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Published ahead of print on June 28, 2006
J Am Soc Nephrol 17: 2127-2135, 2006
© 2006 American Society of Nephrology
doi: 10.1681/ASN.2006030205
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Cell and Transport Physiology

Identification and Functional Characterization of a New Human Kidney–Specific H+/Organic Cation Antiporter, Kidney-Specific Multidrug and Toxin Extrusion 2

Satohiro Masuda*, Tomohiro Terada*, Atsushi Yonezawa*, Yuko Tanihara*, Koshiro Kishimoto*, Toshiya Katsura*, Osamu Ogawa{dagger} and Ken-ichi Inui*

* Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine; and {dagger} Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Address correspondence to: Prof. Ken-ichi Inui, Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. Phone: +81-75-751-3577; Fax: +81-75-751-4207; inui{at}kuhp.kyoto-u.ac.jp

Received for publication March 7, 2006. Accepted for publication May 15, 2006.

A cDNA coding a new H+/organic cation antiporter, human kidney-specific multidrug and toxin extrusion 2 (hMATE2-K), has been isolated from the human kidney. The hMATE2-K cDNA had an open reading frame that encodes a 566–amino acid protein, which shows 94, 82, 52, and 52% identity with the hMATE2, hMATE2-B, hMATE1, and rat MATE1, respectively. Reverse transcriptase–PCR revealed that hMATE2-K mRNA but not hMATE2 was expressed predominantly in the kidney, and hMATE2-B was ubiquitously found in all tissues examined except the kidney. The immunohistochemical analyses revealed that the hMATE2-K as well as the hMATE1 was localized at the brush border membranes of the proximal tubules. HEK293 cells that were transiently transfected with the hMATE2-K cDNA but not hMATE2-B exhibited the H+ gradient–dependent antiport of tetraethylammonium (TEA). Transfection of hMATE2-B had no affect on the hMATE2-K–mediated transport of TEA. hMATE2-K also transported cimetidine, 1-methyl-4-phenylpyridinium (MPP), procainamide, metformin, and N1-methylnicotinamide. Kinetic analyses demonstrated that the Michaelis-Menten constants for the hMATE2-K–mediated transport of TEA, MPP, cimetidine, metformin, and procainamide were 0.83 mM, 93.5 µM, 0.37 mM, 1.05 mM, and 4.10 mM, respectively. Ammonium chloride–induced intracellular acidification significantly stimulated the hMATE2-K–dependent transport of organic cations such as TEA, MPP, procainamide, metformin, N1-methylnicotinamide, creatinine, guanidine, quinidine, quinine, thiamine, and verapamil. These results indicate that hMATE2-K is a new human kidney–specific H+/organic cation antiporter that is responsible for the tubular secretion of cationic drugs across the brush border membranes.




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