title: Informatic deconvolution of biased GPCR signaling mechanisms from in vivo pharmacological experimentation.
abstract: Ligands possessing different physico-chemical structures productively interact with G protein-coupled receptors generating distinct downstream signaling events due to their abilities to activate/select idiosyncratic receptor entities ('receptorsomes') from the full spectrum of potential receptor partners. We have employed multiple novel informatic approaches to identify and characterize the in vivo transcriptomic signature of an arrestin-signaling biased ligand, [D-Trp(12),Tyr(34)]-bPTH(7-34), acting at the parathyroid hormone type 1 receptor (PTH1R), across six different murine tissues after chronic drug exposure. We are able to demonstrate that [D-Trp(12),Tyr(34)]-bPTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated, in an arrestin signaling-dependent manner, across more tissues than that of the pluripotent endogenous PTH1R ligand, hPTH(1-34). This arrestin-focused response signature is strongly linked with the transcriptional regulation of cell growth and development. Our informatic deconvolution of a conserved arrestin-dependent transcriptomic signature from wild type mice demonstrates a conceptual framework within which the in vivo outcomes of biased receptor signaling may be further investigated or predicted.
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: stuart.maudsley@molgen.vib-ua.be.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.affiliation: Metabolism Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Janssens
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Harmonie
authors.initials: H
authors.lastname: Etienne
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Areta
authors.initials: A
authors.lastname: Jushaj
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
authors.forename: Jaana
authors.initials: J
authors.lastname: van Gastel
authors.affiliation: Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Willemsen
authors.affiliation: Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Chen
authors.affiliation: Duke University Medical Center, Duke University, Durham, NC 27705, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Gesty-Palmer
authors.affiliation: Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Luttrell
mesh_terms: D000818:Animals; D002417:Cattle; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D048088:Informatics / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D043562:Receptors, G-Protein-Coupled
keywords: Arrestin; G protein-coupled receptor; In vivo; Informatic; Signaling bias; Transcriptome