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Research ArticleArticle

Use-Dependent ‘Agonist’ Effect of Azimilide on the HERG Channel

Min Jiang, Wen Dun, Jing-Song Fan and Gea-Ny Tseng
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1324-1336;
Min Jiang
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Wen Dun
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Jing-Song Fan
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Gea-Ny Tseng
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Abstract

Azimilide (AZ) is a class III antiarrhythmic drug that has voltage-dependent dual effects on the HERG channel: 1) increasing current amplitude at low-voltage depolarization (agonist effect), and 2) suppressing current at more depolarized voltages (antagonist effect). We examined the mechanism for the agonist effect of AZ on HERG expressed in Xenopus oocytes. The agonist effect resulted from an AZ-induced ‘prepulse potentiation: a strong depolarization prepulse increased the rate and degree of channel activation induced by subsequent depolarization to −50 or −40 mV. The potentiated state decayed slowly in an exponential fashion (time constant, 60–80 s). Degrees of potentiation were proportional to degrees of channel activation during prepulses; hence, the agonist effect of AZ was use dependent. AZ exerted its agonist effect from outside the cell membrane, and the effect did not depend on intracellular G-protein or protein kinase activity. Mutations made in the outer mouth or an extracellular loop connecting the S5 and P regions of HERG, which could hinder or modify conformational changes in the pore region during membrane depolarization, reduced or abolished AZ-induced prepulse potentiation. Importantly, these same mutations also increased the rate and degree of channel activation in the negative voltage range, and the degree of change in the activation properties was inversely correlated with the degree of AZ-induced prepulse potentiation. We propose that conformational changes in the outer mouth and neighboring extracellular domain of HERG during membrane depolarization can affect the process of channel activation. In the presence of AZ, channel activation allowed drug modification of these conformational changes, which subsequently facilitated HERG activation by low-voltage depolarization.

Footnotes

  • Send reprint requests to: Gea-Ny Tseng, Ph.D., Department of Physiology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980551, Richmond, VA 23298-0551. E-mail:gtseng{at}hsc.vcu.edu

  • ↵1 This work was supported by the National Institutes of Health, National Heart, Lung and Blood Institute (Bethesda, MD) Grants HL 46451 and 30557.

  • ↵2 Current address: Department of Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond VA 23298-0551

  • ↵3 Current address: Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, TX 770555-0641.

  • Abbreviations:
    IKr
    rapid component of delayed rectifier current
    AZ
    azimilide
    S5-P loop
    the extracellular loop connecting the S5 and P regions of a K channel subunit
    WT
    wild-type
    V0.5
    half-maximum activation or inactivation voltage
    k
    slope factor of a Boltzmann function
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    PE
    phenylephrine
    DTT
    dithiothreitol
    τ
    time constant
    • Received June 29, 1999.
    • Accepted September 7, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Use-Dependent ‘Agonist’ Effect of Azimilide on the HERG Channel

Min Jiang, Wen Dun, Jing-Song Fan and Gea-Ny Tseng
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1324-1336;

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Research ArticleArticle

Use-Dependent ‘Agonist’ Effect of Azimilide on the HERG Channel

Min Jiang, Wen Dun, Jing-Song Fan and Gea-Ny Tseng
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1324-1336;
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