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Title: The multidrug transporter MATE1 sequesters OCs within an intracellular compartment that has no influence on OC secretion in renal proximal tubules.

Authors: Martínez-Guerrero, L J; Evans, K K; Dantzler, W H; Wright, S H

Published In Am J Physiol Renal Physiol, (2016 Jan 01)

Abstract: Secretion of organic cations (OCs) across renal proximal tubules (RPTs) involves basolateral OC transporter (OCT)2-mediated uptake from the blood followed by apical multidrug and toxin extruder (MATE)1/2-mediated efflux into the tubule filtrate. Whereas OCT2 supports electrogenic OC uniport, MATE is an OC/H(+) exchanger. As assessed by epifluorescence microscopy, cultured Chinese hamster ovary (CHO) cells that stably expressed human MATE1 accumulated the fluorescent OC N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA) in the cytoplasm and in a smaller, punctate compartment; accumulation in human OCT2-expressing cells was largely restricted to the cytoplasm. A second intracellular compartment was also evident in the multicompartmental kinetics of efflux of the prototypic OC [(3)H]1-methyl-4-phenylpyridinium (MPP) from MATE1-expressing CHO cells. Punctate accumulation of NBD-MTMA was markedly reduced by coexposure of MATE1-expressing cells with 5 μM bafilomycin (BAF), an inhibitor of V-type H(+)-ATPase, and accumulation of [(3)H]MPP and [(3)H]NBD-MTMA was reduced by >30% by coexposure with 5 μM BAF. BAF had no effect on the initial rate of MATE1-mediated uptake of NBD-MTMA, suggesting that the influence of BAF was a secondary effect involving inhibition of V-type H(+)-ATPase. The accumulation of [(3)H]MPP by isolated single nonperfused rabbit RPTs was also reduced >30% by coexposure to 5 μM BAF, suggesting that the native expression in RPTs of MATE protein within endosomes can increase steady-state OC accumulation. However, the rate of [(3)H]MPP secretion by isolated single perfused rabbit RPTs was not affected by 5 μM BAF, suggesting that vesicles loaded with OCs(+) are not likely to recycle into the apical plasma membrane at a rate sufficient to provide a parallel pathway for OC secretion.

PubMed ID: 26538438 Exiting the NIEHS site

MeSH Terms: 1-Methyl-4-phenylpyridinium/metabolism; 4-Chloro-7-nitrobenzofurazan/analogs & derivatives; 4-Chloro-7-nitrobenzofurazan/metabolism; Animals; CHO Cells; Cricetulus; Endosomes/metabolism; Fluorescent Dyes/metabolism; Kidney Tubules, Proximal/metabolism*; Kinetics; Male; Microscopy, Fluorescence; Organic Cation Transport Proteins/genetics; Organic Cation Transport Proteins/metabolism*; Organic Cation Transporter 2; Quaternary Ammonium Compounds/metabolism; Rabbits; Renal Elimination*; Renal Reabsorption*; Transfection; Vacuolar Proton-Translocating ATPases/metabolism

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