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  - GPCR endocytosis confers uniformity in responses to chemically distinct ligands
AID  - 10.1124/mol.116.106369
DP  - 2016 Jan 01
TA  - Molecular Pharmacology
PG  - mol.116.106369
4099  - http://molpharm.aspetjournals.org/content/early/2016/11/22/mol.116.106369.short
4100  - http://molpharm.aspetjournals.org/content/early/2016/11/22/mol.116.106369.full
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 biological 'noise' compromising cognate ligand detection. We asked if 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-AR 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 biological noise filter to enhance reliability of cognate ligand detection.