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Research ArticleENDOCRINE AND REPRODUCTIVE

Estrogen Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Chloride Secretion

Ashvani K. Singh, Bruce D. Schultz, John A. Katzenellenbogen, Elmer M. Price, Robert J. Bridges and Neil A. Bradbury
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 195-204;
Ashvani K. Singh
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Bruce D. Schultz
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John A. Katzenellenbogen
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Elmer M. Price
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Robert J. Bridges
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Neil A. Bradbury
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Abstract

Cystic fibrosis (CF) is an autosomal genetic disease associated with impaired epithelial ion transport. Mutations in the CF gene alter the primary sequence of the CF transmembrane conductance regulator (CFTR). Several therapeutic modalities have been proposed for CF patients, including the phytoestrogen genistein. Experiments were completed in cellular and subcellular systems to evaluate the impact of naturally occurring and synthetic estrogens on epithelial ion transport, and specifically on the CF protein CFTR. 17β-Estradiol, a naturally occurring estrogen, caused a rapid and reversible inhibition of forskolin-stimulated chloride secretion across T84 epithelial cell monolayers with a Ki of 8 μM. In addition, 17α-estradiol, a stereoisomer that fails to bind and activate nuclear estrogen receptors was equipotent with 17β-estradiol, arguing against a genomic-mediated mechanism of action. Synthetic estrogens, including diethylstilbesterol and the antiestrogen tamoxifen likewise inhibited forskolin-stimulated ion transport. Aldosterone, dexamethasone, and cholesterol were without effect at the highest concentrations tested (≥1 mM). Studies indicated that diethylstilbesterol and other synthetic estrogens that inhibited anion secretion in intact monolayers likewise inhibited CFTR chloride channel activity with similar concentration dependencies in excised membrane patches. Experiments with radioactive photoactivatable estrogen derivatives demonstrated that these compounds bind directly to CFTR expressed in insect cells. Taken together, the data suggest that estrogens can interact directly with CFTR to alter anion transport.

Footnotes

  • Send reprint requests to: Neil A. Bradbury, Ph.D., Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace St., Pittsburgh, PA 15261. E-mail:nabrad{at}pitt.edu

  • ↵1 This study was supported in part by the Cystic Fibrosis Foundation Grants 1974 (to A.K.S.) and SCHUL960 (to B.D.S.), and National Institutes of Health Grants DK47850 (to N.A.B.) and DK15556 (to J.A.K.).

  • Abbreviations:
    CF
    cystic fibrosis
    CFTR
    cystic fibrosis transmembrane conductance regulator
    Isc
    short-circuit current
    FBS
    fetal bovine serum
    PKA
    protein kinase A
    i
    single-channel current
    I
    mean current
    fc
    corner frequency
    PAGE
    polyacrylamide gel electrophoresis
    CPTcAMP
    8-chlorophenyl-thio-cAMP
    DES
    diethylstilbesterol
    ENac
    epithelial sodium channel
    GABA
    γ-aminobutyric acid
    wt
    wild-type
    • Received March 28, 2000.
    • Accepted June 12, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleENDOCRINE AND REPRODUCTIVE

Estrogen Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Chloride Secretion

Ashvani K. Singh, Bruce D. Schultz, John A. Katzenellenbogen, Elmer M. Price, Robert J. Bridges and Neil A. Bradbury
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 195-204;

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Research ArticleENDOCRINE AND REPRODUCTIVE

Estrogen Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Chloride Secretion

Ashvani K. Singh, Bruce D. Schultz, John A. Katzenellenbogen, Elmer M. Price, Robert J. Bridges and Neil A. Bradbury
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 195-204;
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