title: Molecular biology of nucleoside transporters and their distributions and functions in the brain.
abstract: Pyrimidine and purine nucleosides and their derivatives have critical functions and pharmacological applications in the brain. Nucleosides and nucleobases are precursors of nucleotides, which serve as the energy-rich currency of intermediary metabolism and as precursors of nucleic acids. Nucleosides (e.g., adenosine) and nucleotides are key signaling molecules that modulate brain function through interaction with cell surface receptors. Brain pathologies involving nucleosides and their metabolites range from epilepsy to neurodegenerative disorders and psychiatric conditions to cerebrovascular ischemia. Nucleoside analogs are used clinically in the treatment of brain cancer and viral infections. Nucleosides are hydrophilic molecules, and transportability across cell membranes via specialized nucleoside transporter (NT) proteins is a critical determinant of their metabolism and, for nucleoside drugs, their pharmacologic actions. In mammals, there are two types of nucleoside transport process: bidirectional equilibrative processes driven by chemical gradients, and unidirectional concentrative processes driven by sodium (and proton) electrochemical gradients. In mammals, these processes, both of which are present in brain, are mediated by members of two structurally unrelated membrane protein families (ENT and CNT, respectively). In this Chapter, we review current knowledge of cellular, physiological, pathophysiological and therapeutic aspects of ENT and CNT distribution and function in the mammalian brain, including studies with NT inhibitors and new research involving NT knockout and transgenic mice. We also describe recent progress in functional and molecular studies of ENT and CNT proteins, and summarize emerging evidence of other transporter families with demonstrated or potential roles in the transport of nucleosides and their derivatives in the brain.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Parkinson
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Damaraju
authors.forename: Kathryn
authors.initials: K
authors.lastname: Graham
authors.forename: Sylvia Y M
authors.initials: SY
authors.lastname: Yao
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Baldwin
authors.forename: Carol E
authors.initials: CE
authors.lastname: Cass
authors.forename: James D
authors.initials: JD
authors.lastname: Young
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D033703:Nucleoside Transport Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017494:Proton Pumps / Q000235:genetics / Q000378:metabolism*; D011618:Psychotic Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; D020033:Protein Isoforms; D017494:Proton Pumps