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-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 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.
Footnotes
- Received August 5, 2014.
- Accepted January 30, 2015.
S.M., B.M., and D.G.-P. contributed equally to this work.
This research was supported by the Intramural Research Program of the National Institutes of Health National Institute on Aging; the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM095497]; the National Institutes of Health National Institute of Diabetes, Digestive and Kidney Diseases [Grant R01-DK055524]; the National Institutes of Health National Institute of Child Health and Human Development [Grant T32-HD043446]; the Arthritis Foundation; and the Research Service of the Charleston, SC Veterans Affairs Medical Center. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- U.S. Government work not protected by U.S. copyright
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