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Research ArticleArticle

Extracellular Quaternary Ammonium Blockade of Transient Receptor Potential Vanilloid Subtype 1 Channels Expressed in Xenopus laevis Oocytes

Ricardo E. Rivera-Acevedo, Stephan A. Pless, Stephan K. W. Schwarz and Christopher A. Ahern
Molecular Pharmacology December 2012, 82 (6) 1129-1135; DOI: https://doi.org/10.1124/mol.112.079277
Ricardo E. Rivera-Acevedo
Departments of Anesthesiology, Pharmacology & Therapeutics (R.E.R.-A., S.A.P., S.K.W.S., C.A.A.) and Cellular and Physiological Sciences (S.A.P., C.A.A.), The University of British Columbia, Vancouver, British Columbia, Canada
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Stephan A. Pless
Departments of Anesthesiology, Pharmacology & Therapeutics (R.E.R.-A., S.A.P., S.K.W.S., C.A.A.) and Cellular and Physiological Sciences (S.A.P., C.A.A.), The University of British Columbia, Vancouver, British Columbia, Canada
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Stephan K. W. Schwarz
Departments of Anesthesiology, Pharmacology & Therapeutics (R.E.R.-A., S.A.P., S.K.W.S., C.A.A.) and Cellular and Physiological Sciences (S.A.P., C.A.A.), The University of British Columbia, Vancouver, British Columbia, Canada
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Christopher A. Ahern
Departments of Anesthesiology, Pharmacology & Therapeutics (R.E.R.-A., S.A.P., S.K.W.S., C.A.A.) and Cellular and Physiological Sciences (S.A.P., C.A.A.), The University of British Columbia, Vancouver, British Columbia, Canada
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Abstract

Transient receptor potential vanilloid subtype 1 (TRPV1) channels are essential nociceptive integrators in primary afferent neurons. These nonselective cation channels are inhibited by local anesthetic compounds through an undefined mechanism. Here, we show that lidocaine inhibits TRPV1 channels expressed in Xenopus laevis oocytes, whereas the neutral local anesthetic, benzocaine, does not, suggesting that a titratable amine is required for high-affinity inhibition. Consistent with this possibility, extracellular tetraethylammonium (TEA) and tetramethylammonium application produces potent, voltage-dependent pore block. Alanine substitutions at Phe649 and Glu648, residues in the putative TRPV1 pore region, significantly abrogated the concentration-dependent TEA inhibition. The results suggest that large cations, shown previously to enter cells through activated transient receptor potential channels, can also act as channel blockers.

Footnotes

  • This work was supported in part by the Canada Foundation for Innovation, the British Columbia Knowledge Development Fund (to S.K.W.S. and C.A.A.), the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research (to C.A.A.), the Michael Smith Foundation for Health Research (to C.A.A. and S.A.P.), the Canadian Institutes of Health Research [Banting postdoctoral fellowship] (to S.A.P.), and the St. Pauls Hospital Department of Anesthesia, Vancouver, BC (to R.E.R-.A.).

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

    http://dx.doi.org/10.1124/mol.112.079277.

  • ABBREVIATIONS:

    TRP
    transient receptor potential
    TRPV1
    transient receptor potential vanilloid subtype 1
    Kv
    voltage-gated potassium
    LA
    local anesthetic
    QX-314
    N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium
    TEA
    tetraethylammonium
    TMA
    tetramethylammonium
    QA
    quaternary ammonium.

  • Received April 12, 2012.
  • Accepted September 4, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Extracellular Quaternary Ammonium Block of TRPV1

Ricardo E. Rivera-Acevedo, Stephan A. Pless, Stephan K. W. Schwarz and Christopher A. Ahern
Molecular Pharmacology December 1, 2012, 82 (6) 1129-1135; DOI: https://doi.org/10.1124/mol.112.079277

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Research ArticleArticle

Extracellular Quaternary Ammonium Block of TRPV1

Ricardo E. Rivera-Acevedo, Stephan A. Pless, Stephan K. W. Schwarz and Christopher A. Ahern
Molecular Pharmacology December 1, 2012, 82 (6) 1129-1135; DOI: https://doi.org/10.1124/mol.112.079277
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