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Molecular Pharmacology

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Research ArticleArticle

Transmembrane Peptide as Potent Inhibitor of Oligomerization and Function of Human Organic Anion Transporter 1

Peng Duan, Shanshan Li and Guofeng You
Molecular Pharmacology March 2011, 79 (3) 569-574; DOI: https://doi.org/10.1124/mol.110.070185
Peng Duan
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Shanshan Li
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Guofeng You
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Abstract

Human organic anion transporter 1 (hOAT1) plays a critical role in the body disposition of environmental toxins and clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. We have demonstrated previously that hOAT1 forms homo-oligomers in cultured cells and in rat kidney. However, the functional consequence of such oligomerization has never been elucidated. In the current study, we used a novel approach by examining the effects of short hydrophobic peptides corresponding to transmembrane domains (TMDs) 1 to 12 of hOAT1 on the oligomerization and function of the transporter. We constructed expression vectors encoding short fusion peptides corresponding to TMDs 1 to 12 of hOAT1. These peptides were transfected into hOAT1-expressing COS-7 cells. Our results showed that among all 12 peptides examined, only the peptide corresponding to TMD 6 of hOAT1 significantly disrupted hOAT1 oligomerization demonstrated by cross-linking and coimmunoprecipitation experiments. The same peptide also caused a reduced expression of hOAT1 at the cell surface. As a result, hOAT1-mediated transport activity was compromised. Our data suggest that the peptide corresponding to TMD 6 of hOAT1 is a potent inhibitor of hOAT1 oligomerization and that oligomerization of hOAT1 is critical for the expression of the transporter at the cell surface and consequently for the proper function of the transporter.

Footnotes

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

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK60034]; and the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM079123].

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

    doi:10.1124/mol.110.070185.

  • ABBREVIATIONS:

    OAT1
    organic anion transporter 1
    TMD
    transmembrane domain
    PAH
    p-aminohippuric acid
    PBS
    phosphate-buffered saline
    ER
    endoplasmic reticulum.

  • Received November 27, 2010.
  • Accepted December 15, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (3)
Molecular Pharmacology
Vol. 79, Issue 3
1 Mar 2011
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Research ArticleArticle

Transmembrane Peptide as Potent Inhibitor of Oligomerization and Function of Human Organic Anion Transporter 1

Peng Duan, Shanshan Li and Guofeng You
Molecular Pharmacology March 1, 2011, 79 (3) 569-574; DOI: https://doi.org/10.1124/mol.110.070185

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Research ArticleArticle

Transmembrane Peptide as Potent Inhibitor of Oligomerization and Function of Human Organic Anion Transporter 1

Peng Duan, Shanshan Li and Guofeng You
Molecular Pharmacology March 1, 2011, 79 (3) 569-574; DOI: https://doi.org/10.1124/mol.110.070185
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