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Research ArticleArticle

The Pharmacological Profile of Brain Liver Intestine Na+ Channel: Inhibition by Diarylamidines and Activation by Fenamates

Dominik Wiemuth and Stefan Gründer
Molecular Pharmacology November 2011, 80 (5) 911-919; DOI: https://doi.org/10.1124/mol.111.073726
Dominik Wiemuth
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Stefan Gründer
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Abstract

The brain liver intestine Na+ channel (BLINaC) is a member of the degenerin/epithelial Na+ channel gene family of unknown function. Elucidation of the physiological function of BLINaC would benefit greatly from pharmacological tools that specifically affect BLINaC activity. Guided by the close molecular relation of BLINaC to acid-sensing ion channels, we discovered in this study that rat BLINaC (rBLINaC) and mouse BLINaC are inhibited by micromolar concentrations of diarylamidines and nafamostat, similar to acid-sensing ion channels. Inhibition was voltage-dependent, suggesting pore block as the mechanism of inhibition. Furthermore, we identified the fenamate flufenamic acid and related compounds as agonists of rBLINaC. Application of millimolar concentrations of flufenamic acid to rBLINaC induced a robust, Na+-selective current, which was blocked partially by amiloride. The identification of an artificial agonist of rBLINaC supports the hypothesis that rBLINaC is opened by an unknown physiological ligand. Inhibition by diarylamidines and activation by fenamates define a unique pharmacological profile for BLINaC, which will be useful to unravel the physiological function of this ion channel.

Footnotes

  • This work was supported by the START program of the Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule Aachen.

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

    doi:10.1124/mol.111.073726.

  • ABBREVIATIONS:

    DEG
    degenerin
    ENaC
    epithelial Na+ channel
    ECD
    extracellular domain
    ASIC
    acid-sensing ion channel
    BLINaC
    brain liver intestine Na+ channel
    rBLINaC
    rat brain liver intestine Na+ channel
    mBLINaC
    mouse brain liver intestine Na+ channel
    DAPI
    4,6-diamidino-2-phenylindole
    HSB
    hydroxystilbamidine
    FFA
    flufenamic acid
    NFA
    niflumic acid
    NMDG
    N-methyl-d-glucamine
    NAFA
    nafamostat
    DIMI
    diminazene
    PEN
    pentamidine.

  • Received May 24, 2011.
  • Accepted August 9, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (5)
Molecular Pharmacology
Vol. 80, Issue 5
1 Nov 2011
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Research ArticleArticle

The Pharmacological Profile of BLINaC

Dominik Wiemuth and Stefan Gründer
Molecular Pharmacology November 1, 2011, 80 (5) 911-919; DOI: https://doi.org/10.1124/mol.111.073726

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Research ArticleArticle

The Pharmacological Profile of BLINaC

Dominik Wiemuth and Stefan Gründer
Molecular Pharmacology November 1, 2011, 80 (5) 911-919; DOI: https://doi.org/10.1124/mol.111.073726
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