TY - JOUR
T1 - G protein-coupled receptor endocytosis confers uniformity in responses to chemically distinct ligands
AU - Tsvetanova, Nikoleta G.
AU - Trester-Zedlitz, Michelle
AU - Newton, Billy W.
AU - Riordan, Daniel P.
AU - Sundaram, Aparna B.
AU - Johnson, Jeffrey R.
AU - Krogan, Nevan J.
AU - Von Zastrow, Mark
N1 - Publisher Copyright:
© 2017 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2017/2
Y1 - 2017/2
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85010298705&partnerID=8YFLogxK
U2 - 10.1124/mol.116.106369
DO - 10.1124/mol.116.106369
M3 - Article
C2 - 27879340
AN - SCOPUS:85010298705
SN - 0026-895X
VL - 91
SP - 145
EP - 156
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 2
ER -