Functional crosstalk between the adenosine transporter CNT3 and purinergic receptors in the biliary epithelia

Godoy, Valeria; Medina, Juan F.; Pastor‐Anglada, Marçal

doi:10.1016/j.jhep.2014.06.036

Cited by 11 publications

(8 citation statements)

References 41 publications

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“…hCNT3 is poorly expressed in normal hepatocytes, although it is well represented in biliary epithelia, where it appears to be the major player in extracellular adenosine levels regulation. In cholangiocytes CNT3 is under purinergic regulation via the Adenosine receptor 2A (A2AR), thereby contributing to complete purinergic control of bile flow started by ATP secretion into the bile ( Godoy et al, 2014 ).…”

Section: Nts Beyond Transportmentioning

confidence: 99%

Emerging Roles of Nucleoside Transporters

2018

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Since human Nucleoside Transporters (hNTs) were identified by their activity as transport systems, extensive work has been done to fully characterize them at the molecular and physiological level. Many efforts have been addressed to the identification of their selectivity for natural substrates and nucleoside analogs used to treat several diseases. hNTs belong to two different gene families, SLC28 and SLC29, encoding human Concentrative Nucleoside Transporters (hCNTs) and human Equilibrative Nucleoside Transporters (hENTs), respectively. hCNTs and hENTs are integral membrane proteins, albeit structurally unrelated. Both families share common features as substrate selectivity and often tissue localization. This apparent biological redundancy may anticipate some different roles for hCNTs and hENTs in cell physiology. Thus, hENTs may have a major role in maintaining nucleoside homeostasis, whereas hCNTs could contribute to nucleoside sensing and signal transduction. In this sense, the ascription of hCNT1 to a transceptor reinforces this hypothesis. Moreover, some evidences could suggest a putative role of hCNT2 and hCNT3 as transceptors. The interacting proteins identified for hCNT2 suggest a link to energy metabolism. Moreover, the ability of hCNT2 and hCNT3 to transport adenosine links both proteins to purinergic signaling. On the other hand, the broad selectivity transporters hENTs have a crucial role in salvage pathways and purinergic signaling by means of nucleoside pools regulation. In particular, the two new hENT2 isoforms recently described together with hENT2 seem to be key elements controlling nucleoside and nucleotide pools for DNA synthesis. This review focuses on all these NTs functions beyond their mere translocation ability.

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Section: Nts Beyond Transportmentioning

confidence: 99%

Emerging Roles of Nucleoside Transporters

2018

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“…On the other hand CNT3, which is not expressed in normal hepatocytes but shows broad expression in other epithelial tissues, such as colon and biliary epithelia, also appears to be a major player in regulating extracellular adenosine levels. In fact, CNT3 is under purinergic control via A2a adenosine receptors in cholangiocytes, thereby contributing to end up the initially driven purinergic control of bile flow started by ATP secretion into the bile ( Godoy et al, 2014 ). This evidence suggest that selected NT proteins can indeed be part of the purinome, the molecular network of nucleoside and nucleotide receptors (P1 and P2), enzymes, and transporters responsible for purinergic regulation of cell functions ( Volonte and D’Ambrosi, 2009 ).…”

Section: Nts As Drug Targetsmentioning

confidence: 99%

Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

Pastor‐Anglada

Pérez-Torras

2015

Front. Pharmacol.

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Nucleoside and nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases such as Crohn. Two gene families are implicated in the uptake of nucleosides and nucleoside analogs into cells, SCL28 and SLC29. The former encodes hCNT1, hCNT2, and hCNT3 proteins. They translocate nucleosides in a Na+ coupled manner with high affinity and some substrate selectivity, being hCNT1 and hCNT2 pyrimidine- and purine-preferring, respectively, and hCNT3 a broad selectivity transporter. SLC29 genes encode four members, being hENT1 and hENT2 the only two which are unequivocally implicated in the translocation of nucleosides and nucleobases (the latter mostly via hENT2) at the cell plasma membrane. Some nucleoside-derived drugs can also interact with and be translocated by members of the SLC22 gene family, particularly hOCT and hOAT proteins. Inter-individual differences in transporter function and perhaps, more importantly, altered expression associated with the disease itself might modulate the transporter profile of target cells, thereby determining drug bioavailability and action. Drug transporter pharmacology has been periodically reviewed. Thus, with this contribution we aim at providing a state-of-the-art overview of the clinical evidence generated so far supporting the concept that these membrane proteins can indeed be biomarkers suitable for diagnosis and/or prognosis. Last but not least, some of these transporter proteins can also be envisaged as drug targets, as long as they can show “transceptor” functions, in some cases related to their role as modulators of extracellular adenosine levels, thereby providing a functional link between P1 receptors and transporters.

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“…hCNT3 is a high‐affinity purine and pyrimidine nucleoside transporter that plays a crucial role in the disposition and distribution of physiologic nucleosides and nucleoside analogs because of its broad substrate selectivity, high concentrative capacity, and widespread tissue distribution (12, 27). hCNT3 is also a high‐affinity adenosine transporter recently reported to modulate purinergic signaling in biliary epithelium (28). In absorptive epithelia, apical localization of hCNT3 is crucial to determining the vectorial flux of many antiviral and anticancer nucleosides tested so far (5), thus being a major candidate for modulating drug bioavailability and pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

Galectin‐4 interacts with the drug transporter human concentrative nucleoside transporter 3 to regulate its function

et al. 2015

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The intracellular N-terminal domain of the nucleoside and drug transporter human concentrative nucleoside transporter (hCNT)3 was used as bait in a glutathione S-transferase pull-down approach, to identify hCNT3 protein partners, using human colon homogenates as a prey source. Galectin (Gal)-4 was identified as a potential hCNT3 partner in the colon. The biochemical validation of the Gal-4-hCNT3 interaction was verified by targeted pull-down assays and coimmunoprecipitation experiments in HT-29 cells, which endogenously express hCNT3 and Gal-4. Furthermore, Gal-4 was shown to colocalize with hCNT3 in HT-29 cells. The biologic significance of this interaction was obtained from experiments in which Gal-4 was knocked down, showing that this protein is a regulator of hCNT3 trafficking and retention at the cell membrane, reducing its plasma membrane location by 70%. Conversely, the addition of Gal-4 increased hCNT3 location at the plasma membrane by 77%, thereby demonstrating that this lectin modulates hCNT3 function in colonic cells. The integrity of this partnership may be clinically relevant, because hCNT3 may be responsible for the translocation of thiopurines, such as 6-mercaptopurine, a front-line treatment in inflammatory bowel disease. The expression of Gal-4 and hCNT3 proteins is not impaired in inflamed colon from patients with Crohn's disease, thereby anticipating the integrity of this system for drug targeting.

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Functional crosstalk between the adenosine transporter CNT3 and purinergic receptors in the biliary epithelia

Cited by 11 publications

References 41 publications

Emerging Roles of Nucleoside Transporters

Emerging Roles of Nucleoside Transporters

Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

Galectin‐4 interacts with the drug transporter human concentrative nucleoside transporter 3 to regulate its function

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