3,4-Dichloropropionanilide (DCPA) Inhibits T-Cell Activation by Altering the Intracellular Calcium Concentration following Store Depletion

Lewis, Tricia L.; Brundage, Kathleen M.; Brundage, Rodney Arthur; Barnett, John B.

doi:10.1093/toxsci/kfn031

Cited by 16 publications

(20 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously we showed that the haloanilide DCPA blocks store‐operated Ca 2+ channel function in Jurkat cells with no effect on ER Ca 2+ content (Lewis et al, 2008). DCPA also reduced SOCe in osteoclasts by 27.5% (n = 3; data not shown).…”

Section: Resultsmentioning

confidence: 98%

“…We further establish that DCPA‐mediated CRAC channel inhibition occurs via inhibition of STIM1–Orai1 interaction. DCPA is a haloanilide compound with relatively low systemic toxicity that can inhibit Ca 2+ influx in macrophages and T cells as well as having potent anti‐inflammatory activity (Xie et al, 1997; Ustyugova et al, 2007; Lewis et al, 2008). As such, our findings may have significant therapeutic implications.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The role of calcium release activated calcium channels in osteoclast differentiation

Zhou

Lewis

Robinson

et al. 2011

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

Osteoclasts are specialized macrophage derivatives that secrete acid and proteinases to mobilize bone for mineral homeostasis, growth, and replacement or repair. Osteoclast differentiation generally requires the monocyte growth factor m-CSF and the TNF-family cytokine RANKL, although differentiation is regulated by many other cytokines and by intracellular signals, including Ca2+. Studies of osteoclast differentiation in vitro were performed using human monocytic precursors stimulated with m-CSF and RANKL, revealing significant loss in both the expression and function of the required components of store-operated Ca2+ entry over the course of osteoclast differentiation. However, inhibition of CRAC using either the pharmacological agent 3,4 dichloropropioanilide (DCPA) or by knockdown of Orai1 severely inhibited formation of multinucleated osteoclasts. In contrast, no effect of CRAC channel inhibition was observed on expression of the osteoclast protein tartrate resistant acid phosphatase (TRAP). Our findings suggest that despite the fact that they are downregulated during osteoclast differentiation, CRAC channels are required for cell fusion, a late event in osteoclast differentiation. Since osteoclasts cannot function properly without multinucleation, selective CRAC inhibitors may have utility in management of hyperresorptive states.

show abstract

Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

The role of calcium release activated calcium channels in osteoclast differentiation

Zhou

Lewis

Robinson

et al. 2011

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…2007, 2008). Influx of Ca 2+ from the extracellular environment, following internal Ca 2+ store depletion, provides the elevated and sustained [Ca 2+ ] i levels, which is associated with the activation of the CRAC channels on the plasma membrane (Prakriya and Lewis 2001; Lewis et al. 2008).…”

Section: Discussionmentioning

confidence: 99%

CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death

Chen

et al. 2011

Journal of Neurochemistry

View full text Add to dashboard Cite

Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Recently we have shown that Cd elevates intracellular free calcium ion ([Ca2+]i) level, leading to neuronal apoptosis partly by activating mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin (mTOR) pathways. However, the underlying mechanism remains to be elucidated. Here we show that the effects of Cd elevated [Ca2+]i on MAPK and mTOR network as well as neuronal cell death are through stimulating phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). This is supported by the findings that chelating intracellular Ca2+ with BAPTA/AM or preventing Cd-induced [Ca2+]i elevation using 2-aminoethoxydiphenyl borate (2-APB) blocked Cd activation of CaMKII. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of MAPK/mTOR pathways and cell death. Furthermore, inhibitors of mTOR (rapamycin), JNK (SP600125) and Erk1/2 (U0126), but not of p38 (PD169316), prevented Cd-induced neuronal cell death in part through inhibition of [Ca2+]i elevation and CaMKII phosphorylation. The results indicate that Cd activates MAPK/mTOR network triggering neuronal cell death, by stimulating CaMKII. Our findings underscore a central role of CaMKII in the neurotoxicology of Cd, and suggest that manipulation of intracellular Ca2+ level or CaMKII activity may be exploited for prevention of Cd-induced neurodegenerative disorders.

show abstract

“…Therefore, extracellular Ca 2+ influx is essential [22]. The depletion of intracellular Ca 2+ stores activates STIM/Orai [21,23] and CRAC [11,24] channels, resulting in an influx that sustains the newly elevated Ca 2+ levels.…”

Section: Introductionmentioning

confidence: 99%

Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes

Peng

Wei

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Bitter-tasting chloroquine can suppress T cell activation by inhibiting Ca²⁺ signaling. However, the mechanism of inhibition remains largely unclear. Methods: In this study, CD4⁺ T cells were isolated from the thymus, and the calcium content of CD4⁺ thymocytes was measured using fura-2 AM and a TILL imaging system. Pyrazole-3 (Pyr3), thapsigargin (TG), and caffeine were used to assess the effects of chloroquine on the intracellular Ca²⁺ content of CD4⁺ T cells. Results: In murine CD4⁺ thymocytes, chloroquine decreased the TG-triggered intracellular Ca²⁺ increase in a dose-dependent manner. In the absence of chloroquine under Ca²⁺-free conditions (0 mM Ca²⁺ and 0.5 mM EGTA), TG induced a transient Ca²⁺ increase. After restoration of the extracellular Ca²⁺ concentration to 2 mM, a dramatic Ca²⁺ increase occurred. This elevation was completely blocked by chloroquine and was markedly inhibited by Pyr3, a selective antagonist of transient receptor potential C3 (TRPC3) channel and stromal interaction molecule (STIM)/Orai channel. Furthermore, the TG-induced transient Ca²⁺ increase under Ca²⁺-free conditions was eliminated in the presence of chloroquine. Chloroquine also blocked the dialyzed inositol-1,4,5-trisphosphate (IP₃)-induced intracellular Ca²⁺ increase. However, chloroquine was not able to decrease the caffeine-induced Ca²⁺ increase. Conclusion: These data indicate that chloroquine inhibits the elevation of intracellular Ca²⁺ in thymic CD4⁺ T cells by inhibiting IP₃ receptor-mediated Ca²⁺ release from intracellular stores and TRPC3 channel-mediated and/or STIM/Orai channel-mediated Ca²⁺ influx.

show abstract

3,4-Dichloropropionanilide (DCPA) Inhibits T-Cell Activation by Altering the Intracellular Calcium Concentration following Store Depletion

Cited by 16 publications

References 37 publications

The role of calcium release activated calcium channels in osteoclast differentiation

The role of calcium release activated calcium channels in osteoclast differentiation

CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death

Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes

Contact Info

Product

Resources

About