Delineation of a Conserved Arrestin-Biased Signaling Repertoire In Vivo
| Autor: | William H. Wood, Shamit Patel, Bronwen Martin, Kevin G. Becker, Yongqing Zhang, Calvin A. Johnson, Louis M. Luttrell, Elin Lehrmann, Stuart Maudsley, Huey Cheung, Diane Gesty-Palmer |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Agonist Transcription Genetic Arrestins medicine.drug_class Drug design Parathyroid hormone Biology Species Specificity In vivo Transcriptional regulation Arrestin medicine Animals Humans Receptor Receptor Parathyroid Hormone Type 1 Mice Knockout Pharmacology Pharmacology. Therapy Computational Biology Articles Molecular biology Peptide Fragments Cell biology Mice Inbred C57BL Organ Specificity Parathyroid Hormone Molecular Medicine Cattle Signal transduction Transcriptome Signal Transduction |
| Zdroj: | Molecular pharmacology |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.114.095224 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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