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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Tsvetanova, NG; Trester-Zedlitz, M; Newton, BW; Riordan, DP; Sundaram, AB; Johnson, JR; Krogan, NJ; von Zastrow, M

Published Date

  • February 2017

Published In

Volume / Issue

  • 91 / 2

Start / End Page

  • 145 - 156

PubMed ID

  • 27879340

Pubmed Central ID

  • PMC5267521

Electronic International Standard Serial Number (EISSN)

  • 1521-0111

Digital Object Identifier (DOI)

  • 10.1124/mol.116.106369


  • eng

Conference Location

  • United States