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G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands.

Publication ,  Journal Article
Tsvetanova, NG; Trester-Zedlitz, M; Newton, BW; Riordan, DP; Sundaram, AB; Johnson, JR; Krogan, NJ; von Zastrow, M
Published in: Mol Pharmacol
February 2017

The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications, but, if excessively propagated downstream, would introduce biologic noise compromising cognate ligand detection. We asked whether cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal. We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse β-adrenoceptor agonists, isoproterenol and salmeterol. We show that both ligands generate an identical integrated response, and that this stereotyped output requires endocytosis. We further demonstrate that the endosomal β2-adrenergic receptor signal confers uniformity on the downstream response because it is highly sensitive and saturable. Based on these findings, we propose that GPCR signaling from endosomes functions as a biologic noise filter to enhance reliability of cognate ligand detection.

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Published In

Mol Pharmacol

DOI

EISSN

1521-0111

Publication Date

February 2017

Volume

91

Issue

2

Start / End Page

145 / 156

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Signal Transduction
  • Salmeterol Xinafoate
  • Receptors, G-Protein-Coupled
  • Receptors, Adrenergic, beta-2
  • Proteomics
  • Proteome
  • Phosphorylation
  • Phosphoproteins
  • Pharmacology & Pharmacy
 

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Tsvetanova, N. G., Trester-Zedlitz, M., Newton, B. W., Riordan, D. P., Sundaram, A. B., Johnson, J. R., … von Zastrow, M. (2017). G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands. Mol Pharmacol, 91(2), 145–156. https://doi.org/10.1124/mol.116.106369
Tsvetanova, Nikoleta G., Michelle Trester-Zedlitz, Billy W. Newton, Daniel P. Riordan, Aparna B. Sundaram, Jeffrey R. Johnson, Nevan J. Krogan, and Mark von Zastrow. “G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands.Mol Pharmacol 91, no. 2 (February 2017): 145–56. https://doi.org/10.1124/mol.116.106369.
Tsvetanova NG, Trester-Zedlitz M, Newton BW, Riordan DP, Sundaram AB, Johnson JR, et al. G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands. Mol Pharmacol. 2017 Feb;91(2):145–56.
Tsvetanova, Nikoleta G., et al. “G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands.Mol Pharmacol, vol. 91, no. 2, Feb. 2017, pp. 145–56. Pubmed, doi:10.1124/mol.116.106369.
Tsvetanova NG, Trester-Zedlitz M, Newton BW, Riordan DP, Sundaram AB, Johnson JR, Krogan NJ, von Zastrow M. G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands. Mol Pharmacol. 2017 Feb;91(2):145–156.
Journal cover image

Published In

Mol Pharmacol

DOI

EISSN

1521-0111

Publication Date

February 2017

Volume

91

Issue

2

Start / End Page

145 / 156

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Signal Transduction
  • Salmeterol Xinafoate
  • Receptors, G-Protein-Coupled
  • Receptors, Adrenergic, beta-2
  • Proteomics
  • Proteome
  • Phosphorylation
  • Phosphoproteins
  • Pharmacology & Pharmacy