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Title
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Delineation of a conserved arrestin-biased signaling repertoire in vivo
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Molecular pharmacology. - Bethesda, Md
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Publication
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Bethesda, Md
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2015
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ISSN
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0026-895X
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DOI
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10.1124/MOL.114.095224
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Volume/pages
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87
:4
(2015)
, p. 706-717
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ISI
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000352004100014
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Pubmed ID
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25637603
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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