RT Journal Article
SR Electronic
T1 Delineation of a Conserved Arrestin-Biased Signaling Repertoire In Vivo
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.095224
DO 10.1124/mol.114.095224
A1 Stuart Maudsley
A1 Bronwen Martin
A1 Diane Gesty-Palmer
A1 Huey Cheung
A1 Calvin Johnson
A1 Shamit Patel
A1 Kevin G. Becker
A1 William H. Wood
A1 Yongqing Zhang
A1 Elin Lehrmann
A1 Louis M. Luttrell
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/01/30/mol.114.095224.abstract
AB 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.