Disease relevance of SLC28A2

• Both proteins belong to a gene family that includes the NupC proton/nucleoside symporter of E. coli. cDNAs encoding members of the CNT family have been isolated from rat tissues (jejunum, brain, liver; rCNT1 and rCNT2/SPNT) and, most recently, human kidney (hCNT1 and hSPNT1) [1].
• Bacterial isolates, namely Rhodococcus (HCCS), Sphingomonas (MWFG) and Paracoccus (SPNT) were capable to degrade mixed PAHs (Phe + Fla + Pyr) [2].

High impact information on SLC28A2

• RESULTS: Gemcitabine was transported by most of the tested proteins (the exceptions being the purine-selective rCNT2 and hCNT2), with the greatest uptake occurring in oocytes producing recombinant rCNT1 and hCNT1 [3].
• Despite a huge individual variability in the mRNA amounts for every transporter gene expressed in CLL cells (CNT2, CNT3, ENT1, and ENT2), no relationship between mRNA levels and in vitro fludarabine cytotoxicity was observed [4].
• CNT2 proteins, the high-affinity transporters for purines like adenosine as well as for uridine, have been found in cells comprising the BBB of rats [5].
• Moreover, inhibition of adenosine transport through the concentrative adenosine plasma membrane transporter CNT2 with formycin B results in the blockade of adenosine-mediated AMPK signaling [6].
• These models reveal that hCNT2 affinity is dominated by hydrogen bonding features, whereas hCNT1 and hENT1 displayed mainly electrostatic and steric features [7].

Biological context of SLC28A2

• HNF4alpha is a major determinant of SLC28A1 expression, whereas C/EBPalpha and HNF3gamma modulate SLC28A2 gene expression [8].
• The gene encoding hCNT2 was mapped to chromosome 15q15 [1].
• The Na+/nucleoside cotransporters hCNT1 (650 residues) and hCNT2 (658 residues) are 72% identical in amino acid sequence and contain 13 putative transmembrane helices (TMs) [9].
• Two Na(+)-dependent nucleoside transporters implicated in adenosine and uridine transport in mammalian cells are distinguished functionally on the basis of substrate specificity: CNT1 is selective for pyrimidine nucleosides but also transports adenosine; CNT2 (also termed SPNT) is selective for purine nucleosides but also transports uridine [1].
• Loss of the hepatic phenotype in primary culture is associated with a decrease in hCNT1 and hCNT2 mRNA levels [8].

Anatomical context of SLC28A2

• Here, the molecular cloning and functional characterization of a CNT2/SPNT-type transporter from human small intestine are described [1].
• Human hepatocytes express hCNT1, hCNT2, hENT1, and hENT2 [8].
• When produced in Xenopus oocytes, recombinant hCNT1 is selective for pyrimidine nucleosides (system cit), whereas hCNT2 is selective for purine nucleosides (system cif) [10].
• Of the several cell lines studied, the best hCNT2 transport function was obtained when transiently expressed in U251 cells [11].
• Functional expression and characterization of a sodium-dependent nucleoside transporter hCNT2 cloned from human duodenum [11].

Associations of SLC28A2 with chemical compounds

• Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine [1].
• These data indicate that hCNT2 and hCNT3 have higher affinity for ribavirin than do hENT1 and hENT2 [12].
• Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na(+) nucleoside cotransporters hCNT1 and hCNT2 [10].
• The ribose-modified nucleoside analogs, adenine arabinoside, and 2',3'-dideoxyadenosine induced currents in rSPNT-expressing, but not in hSPNT1-expressing, oocytes [13].
• Cladribine induced currents in oocytes expressing rSPNT (K(0.5) = 57 +/- 12 microM) but not hSPNT1 [13].

Regulatory relationships of SLC28A2

• TGF-beta transcriptionally activates the gene encoding the high-affinity adenosine transporter CNT2 in rat liver parenchymal cells [14].

References