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Research ArticleArticle

Multidrug Resistance-Related Protein 1 (MRP1) Function and Localization Depend on Cortical Actin

Ina Hummel, Karin Klappe, Cigdem Ercan and Jan Willem Kok
Molecular Pharmacology February 2011, 79 (2) 229-240; DOI: https://doi.org/10.1124/mol.110.069013
Ina Hummel
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Karin Klappe
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Cigdem Ercan
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Jan Willem Kok
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Abstract

MRP1 (ABCC1) is known to be localized in lipid rafts. Here we show in two different cell lines that localization of Mrp1/MRP1 (Abcc1/ABCC1) in lipid rafts and its function as an efflux pump are dependent on cortical actin. Latrunculin B disrupts both cortical actin and actin stress fibers. This results in partial loss of actin and Mrp1/MRP1 (Abcc1/ABCC1) from detergent-free lipid raft fractions, partial internalization of Mrp1/MRP1 (Abcc1/ABCC1), and reduction of Mrp1/MRP1 (Abcc1/ABCC1)-mediated efflux. Pretreatment with nocodazole prevents latrunculin B-induced loss of cortical actin and all effects of latrunculin B on Mrp1 (Abcc1) localization and activity. However, pretreatment with tyrphostin A23 does not prevent latrunculin B-induced loss of cortical actin, lipid raft association, and efflux activity, but it does prevent latrunculin B-induced internalization of Mrp1 (Abcc1). Cytochalasin D disrupts actin stress fibers but not cortical actin and this inhibitor much less affects Mrp1/MRP1 (Abcc1/ABCC1) localization in lipid rafts, internalization, and efflux activity. In conclusion, cortical actin disruption results in reduced Mrp1/MRP1 (Abcc1/ABCC1) activity concomitant with a partial shift of Mrp1/MRP1 (Abcc1/ABCC1) out of lipid raft fractions and partial internalization of the ABC transporter. The results suggest that reduced Mrp1 (Abcc1) function is correlated to the loss of lipid raft association but not internalization of Mrp1 (Abcc1).

Footnotes

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

    doi:10.1124/mol.110.069013.

  • ABBREVIATIONS:

    MDR
    multidrug resistance
    ABC
    ATP-binding cassette
    Cav-1
    caveolin-1
    CFDA
    5-carboxyfluorescein diacetate
    Mrp1
    murine multidrug resistance-related protein 1
    MRP1
    human multidrug resistance-related protein 1
    PGP/Pgp
    P-glycoprotein
    ERM
    ezrin, radixin, and moesin
    HBSS
    Hanks' balanced salt solution
    FCS
    fetal calf serum
    PNS
    postnuclear supernatant
    PBS
    phosphate-buffered saline
    RT
    room temperature
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    bp
    base pair(s)
    DCI
    direct competitive inhibitor
    MK571
    (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid.

  • Received September 21, 2010.
  • Accepted November 1, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (2)
Molecular Pharmacology
Vol. 79, Issue 2
1 Feb 2011
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Research ArticleArticle

Multidrug Resistance-Related Protein 1 (MRP1) Function and Localization Depend on Cortical Actin

Ina Hummel, Karin Klappe, Cigdem Ercan and Jan Willem Kok
Molecular Pharmacology February 1, 2011, 79 (2) 229-240; DOI: https://doi.org/10.1124/mol.110.069013

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Research ArticleArticle

Multidrug Resistance-Related Protein 1 (MRP1) Function and Localization Depend on Cortical Actin

Ina Hummel, Karin Klappe, Cigdem Ercan and Jan Willem Kok
Molecular Pharmacology February 1, 2011, 79 (2) 229-240; DOI: https://doi.org/10.1124/mol.110.069013
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