title: G Protein-Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands.
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.
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.) Nikoleta.Tsvetanova@ucsf.edu.
authors.forename: Nikoleta G
authors.initials: NG
authors.lastname: Tsvetanova
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Trester-Zedlitz
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.).
authors.forename: Billy W
authors.initials: BW
authors.lastname: Newton
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Riordan
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.).
authors.forename: Aparna B
authors.initials: AB
authors.lastname: Sundaram
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.).
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Johnson
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.).
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.affiliation: Department of Psychiatry (N.G.T., M.T.-Z., M.Z.), Department of Cellular and Molecular Pharmacology (M.Z.), California Institute for Quantitative Biosciences (B.W.N., J.R.J., N.J.K.), and Lung Biology Center, Department of Medicine (A.B.S.), University of California, San Francisco, San Francisco, California; J. David Gladstone Institute, San Francisco, California (N.J.K.); and Department of Biochemistry, Stanford University, Stanford, California (D.P.R.).
authors.forename: Mark
authors.initials: M
authors.lastname: von Zastrow
mesh_terms: D004705:Endocytosis; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008024:Ligands; D013058:Mass Spectrometry; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000068299:Salmeterol Xinafoate / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D008024:Ligands; D010750:Phosphoproteins; D020543:Proteome; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D000068299:Salmeterol Xinafoate; D007545:Isoproterenol