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Molecular Pharmacology

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Research ArticleArticle

Identification of Essential Histidine and Cysteine Residues of the H+/Organic Cation Antiporter Multidrug and Toxin Extrusion (MATE)

Jun-ichi Asaka, Tomohiro Terada, Masahiro Tsuda, Toshiya Katsura and Ken-ichi Inui
Molecular Pharmacology June 2007, 71 (6) 1487-1493; DOI: https://doi.org/10.1124/mol.106.032938
Jun-ichi Asaka
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Tomohiro Terada
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Masahiro Tsuda
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Toshiya Katsura
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Ken-ichi Inui
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Abstract

Multidrug and toxin extrusion 1 (MATE1) has been isolated as an H+/organic cation antiporter located at the renal brush-border membranes. Previous studies using rat renal brush-border membrane vesicles indicated that cysteine and histidine residues played critical roles in H+/organic cation antiport activity. In the present study, essential histidine and cysteine residues of MATE1 family were elucidated. When 7 histidine and 12 cysteine residues of rat (r)MATE1 conserved among species were mutated, substitution of His-385, Cys-62, and Cys-126 led to a significant loss of tetraethylammonium (TEA) transport activity. Cell surface biotinylation and immunofluorescence analyses with confocal microscopy indicated that rMATE1 mutant proteins were localized at plasma membranes. Mutation of the corresponding residues in human (h)MATE1 and hMATE2-K also diminished the transport activity. The transport of TEA via rMATE1 was inhibited by the sulfhydryl reagent p-chloromercuribenzenesulfonate (PCMBS) and the histidine residue modifier diethyl pyrocarbonate (DEPC) in a concentration-dependent manner. The PCMBS-caused inhibition of the transport via rMATE1 was protected by an excess of various organic cations such as TEA, suggesting that cysteine residues act as substrate-binding sites. In the case of DEPC, no such protective effects were observed. These results suggest that histidine and cysteine residues are required for MATE1 to function and that cysteine residues may serve as substrate-recognition sites.

Footnotes

  • This work was supported in part by the 21st Century Center of Excellence (COE) program “Knowledge Information Infrastructure for Genome Science,” a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Grant-in-Aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan. J.A. is supported as a Research Assistant by the 21st Century COE program “Knowledge Information Infrastructure for Genome Science.”

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.032938.

  • ABBREVIATIONS: MATE, multidrug and toxin extrusion; TEA, tetraethylammonium; DEPC, diethyl pyrocarbonate; PCMBS, p-chloromercuribenzenesulfonate; OCT, organic cation transporter; PAH, p-aminohippurate; TBS, Tris-buffered saline; HEK, human embryonic kidney.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received November 22, 2006.
    • Accepted February 27, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Identification of Essential Histidine and Cysteine Residues of the H+/Organic Cation Antiporter Multidrug and Toxin Extrusion (MATE)

Jun-ichi Asaka, Tomohiro Terada, Masahiro Tsuda, Toshiya Katsura and Ken-ichi Inui
Molecular Pharmacology June 1, 2007, 71 (6) 1487-1493; DOI: https://doi.org/10.1124/mol.106.032938

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Research ArticleArticle

Identification of Essential Histidine and Cysteine Residues of the H+/Organic Cation Antiporter Multidrug and Toxin Extrusion (MATE)

Jun-ichi Asaka, Tomohiro Terada, Masahiro Tsuda, Toshiya Katsura and Ken-ichi Inui
Molecular Pharmacology June 1, 2007, 71 (6) 1487-1493; DOI: https://doi.org/10.1124/mol.106.032938
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