Complex regulation of nucleoside transporter expression in epithelial and immune system cells

Nucleoside transporters have a variety of functions in the cell, such as th e provision of substrates for nucleic acid synthesis and the modulation of purine receptors by determining agonist availability. They also transport a wide range of nucleoside-derived antiviral and anticancer drugs. Most mamm alian cells coexpress several nucleoside transporter isoforms at the plasma membrane, which are differentially regulated. This paper reviews studies o n nucleoside transporter regulation, which has been extensively characteriz ed in the laboratory in several model systems: the hepatocyte, an epithelia l cell type, and immune system cells, in particular B cells, which are non- polarized and highly specialized. The hepatocyte co-expresses at least two Na+-dependent nucleoside transporters, CNT1 and CNT2, which are up-regulate d during cell proliferation but may undergo selective loss in certain exper imental models of hepatocarcinomas. This feature is consistent with evidenc e that CNT expression also depends on the differentiation status of the hep atocyte. Moreover, substrate availability also modulates CNT expression in epithelial cells, as reported for hepatocytes and jejunum epithelia from ra ts fed nucleotide-deprived diets. In human B cell lines, CNT and ENT transp orters are co-express ed but differentially regulated after B cell activati on triggered by cytokines or phorbol esters, as described for murine bone m arrow macrophages induced either to activate or to proliferate. The complex regulation of the expression and activity of nucleoside transporters hints at their relevance in cell physiology.