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Molecular Pharmacology

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Research ArticleArticle

Dependence of Multidrug Resistance Protein-Mediated Cyclic Nucleotide Efflux on the Background Sodium Conductance

Marek Kucka, Karla Kretschmannova, Takayo Murano, Chung-Pu Wu, Hana Zemkova, Suresh V. Ambudkar and Stanko S. Stojilkovic
Molecular Pharmacology February 2010, 77 (2) 270-279; DOI: https://doi.org/10.1124/mol.109.059386
Marek Kucka
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Karla Kretschmannova
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Takayo Murano
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Chung-Pu Wu
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Hana Zemkova
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Suresh V. Ambudkar
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Stanko S. Stojilkovic
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Abstract

Anterior pituitary cells fire action potentials and release cyclic nucleotides both spontaneously and in response to agonist stimulation, but the relationship between electrical activity and cyclic nucleotide efflux has not been studied. In these cells, a tetrodotoxin-resistant background N+ conductance is critical for firing of action potentials, and multidrug resistance proteins (MRPs) MRP4 and MRP5 contribute to cyclic nucleotide efflux. Here, we show that abolition of the background Na+ conductance in rat pituitary cells by complete or partial replacement of extracellular Na+ with organic cations or sucrose induced a rapid and reversible hyperpolarization of cell membranes and inhibition of action potential firing, accompanied by a rapid inhibition of cyclic nucleotide efflux. Valinomycin-induced hyperpolarization of plasma membranes also inhibited cyclic nucleotide efflux, whereas depolarization of cell membranes induced by the inhibition of Ca2+ influx or stimulation of Na+ influx by gramicidin was accompanied by a facilitation of cyclic nucleotide efflux. In contrast, inhibition of cyclic nucleotide efflux by probenecid did not affect the background Na+ conductance. In human embryonic kidney 293 cells stably transfected with human MRP4 or MRP5, replacement of bath Na+ with organic cations also hyperpolarized the cell membranes and inhibited cyclic nucleotide efflux. In these cells, the Na+/H+ antiporter monensin did not affect the membrane potential and was practically ineffective in altering cyclic nucleotide efflux. In both pituitary and MRP4- and MRP5-expressing cells, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571) inhibited cyclic nucleotide efflux. These results indicate that the MRP4/5-mediated cyclic nucleotide efflux can be rapidly modulated by membrane potential determined by the background Na+ conductance.

Footnotes

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

  • This work was supported by the Intramural Research Programs of the National Institutes of Health National Institute of Child Health and Human Development and National Institutes of Health National Cancer Institute Center for Cancer Research.

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

    doi:10.1124/mol.109.059386

  • ABBREVIATIONS:

    AC
    adenylyl cyclase
    AP
    action potential
    GHRH
    growth hormone releasing hormone
    IBMX
    3-isobutyl-1-methylxanthine
    MRP
    multidrug resistance proteins
    Nab
    tetrodotoxin-resistant background sodium conductance
    PDE
    phosphodiesterase
    sGC
    soluble guanylyl cyclase
    TTX
    tetrodotoxin
    HEK
    human embryonic kidney
    TMA
    tetramethylammonium
    NMDG
    N-methyl-d-glucamine
    MK571
    3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid.

  • Received July 13, 2009.
  • Accepted November 9, 2009.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 77 (2)
Molecular Pharmacology
Vol. 77, Issue 2
1 Feb 2010
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Research ArticleArticle

Dependence of Multidrug Resistance Protein-Mediated Cyclic Nucleotide Efflux on the Background Sodium Conductance

Marek Kucka, Karla Kretschmannova, Takayo Murano, Chung-Pu Wu, Hana Zemkova, Suresh V. Ambudkar and Stanko S. Stojilkovic
Molecular Pharmacology February 1, 2010, 77 (2) 270-279; DOI: https://doi.org/10.1124/mol.109.059386

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Research ArticleArticle

Dependence of Multidrug Resistance Protein-Mediated Cyclic Nucleotide Efflux on the Background Sodium Conductance

Marek Kucka, Karla Kretschmannova, Takayo Murano, Chung-Pu Wu, Hana Zemkova, Suresh V. Ambudkar and Stanko S. Stojilkovic
Molecular Pharmacology February 1, 2010, 77 (2) 270-279; DOI: https://doi.org/10.1124/mol.109.059386
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