An approach to assay calcineurin activity and the inhibitory effect of zinc ion

Huang, Junyi; Zhang, Dongmei; Xing, Wei; Ma, Xuhui; Yin, Yi‐Chen; Wang, Qun; Li, Genxi

doi:10.1016/j.ab.2007.12.016

Cited by 21 publications

(15 citation statements)

References 14 publications

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“…Zn 2+ also promotes protein kinase C (PKC) signalling, likely by recruiting PKC to the plasma membrane. By contrast, Zn 2+ inhibits the activity of the phosphatase calcineurin, thus preventing nuclear translocation of the transcription factor NFAT 153, 154 . Furthermore, Zn 2+ inhibits the function of interleukin-1 receptor-associated kinase (IRAK) 4, thereby restraining signalling through the IL-1R and activation of NF-kB.…”

Section: Figurementioning

confidence: 99%

“…For instance, increases in [Zn 2+ ] i were reported to enhance activation of kinases such as Lck and PKC 152 , but to inhibit the phosphatase calcineurin (Fig. 5) 153, 154 . More recently, Zn 2+ influx was reported to mediate T cell activation by enhancing the phosphorylation of ZAP70 and decreasing the recruitment of the tyrosine phosphatase SHP1 to the TCR, thereby prolonging Ca 2+ influx 143 .…”

Section: Zinc Transportersmentioning

confidence: 99%

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Ion channels and transporters in lymphocyte function and immunity

2012

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Section: Figurementioning

confidence: 99%

Section: Zinc Transportersmentioning

confidence: 99%

Ion channels and transporters in lymphocyte function and immunity

2012

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“…Several novel CN inhibitors have been developed in recent years although the underlying molecular mechanisms of most of these compounds are yet to be elucidated in detail ,. Interestingly, a number of groups provided evidence that CN activity can be inhibited by extracellular oxidants, in particular H 2 O 2 .…”

Section: Introductionmentioning

confidence: 99%

Peroxo Compounds of Vanadium(V) and Niobium(V) as Potent Inhibitors of Calcineurin Activity towards RII‐Phosphopeptide

et al. 2017

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Calcineurin (CN) is a major calmodulin binding serine/threonine phosphatase which plays a crucial role in numerous mammalian signal transduction pathways. Calcineurin inhibitors represent a valuable tool for elucidating CN dependent cellular processes. The present work deals with the synthesis and comprehensive characterization of a new polymer anchored peroxo niobium complex, [Nb2(O2)6(carboxylate)2]‐PA (Nb2) [PA=poly(sodium acrylate)], and identification of a set comprising of neat homoleptic as well as polymer immobilized peroxo complexes of vanadium(V) and niobium(V) as potent CN inhibitors. The in‐vitro effect of the complexes on calmodulin mediated dephosphorylation activity of CN was investigated using a physiological substrate of calcineurin, RII‐phosphopeptide as well as a non‐protein substrate p‐nitrophenyl phosphate (p‐NPP). Enzyme kinetic analysis data revealed that the compounds inhibit function of CN via uncompetitive pathway with Ki values ranging between 1–3 μM, suggesting the formation of an enzyme‐inhibitor‐substrate complex during the course of inhibition.

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“…It has been shown that CREB is dephophorylated by CN in many cell types including pancreatic islet cells and neurons [10], suggesting that CREB might be dephosphorylated by CN in T cells as well. CN phosphatase activity is inhibited by zinc in vitro in a concentration-dependent manner [11,12]. Therefore, zinc may have a role in increased IFN-␥ expression through inhibition of CN during T cell activation.…”

Section: Introductionmentioning

confidence: 99%

Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-γ expression in activated human T cells

Aydemir

Liuzzi

McClellan

et al. 2009

Journal of Leukocyte Biology

195

243

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The zinc transporter ZIP8 is highly expressed in T cells derived from human subjects. T cell ZIP8 expression was markedly up-regulated upon in vitro activation. T cells collected from human subjects who had received oral zinc supplementation (15 mg/day) had higher expression of the activation marker IFN-gamma upon in vitro activation, indicating a potentiating effect of zinc on T cell activation. Similarly, in vitro zinc treatment of T cells along with activation resulted in increased IFN-gamma expression with a maximum effect at 3.1 microM. Knockdown of ZIP8 in T cells by siRNA decreased ZIP8 levels in nonactivated and activated cells and concomitantly reduced secretion of IFN-gamma and perforin, both signatures of activation. Overexpression of ZIP8 by transient transfection caused T cells to exhibit enhanced activation. Confocal microscopy established that ZIP8 is localized to the lysosome where ZIP8 abundance is increased upon activation. Loss of lysosomal labile zinc in response to activation was measured by flow cytometry using a zinc fluorophore. Zinc between 0.8 and 3.1 microM reduced CN phosphatase activity. CN was also inhibited by the CN inhibitor FK506 and ZIP8 overexpression. The results suggest that zinc at low concentrations, through inhibition of CN, sustains phosphorylation of the transcription factor CREB, yielding greater IFN-gamma expression in T cells. ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN-gamma regulation in T cells.

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An approach to assay calcineurin activity and the inhibitory effect of zinc ion

Cited by 21 publications

References 14 publications

Ion channels and transporters in lymphocyte function and immunity

Ion channels and transporters in lymphocyte function and immunity

Peroxo Compounds of Vanadium(V) and Niobium(V) as Potent Inhibitors of Calcineurin Activity towards RII‐Phosphopeptide

Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-γ expression in activated human T cells

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