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Molecular Pharmacology

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Research ArticleArticle

Inhibition of the Proton-Coupled Folate Transporter (PCFT-SLC46A1) by Bicarbonate and Other Anions

Rongbao Zhao, Michele Visentin, Sylvia O. Suadicani and I. David Goldman
Molecular Pharmacology July 2013, 84 (1) 95-103; DOI: https://doi.org/10.1124/mol.113.085605
Rongbao Zhao
Departments of Molecular Pharmacology (R.Z., M.V., I.D.G.), Medicine (R.Z., I.D.G.) and Neuroscience and Urology (S.O.S.), Albert Einstein College of Medicine, Bronx, New York
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Michele Visentin
Departments of Molecular Pharmacology (R.Z., M.V., I.D.G.), Medicine (R.Z., I.D.G.) and Neuroscience and Urology (S.O.S.), Albert Einstein College of Medicine, Bronx, New York
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Sylvia O. Suadicani
Departments of Molecular Pharmacology (R.Z., M.V., I.D.G.), Medicine (R.Z., I.D.G.) and Neuroscience and Urology (S.O.S.), Albert Einstein College of Medicine, Bronx, New York
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I. David Goldman
Departments of Molecular Pharmacology (R.Z., M.V., I.D.G.), Medicine (R.Z., I.D.G.) and Neuroscience and Urology (S.O.S.), Albert Einstein College of Medicine, Bronx, New York
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Abstract

The proton-coupled folate transporter (PCFT) plays a key role in intestinal folate absorption, and loss-of-function mutations in the gene encoding this transporter are the molecular basis for hereditary folate malabsorption. Using a stable transfectant with high expression of PCFT, physiologic levels of bicarbonate produced potent and rapidly reversible inhibition of PCFT-mediated transport at neutral pH. Bisulfite and nitrite also inhibited PCFT function at neutral pH, whereas sulfate, nitrate, and phosphate had no impact at all. At weakly acidic pH (6.5), bisulfite and nitrite exhibited much stronger inhibition of PCFT-mediated transport, whereas sulfate and nitrate remained noninhibitory. Inhibition by bisulfite and nitrite at pH 6.5 was associated with a marked decrease in the influx Vmax and collapse of the transmembrane proton gradient attributed to the diffusion of the protonated forms into these cells. Monocarboxylates such as pyruvate and acetate also collapsed the pH gradient and were also inhibitory, whereas citrate and glycine neither altered the proton gradient nor inhibited PCFT-mediated transport. These observations add another dimension to the unfavorable pH environment for PCFT function in systemic tissues: the presence of high concentrations of bicarbonate.

Footnotes

    • Received February 11, 2013.
    • Accepted April 22, 2013.
  • This work was supported by the National Institutes of Health National Cancer Institute [Grant CA82621]; and the National Institutes of Health shared instrumentation [Grant S10RR020949].

  • dx.doi.org/10.1124/mol.113.085605.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (1)
Molecular Pharmacology
Vol. 84, Issue 1
1 Jul 2013
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Research ArticleArticle

Inhibition of PCFT by Bicarbonate, Nitrite, and Bisulfite

Rongbao Zhao, Michele Visentin, Sylvia O. Suadicani and I. David Goldman
Molecular Pharmacology July 1, 2013, 84 (1) 95-103; DOI: https://doi.org/10.1124/mol.113.085605

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Research ArticleArticle

Inhibition of PCFT by Bicarbonate, Nitrite, and Bisulfite

Rongbao Zhao, Michele Visentin, Sylvia O. Suadicani and I. David Goldman
Molecular Pharmacology July 1, 2013, 84 (1) 95-103; DOI: https://doi.org/10.1124/mol.113.085605
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