A β-Arrestin–Biased Agonist of the Parathyroid Hormone Receptor (PTH1R) Promotes Bone Formation Independent of G Protein Activation
- 7 October 2009
- journal article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 1 (1), 1ra1
- https://doi.org/10.1126/scitranslmed.3000071
Abstract
About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through β-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)–PTH-related protein receptor (PTH1R), (d-Trp12,Tyr34)-PTH(7–34) (PTH-βarr), which activates β-arrestin but not classic G protein signaling. In mice, PTH-βarr induces anabolic bone formation, as does the nonselective agonist PTH(1–34), which activates both mechanisms. In β-arrestin2–null mice, the increase in bone mineral density evoked by PTH(1–34) is attenuated and that stimulated by PTH-βarr is ablated. The β-arrestin2–dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the β-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity.Keywords
This publication has 51 references indexed in Scilit:
- Heptahelical Terpsichory. Who Calls the Tune?Journal of Receptors and Signal Transduction, 2008
- β-Arrestin-biased ligands at seven-transmembrane receptorsTrends in Pharmacological Sciences, 2007
- Transduction of Receptor Signals by ß-ArrestinsScience, 2005
- Targeted overexpression of G protein-coupled receptor kinase-2 in osteoblasts promotes bone lossAmerican Journal of Physiology-Endocrinology and Metabolism, 2005
- β-Arrestin2 Regulates the Differential Response of Cortical and Trabecular Bone to Intermittent PTH in Female MiceJournal of Bone and Mineral Research, 2005
- Protein Kinase A-mediated Phosphorylation of the β2-Adrenergic Receptor Regulates Its Coupling to Gs and GiPublished by Elsevier BV ,2002
- Internalization Determinants of the Parathyroid Hormone Receptor Differentially Regulate β-Arrestin/Receptor AssociationPublished by Elsevier BV ,2002
- Classical and new roles of β-arrestins in the regulation of G-PROTEIN-COUPLED receptorsNature Reviews Neuroscience, 2001
- Parathyroid Hormone Activates Mitogen-activated Protein Kinase via a cAMP-mediated Pathway Independent of RasPublished by Elsevier BV ,1997
- Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committeeJournal of Bone and Mineral Research, 1987