Origin, metabolism and function of extracellular adenine nucleotides in the blood

Lüthje, Jürgen

doi:10.1007/bf01741386

Cited by 98 publications

(78 citation statements)

References 119 publications

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“…Such pathways include exocytosis of ATP/UTP-containing vesicles, facilitated diffusion via connexin-43 hemichannels, by putative ABC transporters or potentially by poorly understood electrodiffusional movements through ATP/nucleotide channels (2,(15)(16)(17)(18)(19)(20)(21). Under pathophysiological conditions, the release of nucleotides and the expression of purinergic receptors is increased markedly in injured or stressed cells (17).…”

Section: Nucleotide Releasementioning

confidence: 99%

“…In a model of total hepatic ischemia and reperfusion injury we have shown a significantly decreased survival associated with increased biochemical and structural liver injury in Cd39-null animals as compared to wildtype controls (163). Furthermore, ADP is a major platelet recruiting factor originating from platelet dense granules during activation (17,36,37). ATP also stimulates endothelial cell production of prostacyclin (PGI2) and NO; two vasodilators and inhibitors of platelet aggregation (39,40).…”

Section: Liver Diseasementioning

confidence: 99%

“…ATP and ADP appear to regulate hemostasis through the activation of platelet P2 receptors. ADP is a major platelet recruiting factor originating from platelet dense granules, released upon activation whereas ATP derived from the same sources is considered a competitive antagonist of ADP for platelet P2Y1 receptors (17,36,37). Platelet P2Y12 is perhaps the best known purinergic receptor and several drugs (thienopyridine agents e.g.…”

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confidence: 99%

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The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/ CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2-expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2010 June 25. Published in final edited form as:Front Biosci. ; 13: 2588-2603. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver. KeywordsTransplantation; Liver; Purinergic Receptors; Bile; CD39; ecto-ATPase; Endothelium; Immunology; Metabolism; NTPDase; Platelet; Vasculature; Review INTRODUCTIONPurinergic signaling comprises release of extracellular nucleotides, stimulation of purinergic receptors and the modulation of nucleotide levels by ectoenzymes. Over the past decade, many advances have been made in the study of purinergic receptors and the regulation of extracellular nucleotide concentrations (1). It is now generally accepted that extracellular nucleotides (e.g. ATP, UTP, ADP), and the derivative nucleosides (e.g. adenosine from ATP), are released in a regulated manner by cells to provide the primary components for purinergic responses (2). Specific nucleo...

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Section: Nucleotide Releasementioning

confidence: 99%

Section: Liver Diseasementioning

confidence: 99%

mentioning

confidence: 99%

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The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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“…Extracellular ATP does not cross the cell membrane, but rather mediates its biological actions through interaction with specific transmembrane proteins on the cell surface (1)(2)(3). Several proteins on the cell surface have been described that are capable of binding extracellular ATP and other nucleotides.…”

mentioning

confidence: 99%

Secretion of IL-2 and IFN-γ, But Not IL-4, by Antigen-Specific T Cells Requires Extracellular ATP

Langston

Gewirtz

et al. 2003

The Journal of Immunology

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Extracellular ATP and other nucleotides transmit signals to cells via surface-associated molecules whose binding sites face the extracellular milieu. Ecto-nucleoside triphosphate diphosphohydrolase is such an ATP-binding enzyme that is expressed by activated lymphocytes. We have previously shown that nonhydrolyzable ATP analogs block the lytic activity of NK cells and CD8+ T cells as well as their E-NTPDase activity. These results suggest that the hydrolysis of ATP may play a role in lymphocyte function. Here we report that E-NTPDase activity is up-regulated within 15 min of T cell stimulation and that reversible and irreversible enzyme inhibitors profoundly reduce secretion of IL-2 and IFN-γ, but not IL-4. TNF-α, IL-10, and IL-5 production showed intermediate sensitivity to these ATP analogs. Depletion of extracellular ATP also inhibited secretion of IFN-γ, but not IL-4, supporting the interpretation that extracellular ATP is required for secretion of some, but not all, cytokines. E-NTPDase antagonists reduced transcription of IL-2 mRNA and inhibited TCR-mediated intracellular calcium flux. These results suggest that extracellular ATP plays an essential role in the TCR-mediated signal transduction cascade for expression of certain cytokine genes.

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“…Regardless of the bulk concentrations of nucleosides present in the plasma, P receptor signaling of erythrocytes will also depend on the capacity of ectonucleotidases present at the surface of these cells. Regarding this, isolated human erythrocytes display significant hydrolysis rates of extracellular AMP and ADP, and very low ectoATPase activity (25). However, no studies were made on ectonucleotidases of specific erythrocyte subpopulations that would allow discriminating between mature anucleated cells and reticulocytes.…”

mentioning

confidence: 99%

A Volume Regulatory Response Can Be Triggered by Nucleosides in Human Erythrocytes, a Perfect Osmometer No Longer

Pafundo

Álvarez

Krumschnabel

et al. 2010

Journal of Biological Chemistry

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Human erythrocytes have been regarded as perfect osmometers, which swell or shrink as dictated by their osmotic environment. In contrast, in most other cells, swelling elicits a regulatory volume decrease (RVD) modulated by the activation of purinic and pyrimidinic receptors (P receptors). For human erythrocytes this modulation has not been tested, and we thus investigated whether P receptor activation can induce RVD in these cells. Further, because ectonucleotidases may scavenge ATP or ADP or act as a source for extracellular adenosine and therefore modulate P receptor activation and RVD, we also determined their activity in intact erythrocytes. We found relatively low ectoATPase but significant ectoADPase and ectoAMPase activities. When erythrocytes were exposed to hypotonic medium alone, they swelled as expected for an osmometric response and showed no RVD. Activation of P2 receptors by exogenous ATP or ADP did not trigger RVD, whereas P1 agonists adenosine and adenosine-5-N-ethylcarboxamide induced significant RVD. The effect of adenosine-5-N-ethylcarboxamide was dose-dependent (maximal RVD of 27%; apparent K 1 ⁄ 2 of 1.6 ؎ 1.7 M). The RVD induced by adenosine was blocked 80% with the non-selective P1 antagonist 8-(p-sulfophenyl theophylline) or the P1-A 2B inhibitor MRS1754, but not by inhibitors of P1 subtypes A 1 , A 2A , and A 3 . In addition, forskolin (an inducer of intracellular cAMP formation) could mimic the effect of adenosine, supporting the idea of P1-A 2B receptor activation. In conclusion, we report a novel P1-A 2B receptor-mediated RVD activation in mature human erythrocytes and thus indicate that these long held perfect osmometers are not so perfect after all.

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Origin, metabolism and function of extracellular adenine nucleotides in the blood

Cited by 98 publications

References 119 publications

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Secretion of IL-2 and IFN-γ, But Not IL-4, by Antigen-Specific T Cells Requires Extracellular ATP

A Volume Regulatory Response Can Be Triggered by Nucleosides in Human Erythrocytes, a Perfect Osmometer No Longer

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