title: Delineation of a conserved arrestin-biased signaling repertoire in vivo.
abstract: Biased G protein-coupled receptor agonists engender a restricted repertoire of downstream events from their cognate receptors, permitting them to produce mixed agonist-antagonist effects in vivo. While this opens the possibility of novel therapeutics, it complicates rational drug design, since the in vivo response to a biased agonist cannot be reliably predicted from its in cellula efficacy. We have employed novel informatic approaches to characterize the in vivo transcriptomic signature of the arrestin pathway-selective parathyroid hormone analog [d-Trp(12), Tyr(34)]bovine PTH(7-34) in six different murine tissues after chronic drug exposure. We find that [d-Trp(12), Tyr(34)]bovine PTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated across tissues than that of the pluripotent agonist, human PTH(1-34). This arrestin-focused network is closely associated with transcriptional control of cell growth and development. Our demonstration of a conserved arrestin-dependent transcriptomic signature suggests a framework within which the in vivo outcomes of arrestin-biased signaling may be generalized.
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.) stuart.maudsley@molgen.vib-ua.be.
authors: Stuart
authors: S
authors: Maudsley
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Bronwen
authors: B
authors: Martin
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Diane
authors: D
authors: Gesty-Palmer
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Huey
authors: H
authors: Cheung
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Calvin
authors: C
authors: Johnson
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Shamit
authors: S
authors: Patel
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Kevin G
authors: KG
authors: Becker
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: William H
authors: WH
authors: Wood
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Yongqing
authors: Y
authors: Zhang
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Elin
authors: E
authors: Lehrmann
authors: National Institutes of Health, National Institute on Aging, Baltimore, Maryland (S.M., B.M., S.P., K.G.B., W.H.W., Y.Z., E.L.); Department of Medicine, Duke University Medical Center, Durham, North Carolina (D.G.-P.); National Institutes of Health, Center for Information Technology, Bethesda, Maryland (H.C., C.J.); Department of Medicine and Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina (L.M.L.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (L.M.L.).
authors: Louis M
authors: LM
authors: Luttrell
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D019295:Computational Biology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D019390:Arrestins; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D044168:Receptor, Parathyroid Hormone, Type 1; C082333:arrestin3; C058350:parathyroid hormone (7-34)
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