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First published on November 9, 2007; DOI: 10.1124/mol.107.041848

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Received for publication September 17, 2007.
Revised November 6, 2007.
Accepted for publication November 6, 2007.

FUNCTIONAL CHARACTERIZATION OF A NUCLEOSIDE-DERIVED DRUG TRANSPORTER VARIANT (hCNT3C602R) SHOWING ALTERED SODIUM-BINDING CAPACITY

Ekaitz Errasti-Murugarren 1*, Pedro Cano-Soldado 1, Marcal Pastor-Anglada 1, Francisco Javier Casado 1

1 University of Barcelona

* Address correspondence to: E-mail: eerrasmu7{at}docd3.ub.edu

Abstract

A novel cloned polymorphism of the human concentrative nucleoside transporter hCNT3 was described and functionally characterized. This variant consists of a T/C transition leading to the substitution of cysteine 602 by an arginine residue in the core of transmembrane domain 13. The resulting hCNT3C602R protein has the same selectivity and affinity for natural nucleosides and nucleoside-derived drugs as hCNT3, but much lower concentrative capacity. The insertion of the transporter into a polarized membrane seems unaffected in the variant. In a preliminary survey of a typical Spanish population, this variant showed an allelic frequency of 1%. The functional impairment of the hCNT3C602R polymorphism is attributable to the presence of an arginine rather than the loss of a cysteine at position 602, since an engineered hCNT3 protein with a serine residue at this position (hCNT3C602S) and hCNT3 have similar kinetic parameters. The sodium activation kinetic analysis of both transporters revealed a variation in the affinity for sodium and a shift in the Hill coefficient, that could be consistent with a stoichiometry of 2:1 and 1:1 sodium:nucleoside, for hCNT3 and hCNT3C602R respectively. In conclusion, the presence of an arginine residue in the core of TMD 13 is responsible for the different sodium affinity showed by the polymorphic transporter compared with the reference transporter. Individuals with the hCNT3C602R variant might show a lower nucleoside and nucleoside analog concentrative capacity, which could be clinically relevant.


Key words: Nucleoside/Nucleotide, Structure determinations, Mutagenesis/Chimeric approaches, Genetics, Nucleoside/Nucleotide derivatives


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