Review
Nucleoside transporters: from scavengers to novel therapeutic targets

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Hydrophilic purine and pyrimidine nucleosides rely on specialized carrier proteins for their membrane translocation. The recent identification of two gene families encoding equilibrative and concentrative nucleoside transporters in mammals and other organisms has provided the essential breakthrough to a more complete understanding of the biological significance of nucleoside transport. Although nucleoside salvage is a primary function of these proteins, recent data indicate functions beyond metabolic recycling. In brain and spinal cord, for example, nucleoside transporters have the potential to regulate synaptic levels of neuroactive purines such as adenosine and, thereby, indirectly modulate physiological processes through G-protein-coupled purine P1 receptors. As described in this review, recent research indicates novel putative functions for CNS nucleoside transporters in sleep, arousal, drug and alcohol addiction, nociception and analgesia. The therapeutic use of nucleoside analogue drugs and nucleoside transporter inhibitors in viral, neoplastic, cardiovascular and infectious disease is also described.

Section snippets

The biological significance of nucleoside distribution and uptake

Nucleoside molecules are formed by the combination of a purine or pyrimidine nitrogenous base with a pentose sugar, either ribose or 2-deoxyribose. Purine and pyrimidine nucleosides are crucial for prokaryotic and eukaryotic biology. As the precursors to nucleotides (e.g. ATP) and nucleic acids, they indirectly support strategic processes, including energy provision, protein synthesis and cell replication. As ligands to widely distributed cell-surface purine P1 receptors, they have direct

Identification and characterization of nucleoside transport proteins

Mammalian genomes encode multiple representatives of two structurally unrelated nucleoside transporter families, the equilibrative nucleoside transporters [ENT1–4: Human Genome Organisation (HUGO: http://www.hugo-international.org/) nomenclature SLC29A1-4] [1] and the concentrative nucleoside transporters (CNT1–3: HUGO nomenclature SLC28A1-3) [2]. The ENT family is restricted to eukaryotes, whereas CNT family members are also found in eubacteria (Figure 1). Their names reflect the properties of

The physiological and therapeutic significance of CNS nucleoside transporters

Under conditions of metabolic or physiological stress (e.g. cerebral ischaemia, inflammation and seizure), elevated levels of adenosine trigger retaliatory homeostatic and neuromodulatory actions that protect against neuronal damage [21]. Even in normal physiology, however, adenosine exerts a wide-ranging influence on peripheral and central neurons via G-protein-coupled P1 A1, A2A, A2B and A3 receptors [22]. Intracellular or extracellular adenosine formed, for example, as a result of

Nucleoside transporters as therapeutic targets in disease and infection

Nucleoside analogue drugs (NADs) and nucleoside transporter inhibitors represent a powerful addition to the armamentarium of frontline drugs used to combat the devastating effects of chronic diseases, including those caused by RNA viruses, cancer and parasitic protozoan infection. Advances in the efficacy of NAD-based therapies are inextricably linked to a more detailed profiling of the cellular distributions, transport kinetics and substrate selectivities of the ENT and CNT families. A

Nucleoside transporters as potential targets for antiparasitic drugs

Most parasites that infect humans lack de novo pathways for purine nucleotide synthesis and, thus, rely on the uptake of purine nucleosides and nucleobases from the host for salvage synthesis of these key metabolites. Members of the ENT family have key roles in such purine uptake in the protozoa that are responsible for many important human diseases, including malaria (Plasmodium spp.), sleeping sickness (Trypanosoma spp.) and leishmaniasis (Leishmania spp.) [3]. Owing to the essential nature

Concluding remarks

Nucleoside analogues are currently used for the treatment of a limited number of diseases, in particular some cancers. Recent advances in the understanding of the molecular mechanisms of adenosine transporters and their physiological roles offer the potential of therapeutic intervention in a much broader range of pathologies. Although, to date, no evidence directly links nucleoside transporters to disease pathogenesis, these proteins have a therapeutic potential that is yet to be fully realized.

Acknowledgements

We gratefully acknowledge the financial support of the MRC, the British Heart Foundation, the Wellcome Trust, the Canadian Institutes of Health Research and the Alberta Cancer Board. J.D.Y. is a Heritage Scientist of the Alberta Heritage Foundation for Medical Research, and C.E.C. holds the Canada Research Chair in Oncology. Assistance with artwork was provided by T. Lee, University of Leeds.

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