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Molecular Pharmacology

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Research ArticleArticle

Molecular Basis for a High-Potency Open-Channel Block of Kv1.5 Channel by the Endocannabinoid Anandamide

Eloy G. Moreno-Galindo, Gabriel F. Barrio-Echavarría, José C. Vásquez, Niels Decher, Frank B. Sachse, Martin Tristani-Firouzi, José A. Sánchez-Chapula and Ricardo A. Navarro-Polanco
Molecular Pharmacology May 2010, 77 (5) 751-758; DOI: https://doi.org/10.1124/mol.109.063008
Eloy G. Moreno-Galindo
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Gabriel F. Barrio-Echavarría
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José C. Vásquez
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Niels Decher
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Frank B. Sachse
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Martin Tristani-Firouzi
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José A. Sánchez-Chapula
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Ricardo A. Navarro-Polanco
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Abstract

The endocannabinoid, N-arachidonoylethanolamine (anandamide; AEA) is known to interact with voltage-gated K+ (Kv) channels in a cannabinoid receptor-independent manner. AEA modulates the functional properties of Kv channels, converting channels with slowly inactivating current into apparent fast inactivation. In this study, we characterize the mechanism of action and binding site for AEA on Kv1.5 channels expressed on HEK-293 cells using the patch-clamp techniques. AEA exhibited high-potency block (IC50 ≈ 200 nM) from the cytoplasmic membrane surface, consistent with open-channel block. Alanine-scanning mutagenesis revealed that AEA interacts with two crucial β-branching amino acids, Val505 and Ile508 within the S6 domain. Both residues face toward the central cavity and constitute a motif that forms a hydrophobic ring around the ion conduction pathway. This hydrophobic ring motif may be a critical determinant of cannabinoid receptor-independent AEA modulation in other K+ channel families.

Footnotes

  • This work was supported by the Consejo Nacional de Ciencia y Tecnología, México [Grant CONACyT-054577] and the Nora Eccles Treadwell Foundation.

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

    doi:10.1124/mol.109.063008.

  • ABBREVIATIONS:

    AEA
    N-arachidonoylethanolamine
    Kv
    voltage-gated potassium channel
    TEA
    tetraethylammonium
    HEK
    human embryonic kidney
    WT
    wild type
    K4BAPTA
    1,2-bis (2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, tetrapotassium salt
    S9947
    2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide
    S0100176
    N-benzyl-N-pyridin-3-ylmethyl-2-(toluene-4-sulfonylamino)-benzamide hydrochloride
    AVE0118
    2′-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide
    ICAGEN-4
    N-[3-(4-ethyl-benzene-sulfonylamino)-2-hydroxy-indan-5-yl]-3-methoxy-benzamide
    MSD-D
    2-(4-methoxy-phenyl)-5-methyl-3-oxo-6-p-tolylsulfanyl-2,3-dihydro-pyridazine-4-carbonitrile.

    • Received December 7, 2009.
    • Accepted January 28, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (5)
Molecular Pharmacology
Vol. 77, Issue 5
1 May 2010
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Research ArticleArticle

Molecular Basis for a High-Potency Open-Channel Block of Kv1.5 Channel by the Endocannabinoid Anandamide

Eloy G. Moreno-Galindo, Gabriel F. Barrio-Echavarría, José C. Vásquez, Niels Decher, Frank B. Sachse, Martin Tristani-Firouzi, José A. Sánchez-Chapula and Ricardo A. Navarro-Polanco
Molecular Pharmacology May 1, 2010, 77 (5) 751-758; DOI: https://doi.org/10.1124/mol.109.063008

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Research ArticleArticle

Molecular Basis for a High-Potency Open-Channel Block of Kv1.5 Channel by the Endocannabinoid Anandamide

Eloy G. Moreno-Galindo, Gabriel F. Barrio-Echavarría, José C. Vásquez, Niels Decher, Frank B. Sachse, Martin Tristani-Firouzi, José A. Sánchez-Chapula and Ricardo A. Navarro-Polanco
Molecular Pharmacology May 1, 2010, 77 (5) 751-758; DOI: https://doi.org/10.1124/mol.109.063008
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