Ca2+ Waves Initiate Antigen-Stimulated Ca2+ Responses in Mast Cells

Cohen, Roy; Torres, Alexis J.; Ma, Hongwen; Holowka, David; Baird, Barbara

doi:10.4049/jimmunol.0901615

Cited by 41 publications

(58 citation statements)

References 76 publications

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“…Our previous studies demonstrated that Ca 2+ responses to antigen in RBL mast cells usually initiate as waves that begin at the tips of extended cell protrusions (Cohen et al, 2009), and these results prompted us to investigate whether degranulation is influenced by Ca 2+ waves. To monitor Ca 2+ mobilization and degranulation simultaneously in the same cells, we used Fura Red as the Ca 2+ indicator in cells that were preloaded with FITC-dextran.…”

Section: Simultaneous Imaging Of Ca 2+ and Degranulation Responsesmentioning

confidence: 99%

“…7A, left side, only a small percentage of exocytotic events occurred along protrusions compared with the cell body at this high antigen dose, and the difference in total number of events for cells that initiate Ca 2+ responses as P-waves versus Bwaves was small. These cells were shown to initiate Ca 2+ waves from protrusions with a higher probability at low doses of antigen (Cohen et al, 2009), and we investigated whether a low dose of antigen (1.7 ng/ml) caused a higher probability of exocytosis along these extended protrusions than seen with a high dose of antigen. When this low dose of antigen was used to stimulate degranulation, the average number of exocytotic events per cell was less than at the high antigen dose, and this difference was particularly evident for cells with Ca 2+ waves that initiated in the cell body (Fig.…”

Section: Simultaneous Imaging Of Ca 2+ and Degranulation Responsesmentioning

confidence: 99%

“…We previously found that Ca 2+ entry through TRPC1 is important for Ca 2+ -dependent P-wave initiation, which is particularly manifest at low doses of antigen (Cohen et al, 2009). To determine whether TRPC1 contributes to antigen-stimulated degranulation in RBL cells, we compared the degranulation response of these cells in which TRPC1 is knocked down by expression of a vector containing a TRPC1-interfering small hairpin (sh) RNA sequence with one containing a control shRNA sequence.…”

Section: Trpc1 Knockdown Inhibits Antigen-stimulated Granule Exocytosismentioning

confidence: 99%

“…In particular, delineating the relationships between degranulation and Ca 2+ mobilization requires high spatial and temporal resolution of both cytoplasmic Ca 2+ changes and individual exocytotic events. We recently showed that antigenmediated crosslinking of IgE-FceRI initiates Ca 2+ responses in mast cells in the form of a fast Ca 2+ wave that usually begins in the tip of an extended protrusion, then moves down the length of the cell over a time period of several seconds (Cohen et al, 2009). At low doses of antigen, initiation of this wave depends on Ca 2+ influx by the canonical transient receptor potential channel TRPC1.…”

Section: Introductionmentioning

confidence: 99%

“…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). Very little is known about the physiological function of the extended protrusions in mast cells where Ca 2+ waves initiate.…”

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Cohen

Corwith

Holowka

et al. 2012

Journal of Cell Science

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SummaryMast cell activation initiated by antigen-mediated crosslinking of IgE receptors results in stimulated exocytosis of secretory lysosomes in the process known as degranulation. Much has been learned about the molecular mechanisms important for this process, including the crucial role of Ca 2+ mobilization, but spatio-temporal relationships between stimulated Ca 2+ mobilization and granule exocytosis are incompletely understood. Here we use a novel imaging-based method that uses fluorescein isothiocyanate (FITC)-dextran as a reporter for granule exocytosis in RBL mast cells and takes advantage of the pH sensitivity of FITC. We demonstrate the selectivity of FITCdextran, accumulated by fluid-phase uptake, as a marker for secretory lysosomes, and we characterize its capacity to delineate different exocytotic events, including full fusion, kiss-and-run transient fusion and compound exocytosis. Using this method, we find strong dependence of degranulation kinetics on the duration of cell to substrate attachment. We combine imaging of degranulation and Ca 2+ dynamics to demonstrate a spatial relationship between the sites of Ca 2+ wave initiation in extended cell protrusions and exocytosis under conditions of limited antigen stimulation. In addition, we find that the spatially proximal Ca 2+ signaling and secretory events correlate with participation of TRPC1 channels in Ca 2+ mobilization.

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Section: Simultaneous Imaging Of Ca 2+ and Degranulation Responsesmentioning

confidence: 99%

Section: Simultaneous Imaging Of Ca 2+ and Degranulation Responsesmentioning

confidence: 99%

Section: Trpc1 Knockdown Inhibits Antigen-stimulated Granule Exocytosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Cohen

Corwith

Holowka

et al. 2012

Journal of Cell Science

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Neuropeptide AF Induces Piecemeal Degranulation in Murine Mucosal Mast Cells: A New Mediator in Neuro‐Immune Communication in the Intestinal Lamina Propria?

Abdellah

Remoortel

Mohey-Elsaeed

et al. 2018

The Anatomical Record

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Neuropeptides AF (NPAF), FF (NPFF) and SF (NPSF) are RFamide neuropeptides known to be widely expressed in the mammalian central nervous system, where they fulfill a wide range of functions with pain modulation being the most prominent one. Recent evidence indicates that RFamides act as mediators in mast cell–sensory nerve communications related to allergic disease. Previous work by our group has shown that the expression levels of some members of the Mas‐related gene receptor (Mrgpr) family in both enteric neurons and mucosal mast cells change during intestinal inflammation. The Mrgpr subtypes C11 and A4 can be activated by NPAF, while A1 and C11 are triggered by NPFF. The aim of the present study was to investigate whether RFamides of the NPFF group are expressed in the gastrointestinal tract and to identify possible targets and receptors that might be involved in RFamide‐associated mast cell modulation. To this end, the expression and distribution patterns of NPFF/AF receptors and the NPFF precursor protein were determined in bone marrow‐derived mucosal mast cells (BMMCs) by immunocytochemistry and (RT‐) PCR. BMMCs were found to express MrgprA4 and A1, and functional analysis of the effects of NPAF by means of a β‐hexosaminidase assay, mMCP‐1 ELISA, electron microscopy and live cell calcium imaging revealed a piecemeal degranulation induced by NPAF. However, knock‐out of MrgprA4 and A1 did not reduce the effect of NPAF, indicating that the BMMC response to NPAF was receptor independent. ProNPFF was expressed in neurons and BMMCs, suggesting that both cell types are potential sources of NPAF in situ. Our results show that the RFamide NPAF can be considered as a novel modulator of BMMC activity in the neuro‐immune communication in the gastrointestinal tract, although the exact signaling pathway remains to be elucidated. Anat Rec, 00:000–000, 2018. © 2018 Wiley Periodicals, Inc. Anat Rec, 301:1103–1114, 2018. © 2018 Wiley Periodicals, Inc.

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Pathophysiological significance and modulation of the transient receptor potential canonical 3 ion channel

Boda,

Yasmen,

Jiang

et al. 2024

Medicinal Research Reviews

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Transient receptor potential canonical 3 (TRPC3) protein belongs to the TRP family of nonselective cation channels. Its activation occurs by signaling through a G protein‐coupled receptor (GPCR) and a phospholipase C‐dependent (PLC) pathway. Perturbations in the expression of TRPC3 are associated with a plethora of pathophysiological conditions responsible for disorders of the cardiovascular, immune, and central nervous systems. The recently solved cryo‐EM structure of TRPC3 provides detailed inputs about the underlying mechanistic aspects of the channel, which in turn enables more efficient ways of designing small‐molecule modulators. Pharmacologically targeting TRPC3 in animal models has demonstrated great efficacy in treating diseases including cancers, neurological disorders, and cardiovascular diseases. Despite extensive scientific evidence supporting some strong correlations between the expression and activity of TRPC3 and various pathophysiological conditions, therapeutic strategies based on its pharmacological modulations have not led to clinical trials. The development of small‐molecule TRPC3 modulators with high safety, sufficient brain penetration, and acceptable drug‐like profiles remains in progress. Determining the pathological mechanisms for TRPC3 involvement in human diseases and understanding the requirements for a drug‐like TRPC3 modulator will be valuable in advancing small‐molecule therapeutics to future clinical trials. In this review, we provide an overview of the origin and activation mechanism of TRPC3 channels, diseases associated with irregularities in their expression, and new development in small‐molecule modulators as potential therapeutic interventions for treating TRPC3 channelopathies.

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Ca2+ Waves Initiate Antigen-Stimulated Ca2+ Responses in Mast Cells

Cited by 41 publications

References 76 publications

Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Spatiotemporal Resolution of Mast Cell Granule Exocytosis

Neuropeptide AF Induces Piecemeal Degranulation in Murine Mucosal Mast Cells: A New Mediator in Neuro‐Immune Communication in the Intestinal Lamina Propria?

Pathophysiological significance and modulation of the transient receptor potential canonical 3 ion channel

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