Physiology of Nucleoside Transporters: Back to the Future. . . .

Rose, Jennifer B.; Coe, Imogen R.

doi:10.1152/physiol.00036.2007

Cited by 47 publications

(50 citation statements)

References 97 publications

(109 reference statements)

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“…ENTs are evolutionarily conserved proteins that affect a diverse array of processes (Rose and Coe, 2008;Young et al, 2008). In mammals, ENT function regulates behaviors such as sleep/arousal states, drug dependence/addiction, and mood disorders (Alanko et al, 2003;Choi et al, 2004;Guillén-Gó mez et al, 2004;Chen et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Equilibrative Nucleoside Transporter 2 Regulates Associative Learning and Synaptic Function inDrosophila

Knight

Harvey²,

Iliadi³

et al. 2010

J. Neurosci.

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Nucleoside transporters are evolutionarily conserved proteins that are essential for normal cellular function. In the present study, we examined the role of equilibrative nucleoside transporter 2 (ent2) in Drosophila. Null mutants of ent2 are lethal during late larval/early pupal stages, indicating that ent2 is essential for normal development. Hypomorphic mutant alleles of ent2, however, are viable and exhibit reduced associative learning. We additionally used RNA interference to knock down ent2 expression in specific regions of the CNS and show that ent2 is required in the ␣/␤ lobes of the mushroom bodies and the antennal lobes. To determine whether the observed behavioral defects are attributable to defects in synaptic transmission, we examined transmitter release at the larval neuromuscular junction (NMJ). Excitatory junction potentials were significantly elevated in ent2 mutants, whereas paired-pulse plasticity was reduced. We also observed an increase in stimulus dependent calcium influx in the presynaptic terminal. The defects observed in calcium influx and transmitter release probability at the NMJ were rescued by introducing an adenosine receptor mutant allele (AdoR 1 ) into the ent2 mutant background. The results of the present study provide the first evidence of a role for ent2 function in Drosophila and suggest that the observed defects in associative learning and synaptic function may be attributable to changes in adenosine receptor activation.

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Section: Discussionmentioning

confidence: 99%

“…By acting as energy transfer molecules (e.g., ATP and GTP) and precursors for nucleic acid synthesis, nucleosides play an important role in many cellular homeostatic processes (Rose and Coe, 2008). Additionally, adenosine can act on P 1 purinergic receptors to modulate neuronal and endocrine signaling (Burnstock, 2008).…”

Section: Introductionmentioning

confidence: 99%

Equilibrative Nucleoside Transporter 2 Regulates Associative Learning and Synaptic Function inDrosophila

Knight

Harvey²,

Iliadi³

et al. 2010

J. Neurosci.

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“…1, H-M). In all cases, an inner bundle of TM helices (1,2,4,5,7,8,10, and 11) surrounds a hydrophilic cavity near the center of the bilayers. The other three TM helices (3, 6, and 9) are predicted to be peripheral to the central pore and face the surrounding membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Nucleoside permeases also mediate the uptake of a number of nucleoside analog drugs used to combat the devastating effects of chronic diseases, including those caused by RNA viruses, cancer, and parasitic protozoan infections (5,6).…”

mentioning

confidence: 99%

An ab Initio Structural Model of a Nucleoside Permease Predicts Functionally Important Residues

Valdés¹,

Arastu‐Kapur

Landfear³

et al. 2009

Journal of Biological Chemistry

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Permeases belonging to the equilibrative nucleoside transporter family promote uptake of nucleosides and/or nucleobases into a wide range of eukaryotes and mediate the uptake of a variety of drugs used in the treatment of cancer, heart disease, AIDS, and parasitic infections. No experimental three-dimensional structure exists for any of these permeases, and they are not present in prokaryotes, the source of many membrane proteins used in crystal structure determination. To generate a structural model for such a transporter, the LdNT1.1 nucleoside permease from the parasitic protozoan Leishmania donovani was modeled using ab initio computation. Site-directed mutations that strongly impair transport or that alter substrate specificity map to the central pore of the ab initio model, whereas mutations that have less pronounced phenotypes map to peripheral positions. The model suggests that aromatic residues present in transmembrane helices 1, 2, and 7 may interact to form an extracellular gate that closes the permeation pathway in the inward oriented conformation. Mutation of two of these three residues abrogated transport activity, consistent with the prediction of the model. The ab initio model is similar to one derived previously using threading analysis, a distinct computational approach, supporting the overall accuracy of both models. However, significant differences in helix orientation and residue position between the two models are apparent, and the mutagenesis data suggest that the ab initio model represents an improvement regarding structural details over the threading model. The putative gating interaction may also help explain differences in substrate specificity between members of this family.Nucleoside transporters play pivotal roles in nucleoside salvage pathways, regulation of adenosine signaling, and the pharmacology of antineoplastic and antiviral nucleoside drugs (1, 2).Salvage of nucleosides and nucleobases is the first step of nucleoside utilization in those cells that lack the metabolic machinery to make purine nucleotides de novo, including protozoan parasites (3) and brain and bone marrow cells in mammals (4). Nucleoside permeases also mediate the uptake of a number of nucleoside analog drugs used to combat the devastating effects of chronic diseases, including those caused by RNA viruses, cancer, and parasitic protozoan infections (5, 6).Equilibrative nucleoside transporters (ENTs) 4 are a unique family of proteins (the SLC29 family), with no apparent sequence homology to other types of permeases, that enable facilitated diffusion of nucleosides, nucleoside analogs, and nucleobases across cell membranes. Although widely distributed among eukaryotes from protozoa to humans, ENT-like homologs have not been identified in prokaryotes, and therefore crystallization of these transporters is likely to be even more challenging than for those membrane proteins that do have orthologs in prokaryotes. In the absence of a crystallographic structure, the use of genetic and biochemical approaches, especial...

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“…Nucleoside antimetabolites are the most widely used and effective types of anticancer drugs [2]. Recently, several improved purine nucleoside analogues derived from adenine have been developed; one such compound, clofarabine (2-chloro-2-arabino-fluro-2-deoxyadenosine), has broad cytotoxic activity, showing therapeutic promise, and is currently approved for relapsed acute lymphoblastic leukemia [3].…”

mentioning

confidence: 99%

Melatonin overcomes resistance to clofarabine in two leukemic cell lines by increased expression of deoxycytidine kinase

Yamanishi

Narazaki

Asano

2015

Experimental Hematology

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Physiology of Nucleoside Transporters: Back to the Future. . . .

Cited by 47 publications

References 97 publications

Equilibrative Nucleoside Transporter 2 Regulates Associative Learning and Synaptic Function inDrosophila

Equilibrative Nucleoside Transporter 2 Regulates Associative Learning and Synaptic Function inDrosophila

An ab Initio Structural Model of a Nucleoside Permease Predicts Functionally Important Residues

Melatonin overcomes resistance to clofarabine in two leukemic cell lines by increased expression of deoxycytidine kinase

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