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| Status |
Public on Mar 05, 2015 |
| Title |
Delineation of a conserved arrestin-biased signaling repertoire in vivo |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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 vitro efficacy. We have employed novel informatic approaches to characterize the in vivo transcriptomic signature of the arrestin pathway-selective parathyroid hormone analog [D-Trp12, Tyr34]-bPTH(7-34) in six different murine tissues after chronic drug exposure. We find that [D-Trp12, Tyr34]-bPTH(7-34) elicits a distinctive arrestin-signaling focused transcriptomic response that is more coherently regulated across tissues than that of the pluripotent agonist, hPTH(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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| Overall design |
Eleven-week-old male wild type C57BL/6J or congenic arrestin3-null mice were infused with human 40 µg/kg d PTH(1-34), 40 µg/kg d bovine (D-Trp12, Tyr34)-PTH(7-34), or PBS vehicle via Alzet osmotic minipumps (Model #1004, Durect Corp., Cupertino, CA) for 28 days. Minipumps were implanted subcutaneously in the upper back of anesthetized mice. The pump released 0.25 uL/hr in vehicle of 1 mM acetic acid in sterile PBS. At the end of the infusion period, animals were sacrificed and target tissues: calvarial bone, heart, lung, liver, kidney and aorta, were harvested and stored at -80 ˚C until mRNA isolation. Animal protocols were approved by the institutional animal care and use committee at Duke University School of Medicine and were in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
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| Contributor(s) |
Maudsley S, Martin B, Gesty-Palmer D, Cheung H, Johnson C, Patel S, Becker KG, Wood III WH, Zhang Y, Lehrmann E, Luttrell LM |
| Citation(s) |
30608923, 25637603, 25986936 |
| Submission date |
Dec 23, 2014 |
| Last update date |
Jun 22, 2020 |
| Contact name |
Supriyo De |
| Organization name |
NIA-IRP, NIH
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| Department |
Laboratory of Genetics and Genomics
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| Lab |
Computational Biology & Genomics Core
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| Street address |
251 Bayview Blvd
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| City |
Baltimore |
| State/province |
Maryland |
| ZIP/Postal code |
21224 |
| Country |
USA |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (62)
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| Relations |
| BioProject |
PRJNA271097 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE64485_RAW.tar |
3.1 Mb |
(http)(custom) |
TAR |
| GSE64485_non-normalized.txt.gz |
9.6 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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