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Research ArticleArticle

Quantifying Ligand Bias at Seven-Transmembrane Receptors

Sudarshan Rajagopal, Seungkirl Ahn, David H. Rominger, William Gowen-MacDonald, Christopher M. Lam, Scott M. DeWire, Jonathan D. Violin and Robert J. Lefkowitz
Molecular Pharmacology September 2011, 80 (3) 367-377; DOI: https://doi.org/10.1124/mol.111.072801
Sudarshan Rajagopal
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Seungkirl Ahn
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David H. Rominger
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William Gowen-MacDonald
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Christopher M. Lam
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Scott M. DeWire
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Jonathan D. Violin
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Robert J. Lefkowitz
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Abstract

Seven transmembrane receptors (7TMRs), commonly referred to as G protein-coupled receptors, form a large part of the “druggable” genome. 7TMRs can signal through parallel pathways simultaneously, such as through heterotrimeric G proteins from different families, or, as more recently appreciated, through the multifunctional adapters, β-arrestins. Biased agonists, which signal with different efficacies to a receptor's multiple downstream pathways, are useful tools for deconvoluting this signaling complexity. These compounds may also be of therapeutic use because they have distinct functional and therapeutic profiles from “balanced agonists.” Although some methods have been proposed to identify biased ligands, no comparison of these methods applied to the same set of data has been performed. Therefore, at this time, there are no generally accepted methods to quantify the relative bias of different ligands, making studies of biased signaling difficult. Here, we use complementary computational approaches for the quantification of ligand bias and demonstrate their application to two well known drug targets, the β2 adrenergic and angiotensin II type 1A receptors. The strategy outlined here allows a quantification of ligand bias and the identification of weakly biased compounds. This general method should aid in deciphering complex signaling pathways and may be useful for the development of novel biased therapeutic ligands as drugs.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL16037, HL70631, HL07101-34].

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

    doi:10.1124/mol.111.072801.

  • ABBREVIATIONS:

    7TMR
    seven transmembrane receptor
    β2AR
    β2 adrenergic receptor
    AT1AR
    angiotensin II type 1A receptor
    HEK
    human embryonic kidney
    IP1
    inositol 1-phosphate
    Pin
    pindolol
    DCI
    dichloroisoproterenol
    Slm
    salmeterol
    For
    formoterol
    SGG
    Sar1Gly4Gly8 angiotensin II
    SII
    Sar1Ile4Ile8 angiotensin II
    TRV120027
    Sar-Arg-Val-Tyr-Ile-His-Pro-d-Ala-OH
    TRV120026
    Sar-Arg-Val-Tyr-Tyr-His-Pro-NH2
    TRV120055
    Sar-Arg-Val-Tyr-Val-His-NH2
    TRV120056
    Asp-Arg-Val-Tyr-Ile-His-Pro-Gly
    TRV120044
    N-methyl-l-alanine-Arg-Val-Tyr-Ile-His-Pro-d-Ala
    TRV120045
    Sar-Arg-Val-Tyr-Arg-His-Pro-NH2
    TRV120034
    N-methyl-l-alanine-Arg-Val-Tyr-Ile-His-Pro-Ala
    TEV
    Tobacco Etch Virus.

  • Received April 6, 2011.
  • Accepted May 24, 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

Quantifying Ligand Bias at Seven-Transmembrane Receptors

Sudarshan Rajagopal, Seungkirl Ahn, David H. Rominger, William Gowen-MacDonald, Christopher M. Lam, Scott M. DeWire, Jonathan D. Violin and Robert J. Lefkowitz
Molecular Pharmacology September 1, 2011, 80 (3) 367-377; DOI: https://doi.org/10.1124/mol.111.072801

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Research ArticleArticle

Quantifying Ligand Bias at Seven-Transmembrane Receptors

Sudarshan Rajagopal, Seungkirl Ahn, David H. Rominger, William Gowen-MacDonald, Christopher M. Lam, Scott M. DeWire, Jonathan D. Violin and Robert J. Lefkowitz
Molecular Pharmacology September 1, 2011, 80 (3) 367-377; DOI: https://doi.org/10.1124/mol.111.072801
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