Nucleoside transporters in the purinome

Santos-Rodrigues, Alexandre dos; Grañé-Boladeras, Natàlia; Bicket, Alex; Coe, Imogen R.

doi:10.1016/j.neuint.2014.03.014

Cited by 34 publications

(30 citation statements)

References 124 publications

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“…Intracellular ADO is produced either by the hydrolysis of S-adenosyl homocysteine (de novo synthesis) or via hydrolysis of 3´5´-cAMP by phosphodiesterases (PDEs). There are three ways of reducing levels of intracellular ADO: it can be transported and released into the extracellular space, as indicated above, by bidirectional nucleoside transporters, which depend on the concentration gradient between intra-and extracellular space [20]; it can be phosphorylated to AMP by ADO kinase, a salvage enzyme, which is oxygen dependent and, therefore, can be inhibited in the hypoxic environment [21] and it can be deaminated by adenosine deaminase (ADA) to inosine [22]. Thus, the intracellular concentration of ADO is strictly regulated and maintained at physiologically acceptable levels by a tight enzymatic control (FIGURE 1).…”

Section: Abstract: 5´-adenosine Monophosphate • Adenosine • Adenosinementioning

confidence: 99%

Immunoregulatory activity of adenosine and its role in human cancer progression

Muller-Haegele

Müller

Whiteside

2014

Expert Review of Clinical Immunology

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The adenosinergic pathway plays an important role in cancer progression. Aside from regulating functions of tumor cells and tissue cells present in the tumor microenvironment, extracellular adenosine is an autocrine or paracrine factor with powerful immunoregulatory activity. Adenosine signaling downregulates functions of most immune effector cells but enhances expansion and activity of immune cells responsible for suppression of anti-tumor immune responses. Adenosine is critical for limiting potential tissue-destructive effects of activated immune cells. It also facilitates tumor escape from the immune control. This review illustrates the involvement of adenosine and its four receptors, A1R, A2AR, A2BR and A3R, in the complex regulation of cellular and molecular cross talk that contributes to cancer progression. It also considers the potential of therapeutics targeting the adenosinergic pathway for benefiting cancer patients.

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Section: Abstract: 5´-adenosine Monophosphate • Adenosine • Adenosinementioning

confidence: 99%

Immunoregulatory activity of adenosine and its role in human cancer progression

Muller-Haegele

Müller

Whiteside

2014

Expert Review of Clinical Immunology

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“…The purinergic elements consist of ecto-nucleotide-metabolizing enzymes hydrolyzing nucleoside phosphates, purinergic receptors classified as P1 for adenosine and P2 for nucleoside tri-/diphosphates, nucleoside transporters, and finally, adenosine deaminase, which converts adenosine to inactive inosine. These purinergic elements have tightly concerted actions under physiological conditions and trigger, maintain and terminate purinergic signaling [16–24]. …”

Section: Introductionmentioning

confidence: 99%

The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain

et al. 2017

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Microglial cells invade the brain as amoeboid precursors and acquire a highly ramified morphology in the postnatal brain. Microglia express all essential purinergic elements such as receptors, nucleoside transporters and ecto-enzymes, including CD39 (NTPDase1) and CD73 (5'-nucleotidase), which sequentially degrade extracellular ATP to adenosine. Here, we show that constitutive deletion of CD39 and CD73 or both caused an inhibition of the microglia ramified phenotype in the brain with a reduction in the length of processes, branching frequency and number of intersections with Sholl spheres. In vitro, unlike wild-type microglia, cd39-/- and cd73-/- microglial cells were less complex and did not respond to ATP with the transformation into a more ramified phenotype. In acute brain slices, wild-type microglia retracted approximately 50% of their processes within 15 min after slicing of the brain, and this phenomenon was augmented in cd39-/- mice; moreover, the elongation of microglial processes towards the source of ATP or towards a laser lesion was observed only in wild-type but not in cd39-/- microglia. An elevation of extracellular adenosine 1) by the inhibition of adenosine transport with dipyridamole, 2) by application of exogenous adenosine or 3) by degradation of endogenous ATP/ADP with apyrase enhanced spontaneous and ATP-induced ramification of cd39-/- microglia in acute brain slices and facilitated the transformation of cd39-/- and cd73-/- microglia into a ramified process-bearing phenotype in vitro. These data indicate that under normal physiological conditions, CD39 and CD73 nucleotidases together with equilibrative nucleoside transporter 1 (ENT1) control the fate of extracellular adenosine and thereby the ramification of microglial processes.

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“…ENT substrates include nucleosides and nucleobases, such as adenosine and hypoxanthine (Hx), as well as nucleoside-derived drugs, used in a variety of anti-cancer, -viral, and -parasite therapies. A total of 4 members of the ENT family have been identified in mammals to date (ENT1-ENT4) although ENT1 and ENT2 are the major contributors to nucleoside transport across the plasma membrane in many tissues (2,3).…”

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confidence: 99%

Oligomerization of equilibrative nucleoside transporters: a novel regulatory and functional mechanism involving PKC and PP1

et al. 2018

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Equilibrative nucleoside transporters (ENTs) translocate nucleosides and nucleobases across plasma membranes, as well as a variety of anti‐cancer, ‐viral, and ‐parasite nucleoside analogs. They are also key members of the purinome complex and regulate the protective and anti‐inflammatory effects of adenosine. Despite their important role, little is known about the mechanisms involved in their regulation. We conducted membrane yeast 2‐hybrid and coimmunoprecipitation studies and identified, for the first time to our knowledge, the existence of protein‐protein interactions between human ENT1 and ENT2 (hENT1 and hENT2) proteins in human cells and the formation of hetero‐ and homo‐oligomers at the plasma membrane and the submembrane region. The use of NanoLuc Binary Technology allowed us to analyze changes in the oligomeric status of hENT1 and hENT2 and how they rapidly modify the uptake profile for nucleosides and nucleobases and allow cells to respond promptly to external signals or changes in the extracellular environment. These changes in hENTs oligomerization are triggered by PKC activation and subsequent action of protein phosphatase 1.—Grañe‐Boladeras, N., Williams, D., Tarmakova, Z., Stevanovic, K., Villani, L. A., Mehrabi, P., Siu, K. W. M., Pastor‐Anglada, M., Coe, I. R. Oligomerization of equilibrative nucleoside transporters: a novel regulatory and functional mechanism involving PKC and PP1. FASEB J. 33, 3841–3850 (2019). http://www.fasebj.org

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Nucleoside transporters in the purinome

Cited by 34 publications

References 124 publications

Immunoregulatory activity of adenosine and its role in human cancer progression

Immunoregulatory activity of adenosine and its role in human cancer progression

The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain

Oligomerization of equilibrative nucleoside transporters: a novel regulatory and functional mechanism involving PKC and PP1

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