, 2009;Shimizu et al, 2009). The antigen-and PGE 2 -induced Ca 2+ signal in mast cells is initially dependent on the activation of PLC and PLC, respectively, with resulting generation of Ins(1,4,5)P 3 , which liberates Ca 2+ from intracellular stores (Kuehn et al, 2008a;Ma and Beaven, 2009). PLC activation, Ins(1,4,5)P 3 generation and the resulting Ca 2+ signal were substantially enhanced in BMMCs when stimulated concurrently with antigen and PGE 2 (Kuehn et al, 2008a) (Fig.…”

Spatiotemporal Resolution of Mast Cell Granule Exocytosis

“…In this process, stimulated tyrosine phosphorylation of FceRI leads to inositol 1,4,5-trisphosphate (IP 3 ) production by phospholipase Cc (PLCc), which causes Ca 2+ depletion from endoplasmic reticulum stores to induce storeoperated Ca 2+ entry (SOCE) (Di Capite and Parekh, 2009). Activation of SOCE elicits oscillatory cytosolic Ca 2+ elevations that, together with activated protein kinase C, trigger granule exocytosis (Kim et al, 1997;Ma and Beaven, 2009).…”

“…At low doses of antigen, initiation of this wave depends on Ca 2+ influx by the canonical transient receptor potential channel TRPC1. The initiating waves are typically followed by periodic Ca 2+ oscillations that depend on Ca 2+ influx through SOCE (Ma and Beaven, 2009;Vig et al, 2008). These oscillations encode temporal information relevant to degranulation events (Kim et al, 1997), but they do not manifest the spatial localization displayed by wave propagation (Cohen et al, 2009).…”