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1 Department of Pharmacy, Kyoto University Hospital, Kyoto, Kyoto, Japan
2 Department of Pharmacy, Kyoto University Hospital, Kyoto, Kyoto, Japan; Kyoto, Kyoto, Japan
* To whom correspondence should be addressed. E-mail: inui{at}kuhp.kyoto-u.ac.jp.
Recently, we have isolated the rat (r) H+/organic cation antiporter MATE1 (multidrug and toxin extrusion 1), and reported its tissue distribution and transport characteristics. Functional characterization suggested that an oppositely-directed H+ gradient serves as a driving force for the transport of a prototypical organic cation tetraethylammonium by MATE1, but there is no direct evidence to prove this. In the present study, therefore, we elucidated the driving force of tetraethylammonium transport via rMATE1 using plasma membrane vesicles isolated from HEK293 cells stably expressing rMATE1 (HEK-rMATE1 cells). A 70 kDa rMATE1 protein was confirmed to exist in HEK-rMATE1 cells, and the transport of various organic cations including [14C]tetraethylammonium was stimulated in intracellular acidified HEK-rMATE1 cells, but not mock cells. The transport of [14C]tetraethylammonium in membrane vesicles from HEK-rMATE1 cells exhibited the overshoot phenomenon only when there was an outwardly-directed H+ gradient, as observed in rat renal brush-border membrane vesicles. The overshoot phenomenon was not observed in the vesicles from mock cells. The stimulated [14C]tetraethylammonium uptake by an H+ gradient ([H+]in>[H+]out) was significantly reduced in the presence of a protonophore, p-trifluoromethoxyphenylhydrazone (FCCP). [14C]Tetraethylammonium uptake was not changed in the presence of valinomycin-induced membrane potential. These findings definitively indicate that an oppositely-directed H+ gradient serves as a driving force of tetraethylammonium transport via rMATE1, and this is the first demonstration to identify the driving force of the MATE family. The present experimental strategy is very useful to identify the driving force of cloned transporters whose driving force has not been evaluated.
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