Recent molecular advances in studies of the concentrative Na+-dependent nucleoside transporter (CNT) family: identification and characterization of novel human and mouse proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib)

Abstract

The human concentrative (Na+-linked) plasma membrane transport proteins hCNT1 and hCNT2, found primarily in specialized epithelia, are selective for pyrimidine nucleosides (system cit) and purine nucleosides (system cif), respectively. Both have orthologs in other mammalian species and belong to a gene family (CNT) that also includes members in lower vertebrates, insects, nematodes, pathogenic yeast and bacteria. The CNT transporter family also includes a newly identified human and mouse CNT3 transporter isoform. This paper reviews the studies of CNT transport proteins that led to the identification of hCNT3 and mCNT3, and gives an overview of the structural and functional properties of these latest CNT family members. hCNT3 and mCNT3 have primary structures that place them in a CNT subfamily separate from CNT1/2, transport a wide range of physiological pyrimidine and purine nucleosides and antineoplastic and antiviral nucleoside drugs (system cib), and exhibit a Na+:uridine coupling ratio of at least 2:1 (cf 1:1 for hCNT1/2). Cells and tissues containing hCNT3 transcripts include mammary gland, differentiated HL-60 cells, pancreas, bone marrow, trachea, liver, prostrate and regions of intestine, brain and heart. In HL-60 cells, hCNT3 is transcriptionally regulated by phorbol myristate (PMA). The hCNT3 gene, which contains an upstream PMA response element, mapped to 9q22.2 (cf chromosome 15 for hCNT1 and hCNT2).

Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells

“…It has been shown that modulation of cellular enzymes of gemcitabine transport and metabolism influences drug activity in vitro (Mackey et al, 1998(Mackey et al, , 1999Goan et al, 1999;Ritzel et al, 2001). Cellular enzymes of gemcitabine transport and metabolism, that is, hENT1, dCK, RRM1, and RRM2, are well documented.…”

“…In recent studies performed on human cancer cell lines, human equilibrative nucleoside transporter-1 (hENT1) was found to be the major gemcitabine transporter (Garcia-Manteiga et al, 2003). If gemcitabine is not transported into the cell via hENT1 it cannot inhibit cell growth (Mackey et al, 1998;Rauchwerger et al, 2000), but increased hENT1 abundance facilitates efficient cellular entry of gemcitabine and confers increased cytotoxicity (Mackey et al, 1999;Ritzel et al, 2001). Inside the cell, gemcitabine is phosphorylated by deoxycytidine kinase (dCK) in a rate-limiting step.…”

Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation

“…Moreover, our results are in line with previous reports that suggested a common nucleoside transport system for 5-azaCyd as well as cytidine and uridine with similar efficiency (33). Further studies are required to determine whether additional hCNT proteins, such as hCNT3 (34), can also mediate 5-azaCyd transport.…”

The Antiepileptic Potential of Nucleosides

“…In contrast to ENTs, CNTs demonstrate some substrate specificity [43,335] (Table 1). CNT1 transports pyrimidine nucleosides and to some degree, Ado, CNT2 transports purine nucleosides and Urd, while CNT3 transports both classes with the ability to create a 10-fold higher concentration gradient due to 2:1 Na + -nucleoside coupling, suggesting that it might play a role under special circumstances [336]. There are fewer compounds available for the inhibition of concentrative nucleoside transporters than for equilibrative nucleoside transporters.…”