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Mol Pharmacol. 2015 Apr;87(4):706-17. doi: 10.1124/mol.114.095224. Epub 2015 Jan 30.

Delineation of a conserved arrestin-biased signaling repertoire in vivo.

Author information

1
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.
2
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.).

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.

PMID:
25637603
PMCID:
PMC4366796
DOI:
10.1124/mol.114.095224
[Indexed for MEDLINE]
Free PMC Article

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