Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling

Abstract

Concentrative and Equilibrative Nucleoside Transporter proteins (CNT and ENT, respectively) are encoded by gene families SLC28 and SLC29. They mediate the uptake of natural nucleosides and a variety of nucleoside-derived drugs, mostly used in anticancer therapy. CNT and ENT proteins are mostly localized in the apical and basolateral sides, respectively, in (re)absorptive epithelia. This anatomic distribution determines nucleoside and nucleoside-derived vectorial flux. CNT expression (particularly CNT2) is associated with differentiation and is also nutritionally regulated in intestinal epithelia, whereas ENT protein amounts (mostly ENT1) are increased when cells are exposed to proliferative stimuli such as EGF, TGF-alpha or wounding. Although all these features suggest a role for NT proteins in nucleoside salvage and (re)absorption, recent data demonstrate that CNT2 might be under purinergic control, in a manner that is dependent on energy metabolism. A physiological link between CNT2 function and intracellular metabolism is also supported by the evidence that extracellular adenosine can activate the AMP-dependent kinase (AMPK), by a mechanism which relies upon adenosine transport and phosphorylation. Thus the complex pattern of NT isoform expression in mammalian cells can fulfill physiological roles other than salvage.

Endogenous Luminal Surface Adenosine Signaling Regulates Duodenal Bicarbonate Secretion in Rats

“…Pharmacological inhibition of the proteins implicated in adenosine scavenging increases extracellular ADO concentration, increasing I sc via the basolateral A 2B receptor. Since that report was published many of the proteins involved in the adenosine scavenging mechanism have been identified; the phenomenon described probably was caused by ENTs localized on the T84 cell basolateral membrane, which transport in either direction in a concentrationdependent fashion and may regulate intracellular nucleoside concentrations (Pastor-Anglada et al, 2007). Furthermore, our findings are consistent with the previous report that luminal ADA and CNT, not ENT, regulate luminal ADO concentrations in the human airway epithelia (Hirsh et al, 2007).…”

“…These data demonstrate the presence of endogenous ADO generation in the lumen. Furthermore, ForB, not NBTI, enhanced ADO-induced DBS, suggesting that brush border CNT, unlike ENT, is related to nucleoside transport from the lumen to the enterocytes as predicted (Pastor-Anglada et al, 2007). Present on the apical membrane of epithelial cells, CNTs may absorb luminal nucleosides into the enterocytes.…”

“…Furthermore, luminal ADO is absorbed via the enterocyte nucleoside transporters (NTs), such as concentrative NT (CNT or SLC28) and the equilibrative NT (ENT or SLC29) (Pastor-Anglada et al, 2007). These observations suggest that luminal ADO signaling activity may be affected by ADA and NT activity, as reported in the airway epithelium (Hirsh et al, 2007).…”

Conserved Glutamate Residues Glu-343 and Glu-519 Provide Mechanistic Insights into Cation/Nucleoside Cotransport by Human Concentrative Nucleoside Transporter hCNT3

“…More widely distributed in cells and tissues than paralogs hCNT1 or hCNT2 (10), and with a central role in renal nucleoside and nucleoside drug transport (37,40), the multifunctional capability of hCNT3 and robust heterologous expression in Xenopus oocytes makes it the protein of choice for molecular characterization by site-directed mutagenesis and other approaches. Here we report an investigation of hCNT3 glutamate and aspartate residues.…”

Evaluation of changes in rat fatigability and biochemical parameters after oral and intra-peritoneal administration of adenosine tri phosphate: an experimental study

“…In liver, adenosine will be broken down to uric acid by the enzymes adenosine deaminase and xanthine oxidase. 18 Hyperuricemia is an independent risk factor for development of metabolic syndrome, gout and insulin resistance. [19][20][21] Hence this study was undertaken with an objective to evaluate efficacy of ATP by oral and intraperitoneal route using rat fatigability model and associated changes in biochemical parameters.…”