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.
Footnotes
- Received August 3, 2016.
- Accepted November 18, 2016.
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA010711 and DA012864 to M.v.Z.], National Institutes of Health National Institute of Mental Health [Grant MH109633 to N.G.T.], National Institutes of Health National Institute of General Medical Sciences [Grants GM081879, GM082250, and GM107671 to N.J.K.], and National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL124049 to A.B.S.]. N.G.T. is also supported by the American Heart Association.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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