PT - JOURNAL ARTICLE AU - Nikoleta G. Tsvetanova AU - Michelle Trester-Zedlitz AU - Billy W. Newton AU - Daniel P. Riordan AU - Aparna B. Sundaram AU - Jeffrey R. Johnson AU - Nevan J. Krogan AU - Mark von Zastrow TI - G Protein–Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands AID - 10.1124/mol.116.106369 DP - 2017 Feb 01 TA - Molecular Pharmacology PG - 145--156 VI - 91 IP - 2 4099 - http://molpharm.aspetjournals.org/content/91/2/145.short 4100 - http://molpharm.aspetjournals.org/content/91/2/145.full SO - Mol Pharmacol2017 Feb 01; 91 AB - 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.