Nucleoside transporters of mammalian cells

In this review, we have summarized recent advances in our understanding of the biology of nucleoside transport arising from new insights provided by the isolation and functional expression of cDNAs encoding the major nucleoside transporters of mammalian cells. Nucleoside transporters are required for permeation of nucleosides across biological membranes and are present in the plasma membranes of most cell types. There is growing evidence that functional nucleoside transporters are required for translocation of nucleosides between intracellular compartments and thus are also present in organellar membranes. Functional studies during the 1980s established that nucleoside transport in mammalian cells occurs by two mechanistically distinct processes, facilitated diffusion and Na(+)-nucleoside cotransport. The determination of the primary amino acid sequences of the equilibrative and concentrative transporters of human and rat cells has provided a structural basis for the functional differences among the different transporter subtypes. Although nucleoside transporter proteins were first purified from human erythrocytes a decade ago, the low abundance of nucleoside transporter proteins in membranes of mammalian cells has hindered analysis of relationships between transporter structure and function. The molecular cloning of cDNAs encoding nucleoside transporters and the development of heterologous expression systems for production of recombinant nucleoside transporters, when combined with recombinant DNA technologies, provide powerful tools for characterization of functional domains within transporter proteins that are involved in nucleoside recognition and translocation. As relationships between molecular structure and function are determined, it should be possible to develop new approaches for optimizing the transportability of nucleoside drugs into diseased tissues, for development of new transport inhibitors, including reagents that are targeted to the concentrative transporters, and, eventually, for manipulation of transporter function through an understanding of the regulation of transport activity.