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Research ArticleArticle

Allosteric Modulation of the M3 Muscarinic Receptor by Amiodarone and N-Ethylamiodarone: Application of the Four-Ligand Allosteric Two-State Model

Edward Stahl, Gwendolynne Elmslie and John Ellis
Molecular Pharmacology September 2011, 80 (3) 378-388; DOI: https://doi.org/10.1124/mol.111.072991
Edward Stahl
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Gwendolynne Elmslie
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John Ellis
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Abstract

We have reported previously that amiodarone interacts with muscarinic receptors via a novel allosteric site. This study presents mechanistic details on the nature of that interaction. Amiodarone enhanced the maximal level of agonist-stimulated release of arachidonic acid (AA) from Chinese hamster ovary cells that expressed M3 muscarinic receptors; this enhancement was observed for acetylcholine and for the partial agonist pilocarpine. A similar effect of amiodarone was observed when pilocarpine was used to stimulate inositol phosphate (IP) metabolism, but not when acetylcholine was used. Subsequent studies showed that the IP response exhibited a much larger receptor reserve than the AA response, and reduction of that reserve by receptor alkylation unmasked amiodarone's enhancement of the maximal IP response to acetylcholine. Modulating the receptor reserve also revealed acetylcholine's greater affinity (KA) for the conformation of the receptor that mediates the AA response. The amiodarone analog N-ethylamiodarone (NEA) did not alter maximal agonist response but merely reduced agonist potency (that is, it appeared to be an antagonist). However, the action of NEA could be clearly distinguished from the action of the orthosteric antagonist NMS. Demonstration of this point was facilitated by an elaboration of Hall's allosteric two-state model; this new model represents a system composed of two ligands that compete with each other at the orthosteric site and two ligands that compete with each other at the allosteric site. In conclusion, amiodarone competes with NEA at a novel, extracellular, allosteric site to enhance the maximal stimulation evoked by acetylcholine and pilocarpine in two different responses.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Aging [Grant R01-AG05214].

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

    doi:10.1124/mol.111.072991.

  • ABBREVIATIONS:

    ACh
    acetylcholine
    GPCR
    G protein-coupled receptor
    W84
    hexamethylene-bis-[dimethyl-(3-phthalimidopropyl)ammonium]dibromide
    ATSM
    allosteric two-state model
    TCM
    ternary complex model
    CTCM
    cubic ternary complex model
    NMS
    N-methylscopolamine
    PAM
    positive allosteric modulator
    4L-ATSM
    four-ligand allosteric two-state model
    NEA
    N-ethylamiodarone
    AA
    arachidonic acid
    PB
    phosphate buffer
    PBS
    phosphate-buffered saline
    CHO
    Chinese hamster ovary
    EM-BSA
    Eagle's basal medium with 20 mM HEPES and 2 mg/ml fatty acid-free bovine serum albumin
    IP
    inositol phosphate
    POB
    phenoxybenzamine
    NAM
    negative allosteric modulator.

  • Received April 21, 2011.
  • Accepted May 20, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Allosteric Modulation of the M3 Muscarinic Receptor by Amiodarone and N-Ethylamiodarone: Application of the Four-Ligand Allosteric Two-State Model

Edward Stahl, Gwendolynne Elmslie and John Ellis
Molecular Pharmacology September 1, 2011, 80 (3) 378-388; DOI: https://doi.org/10.1124/mol.111.072991

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Research ArticleArticle

Allosteric Modulation of the M3 Muscarinic Receptor by Amiodarone and N-Ethylamiodarone: Application of the Four-Ligand Allosteric Two-State Model

Edward Stahl, Gwendolynne Elmslie and John Ellis
Molecular Pharmacology September 1, 2011, 80 (3) 378-388; DOI: https://doi.org/10.1124/mol.111.072991
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