Fundamental Ca2+ Signaling Mechanisms in Mouse Dendritic Cells: CRAC Is the Major Ca2+ Entry Pathway

Hsu, Shyue‐Fang; O’Connell, Peta J.; Klyachko, Vitaly A.; Badminton, Michael Norman; Thomson, Angus W.; Jackson, Meyer B.; Clapham, David E.; Ahern, Gerard P.

doi:10.4049/jimmunol.166.10.6126

Cited by 82 publications

(94 citation statements)

References 46 publications

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“…3C, n ϭ 16). The surface area of DCs measured from serial two-photon sections ranged from 1,800 to 2,400 m 2 , consistent with areas derived from membrane capacitance measurements on DCs in vitro (17). Typically, more than two-thirds of the total volume of a DC was deployed as dendrites, radiating on average 19 m (SE ϭ 0.58, n ϭ 161) and in some cases Ͼ60 m away from the soma of the cell.…”

Section: Resultsmentioning

confidence: 60%

T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node

Miller

Hejazi²,

Wei³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

382

428

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Dendritic cells (DCs) ingest antigens in peripheral tissues and migrate to lymph nodes where they present MHC class II-bound antigen to CD4 ؉ T cells. We used two-photon microscopy to image the single-cell dynamics of interactions between DCs and T cells within intact lymph nodes in the absence of relevant antigen. DCs were fluorescently labeled in vivo by cutaneous injection of alum adjuvant including carboxyfluorescein diacetate succinimidyl ester (CFSE). CFSE-positive DCs (CD11c ؉ , CD11b ؉ , and low-to-intermediate CD8 ؉ ) were observed in draining lymph nodes 24 -72 h later. Labeled DCs meandered slowly (2-3 m⅐min ؊1 ) in the T cell zone near B cell follicles but vigorously extended long agile dendrites. Encounters between T cells and DCs arose as T cells moved autonomously along random paths. Moreover, T cells did not accumulate around DCs, and their relative velocities approaching and departing DCs were equivalent, implying that T cells are not attracted toward DCs by chemotactic gradients but rather encounter them by chance. T cell͞DC contacts occurred primarily on dendrites at arm's length from the DC soma and typically lasted Ϸ3 min, enabling an individual DC to interact with up to 5,000 T cells per hour. We conclude that dynamic DC gesticulation and random T cell motility together enhance the stochastic scanning of the T cell repertoire, thereby enabling rapid initiation of the immune response.two-photon microscopy ͉ T lymphocyte

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Section: Resultsmentioning

confidence: 60%

T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node

Miller

Hejazi²,

Wei³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

382

428

View full text Add to dashboard Cite

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“…Contrary to Kupffer cells, DCs have been shown to possess Ca 2ϩ release-activated Ca 2ϩ channels (CRAC) as a main Ca 2ϩ entry pathway (12). Accordingly, Ca 2ϩ influx is enhanced by membrane hyperpolarization (12). The present study explores the mechanism of Ca 2ϩ entry into DCs.…”

Section: Endritic Cells (Dcs)mentioning

confidence: 97%

“…Kupffer cells contain L-type voltage-dependent Ca 2ϩ channels (11) and thus depolarization of the cell membrane is required for the Ca 2ϩ influx into these cells. Contrary to Kupffer cells, DCs have been shown to possess Ca 2ϩ release-activated Ca 2ϩ channels (CRAC) as a main Ca 2ϩ entry pathway (12). Accordingly, Ca 2ϩ influx is enhanced by membrane hyperpolarization (12).…”

Section: Endritic Cells (Dcs)mentioning

confidence: 99%

Ion Channels Modulating Mouse Dendritic Cell Functions

Matzner

Zemtsova

Xuân

et al. 2008

The Journal of Immunology

105

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Ca2+-mediated signal transduction pathways play a central regulatory role in dendritic cell (DC) responses to diverse Ags. However, the mechanisms leading to increased [Ca2+]i upon DC activation remained ill-defined. In the present study, LPS treatment (100 ng/ml) of mouse DCs resulted in a rapid increase in [Ca2+]i, which was due to Ca2+ release from intracellular stores and influx of extracellular Ca2+ across the cell membrane. In whole-cell voltage-clamp experiments, LPS-induced currents exhibited properties similar to the currents through the Ca2+ release-activated Ca2+ channels (CRAC). These currents were highly selective for Ca2+, exhibited a prominent inward rectification of the current-voltage relationship, and showed an anomalous mole fraction and a fast Ca2+-dependent inactivation. In addition, the LPS-induced increase of [Ca2+]i was sensitive to margatoxin and ICAGEN-4, both inhibitors of voltage-gated K+ (Kv) channels Kv1.3 and Kv1.5, respectively. MHC class II expression, CCL21-dependent migration, and TNF-α and IL-6 production decreased, whereas phagocytic capacity increased in LPS-stimulated DCs in the presence of both Kv channel inhibitors as well as the ICRAC inhibitor SKF-96365. Taken together, our results demonstrate that Ca2+ influx in LPS-stimulated DCs occurs via Ca2+ release-activated Ca2+ channels, is sensitive to Kv channel activity, and is in turn critically important for DC maturation and functions.

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“…(66,67) Conversely, agents that mobilize free cytosolic Ca 2þ can promote DC maturation in the absence of typical maturation-inducing cytokines or stimuli. (66,68,69) Stimuli that raise free cytosolic Ca 2þ trigger the secretion of cytokines and inflammatory molecules. (70)(71)(72) An increase in free cytosolic Ca 2þ is also essential for the uptake and processing of apoptotic bodies.…”

Section: Dendritic Cell (Dc) Functionmentioning

confidence: 99%

The IRBIT domain adds new functions to the AHCY family

2008

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SummaryDuring the past few years, the IRBIT domain has emerged as an important add-on of S-adenosyl-L-homocystein hydrolase (AHCY), thereby creating the new family of AHCY-like proteins. In this review, we discuss the currently available data on this new family of proteins. We describe the IRBIT domain as a unique part of these proteins and give an overview of its regulation via (de)phosphorylation and proteolysis. The second part of this review is focused on the potential functions of the AHCY-like proteins. We propose that the IRBIT domain serves as an anchor for targeting AHCY-like proteins towards cytoplasmic targets. This leads to regulation of (i) The AHCY family AHCY S-adenosyl-L-homocystein (SAH) hydrolase (AHCY) is a ubiquitous, tetrameric enzyme that catalyzes the reversible hydrolysis of SAH to adenosine and L-homocysteine. SAH is formed as a by-product of S-adenosyl-L-methionine (SAM) through transmethylation reactions. The hydrolysis of SAH is required to maintain low cellular concentrations of SAH, which is a product inhibitor of S-adenosyl-L-methionine (SAM)-dependent transmethylation reactions.(1-4) Inhibition of AHCY results in the intracellular accumulation of SAH, causing a significant increase in the intracellular SAH/SAM ratio and the subsequent inhibition of SAM-dependent methylations.( 5 -8) SAM is the major methyl donor for delivery of methyl groups to DNA, RNA, proteins and cellular metabolites in eukaryotes and SAH hydrolysis is the only source of homocysteine in mammals.(9) AHCY has become an attractive target for design of broad-spectrum antiviral agents because of the inhibitory effects of elevated intracellular SAH concentrations on viral mRNA cap-methylating enzymes. (10,11) In addition to these antiviral effects, AHCY inhibitors have also been attributed antiparasitic, (12,13) anti-arthritic (14) and immunosuppressive (15) effects.The importance of AHCY for mammalian survival is suggested by the fact that a chromosomal deletion that includes the gene encoding AHCY causes embryonic lethality in mice.(16) Elevated homocysteine levels have been reported as a risk factor for dementia and Alzheimer's disease, (17) and as a possible risk marker for vascular disease. (18,19) Human AHCY deficiency, such as in hypermethionemia, results in severe biochemical abnormalities, including plasma elevations of 150-fold in SAH, 30-fold in SAM and 12-fold in methionine. (20,21) So far, three mutations in the AHCY gene have been found to reduce the activity of the AHCY enzyme, resulting in the signs and symptoms of hypermethionemia. (22,23) AHCY orthologues have been identified in many species, including bacteria, nematodes, yeast, plants, insects and vertebrates. In contrast, the AHCY-like (AHCYL) family members AHCYL1 (also termed IRBIT, the inositol 1,4, 5-trisphosphate (IP 3 ) receptor (IP 3 R) binding protein released by IP 3 ) and AHCYL2 (KIAA0828 in human) are only predicted in segmented multicellular organisms, like vertebrates (eg Takifugu rubripes (fugu fish), Danio rerio (zebrafish), Xen...

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Fundamental Ca2+ Signaling Mechanisms in Mouse Dendritic Cells: CRAC Is the Major Ca2+ Entry Pathway

Cited by 82 publications

References 46 publications

T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node

T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node

Ion Channels Modulating Mouse Dendritic Cell Functions

The IRBIT domain adds new functions to the AHCY family

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