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Quantifying ligand bias at seven-transmembrane receptors.

Publication ,  Journal Article
Rajagopal, S; Ahn, S; Rominger, DH; Gowen-MacDonald, W; Lam, CM; Dewire, SM; Violin, JD; Lefkowitz, RJ
Published in: Mol Pharmacol
September 2011

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.

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Published In

Mol Pharmacol

DOI

EISSN

1521-0111

Publication Date

September 2011

Volume

80

Issue

3

Start / End Page

367 / 377

Location

United States

Related Subject Headings

  • Receptors, Cell Surface
  • Receptor, Angiotensin, Type 2
  • Radioligand Assay
  • Pharmacology & Pharmacy
  • Ligands
  • Inositol Phosphates
  • Humans
  • Cyclic AMP
  • Cell Line
  • 1115 Pharmacology and Pharmaceutical Sciences
 

Citation

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Rajagopal, S., Ahn, S., Rominger, D. H., Gowen-MacDonald, W., Lam, C. M., Dewire, S. M., … Lefkowitz, R. J. (2011). Quantifying ligand bias at seven-transmembrane receptors. Mol Pharmacol, 80(3), 367–377. https://doi.org/10.1124/mol.111.072801
Rajagopal, Sudarshan, Seungkirl Ahn, David H. Rominger, William Gowen-MacDonald, Christopher M. Lam, Scott M. Dewire, Jonathan D. Violin, and Robert J. Lefkowitz. “Quantifying ligand bias at seven-transmembrane receptors.Mol Pharmacol 80, no. 3 (September 2011): 367–77. https://doi.org/10.1124/mol.111.072801.
Rajagopal S, Ahn S, Rominger DH, Gowen-MacDonald W, Lam CM, Dewire SM, et al. Quantifying ligand bias at seven-transmembrane receptors. Mol Pharmacol. 2011 Sep;80(3):367–77.
Rajagopal, Sudarshan, et al. “Quantifying ligand bias at seven-transmembrane receptors.Mol Pharmacol, vol. 80, no. 3, Sept. 2011, pp. 367–77. Pubmed, doi:10.1124/mol.111.072801.
Rajagopal S, Ahn S, Rominger DH, Gowen-MacDonald W, Lam CM, Dewire SM, Violin JD, Lefkowitz RJ. Quantifying ligand bias at seven-transmembrane receptors. Mol Pharmacol. 2011 Sep;80(3):367–377.
Journal cover image

Published In

Mol Pharmacol

DOI

EISSN

1521-0111

Publication Date

September 2011

Volume

80

Issue

3

Start / End Page

367 / 377

Location

United States

Related Subject Headings

  • Receptors, Cell Surface
  • Receptor, Angiotensin, Type 2
  • Radioligand Assay
  • Pharmacology & Pharmacy
  • Ligands
  • Inositol Phosphates
  • Humans
  • Cyclic AMP
  • Cell Line
  • 1115 Pharmacology and Pharmaceutical Sciences