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Research ArticleArticle

Molecular Mechanisms of Chloroquine Inhibition of Heterologously Expressed Kir6.2/SUR2A Channels

Daniela Ponce-Balbuena, Aldo A. Rodríguez-Menchaca, Angélica López-Izquierdo, Tania Ferrer, Harley T. Kurata, Colin G. Nichols and José A. Sánchez-Chapula
Molecular Pharmacology November 2012, 82 (5) 803-813; DOI: https://doi.org/10.1124/mol.112.079152
Daniela Ponce-Balbuena
“Unidad de Investigación Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (D.P.-B., A.L.-I., T.F., J.A.S.-C.); Departamento de Fisiología de la Facultad de Medicina de la Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (A.A.R.-M.); Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.T.K.); and Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, Missouri (C.G.N.)
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Aldo A. Rodríguez-Menchaca
“Unidad de Investigación Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (D.P.-B., A.L.-I., T.F., J.A.S.-C.); Departamento de Fisiología de la Facultad de Medicina de la Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (A.A.R.-M.); Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.T.K.); and Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, Missouri (C.G.N.)
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Angélica López-Izquierdo
“Unidad de Investigación Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (D.P.-B., A.L.-I., T.F., J.A.S.-C.); Departamento de Fisiología de la Facultad de Medicina de la Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (A.A.R.-M.); Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.T.K.); and Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, Missouri (C.G.N.)
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Tania Ferrer
“Unidad de Investigación Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (D.P.-B., A.L.-I., T.F., J.A.S.-C.); Departamento de Fisiología de la Facultad de Medicina de la Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (A.A.R.-M.); Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.T.K.); and Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, Missouri (C.G.N.)
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Harley T. Kurata
“Unidad de Investigación Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (D.P.-B., A.L.-I., T.F., J.A.S.-C.); Departamento de Fisiología de la Facultad de Medicina de la Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (A.A.R.-M.); Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.T.K.); and Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, Missouri (C.G.N.)
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Colin G. Nichols
“Unidad de Investigación Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (D.P.-B., A.L.-I., T.F., J.A.S.-C.); Departamento de Fisiología de la Facultad de Medicina de la Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (A.A.R.-M.); Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.T.K.); and Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, Missouri (C.G.N.)
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José A. Sánchez-Chapula
“Unidad de Investigación Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, México (D.P.-B., A.L.-I., T.F., J.A.S.-C.); Departamento de Fisiología de la Facultad de Medicina de la Universidad Autónoma de San Luis Potosí, San Luis Potosí, México (A.A.R.-M.); Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (H.T.K.); and Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, Missouri (C.G.N.)
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Abstract

Chloroquine and related compounds can inhibit inwardly rectifying potassium channels by multiple potential mechanisms, including pore block and allosteric effects on channel gating. Motivated by reports that chloroquine inhibition of cardiac ATP-sensitive inward rectifier K+ current (IKATP) is antifibrillatory in rabbit ventricle, we investigated the mechanism of chloroquine inhibition of ATP-sensitive potassium (KATP) channels (Kir6.2/SUR2A) expressed in human embryonic kidney 293 cells, using inside-out patch-clamp recordings. We found that chloroquine inhibits the Kir6.2/SUR2A channel by interacting with at least two different sites and by two mechanisms of action. A fast-onset effect is observed at depolarized membrane voltages and enhanced by the N160D mutation in the central cavity, probably reflecting direct channel block resulting from the drug entering the channel pore from the cytoplasmic side. Conversely, a slow-onset, voltage-independent inhibition of IKATP is regulated by chloroquine interaction with a different site and probably involves disruption of interactions between Kir6.2/SUR2A and phosphatidylinositol 4,5-bisphosphate. Our findings reveal multiple mechanisms of KATP channel inhibition by chloroquine, highlighting the numerous convergent regulatory mechanisms of these ligand-dependent ion channels.

Footnotes

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01 HL45742] (to C.G.N.); and Consejo Nacional de Ciencia y Tecnología–Secretaría de Educación Pública (México) [Grant CB-2008-01-105941] (to J.A.S.-C.). H.T.K. is supported by New Investigator awards from the Heart and Stroke Foundation of Canada and the Michael Smith Foundation for Health Research.

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

    http://dx.doi.org/10.1124/mol.112.079152.

  • ABBREVIATIONS:

    KATP
    ATP-sensitive potassium
    SUR
    sulfonylurea receptor
    PIP2
    phosphatidylinositol 4,5-bisphosphate
    IK1
    inward rectifier K+ current
    IKATP
    ATP-sensitive inward rectifier K+ current
    IKACh
    K+ current activated by muscarinic agonist
    HEK
    human embryonic kidney
    WT
    wild-type
    CAD
    cationic amphiphilic drug.

  • Received April 5, 2012.
  • Accepted July 31, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Research ArticleArticle

IKATP (Kir6.2/SUR2A) Channel Inhibition by Chloroquine

Daniela Ponce-Balbuena, Aldo A. Rodríguez-Menchaca, Angélica López-Izquierdo, Tania Ferrer, Harley T. Kurata, Colin G. Nichols and José A. Sánchez-Chapula
Molecular Pharmacology November 1, 2012, 82 (5) 803-813; DOI: https://doi.org/10.1124/mol.112.079152

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Research ArticleArticle

IKATP (Kir6.2/SUR2A) Channel Inhibition by Chloroquine

Daniela Ponce-Balbuena, Aldo A. Rodríguez-Menchaca, Angélica López-Izquierdo, Tania Ferrer, Harley T. Kurata, Colin G. Nichols and José A. Sánchez-Chapula
Molecular Pharmacology November 1, 2012, 82 (5) 803-813; DOI: https://doi.org/10.1124/mol.112.079152
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