Delineation of a conserved arrestin-biased signaling repertoire in vivo

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Abstract

Biased G protein-coupled receptor agonists engender a restricted repertoire of downstream events from their cognate receptors, permitting them to producemixed 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-Trp12, Tyr34]bovine PTH(7-34) in six different murine tissues after chronic drug exposure. We find that [D-Trp12, Tyr34]bovine PTH(7-34) elicits a distinctive arrestinsignaling 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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Maudsley, S., Martin, B., Gesty-Palmer, D., Cheung, H., Johnson, C., Patel, S., … Luttrell, L. M. (2015). Delineation of a conserved arrestin-biased signaling repertoire in vivo. Molecular Pharmacology, 87(4), 706–717. https://doi.org/10.1124/mol.114.095224

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