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Functional characterization of a nucleoside-derived drug transporter variant (hCNT3C602R) showing altered sodium-binding capacity.

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 hCNT3(C602R) 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 hCNT3(C602R) polymorphism is attributable to the presence of an arginine rather than the loss of a cysteine at position 602, because an engineered hCNT3 protein with a serine residue at this position (hCNT3(C602S)) 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 hCNT3(C602R), respectively. In conclusion, the presence of an arginine residue in the core of transmembrane domain 13 is responsible for the different sodium affinity showed by the polymorphic transporter compared with the reference transporter. Individuals with the hCNT3(C602R) variant might show a lower nucleoside and nucleoside analog concentrative capacity, which could be clinically relevant.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Errasti-Murugarren E,Cano-Soldado P,Pastor-Anglada M,Casado FJ

doi

10.1124/mol.107.041848

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

379-86

issue

2

eissn

0026-895X

issn

1521-0111

pii

mol.107.041848

journal_volume

73

pub_type

杂志文章

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