TitleG Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands.
Publication TypeJournal Article
Year of Publication2017
AuthorsTsvetanova NG, Trester-Zedlitz M, Newton BW, Riordan DP, Sundaram AB, Johnson JR, Krogan NJ, von Zastrow M
JournalMol Pharmacol
Volume91
Issue2
Pagination145-156
Date Published2017 Feb
ISSN1521-0111
KeywordsEndocytosis, Endosomes, HEK293 Cells, Humans, Isoproterenol, Ligands, Mass Spectrometry, Models, Biological, Oligonucleotide Array Sequence Analysis, Phosphoproteins, Phosphorylation, Proteome, Proteomics, Receptors, Adrenergic, beta-2, Receptors, G-Protein-Coupled, Salmeterol Xinafoate, Signal Transduction, Transcription, Genetic
Abstract

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.

DOI10.1124/mol.116.106369
Alternate JournalMol. Pharmacol.
PubMed ID27879340
PubMed Central IDPMC5267521
Grant ListP01 DA010154 / DA / NIDA NIH HHS / United States
R01 GM107671 / GM / NIGMS NIH HHS / United States
R37 DA010711 / DA / NIDA NIH HHS / United States
K08 HL124049 / HL / NHLBI NIH HHS / United States
P50 GM081879 / GM / NIGMS NIH HHS / United States
K99 MH109633 / MH / NIMH NIH HHS / United States
R29 DA010711 / DA / NIDA NIH HHS / United States
P50 GM082250 / GM / NIGMS NIH HHS / United States
R01 DA012864 / DA / NIDA NIH HHS / United States
R01 DA010711 / DA / NIDA NIH HHS / United States