title: β-arrestin-selective G protein-coupled receptor agonists engender unique biological efficacy in vivo.
abstract: Biased G protein-coupled receptor agonists are orthosteric ligands that possess pathway-selective efficacy, activating or inhibiting only a subset of the signaling repertoire of their cognate receptors. In vitro, D-Trp(12),Tyr(34)-bPTH(7-34) [bPTH(7-34)], a biased agonist for the type 1 PTH receptor, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, both bPTH(7-34) and the conventional agonist hPTH(1-34) stimulate anabolic bone formation. To understand how two PTH receptor ligands with markedly different in vitro efficacy could elicit similar in vivo responses, we analyzed transcriptional profiles from calvarial bone of mice treated for 8 wk with vehicle, bPTH(7-34) or hPTH(1-34). Treatment of wild-type mice with bPTH(7-34) primarily affected pathways that promote expansion of the osteoblast pool, notably cell cycle regulation, cell survival, and migration. These responses were absent in β-arrestin2-null mice, identifying them as downstream targets of β-arrestin2-mediated signaling. In contrast, hPTH(1-34) primarily affected pathways classically associated with enhanced bone formation, including collagen synthesis and matrix mineralization. hPTH(1-34) actions were less dependent on β-arrestin2, as might be expected of a ligand capable of G protein activation. In vitro, bPTH(7-34) slowed the rate of preosteoblast proliferation, enhanced osteoblast survival when exposed to an apoptotic stimulus, and stimulated cell migration in wild-type, but not β-arrestin2-null, calvarial osteoblasts. These results suggest that bPTH(7-34) and hPTH(1-34) affect bone mass in vivo through predominantly separate genomic mechanisms created by largely distinct receptor-signaling networks and demonstrate that functional selectivity can be exploited to change the quality of G protein-coupled receptor efficacy.
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors: Diane
authors: D
authors: Gesty-Palmer
authors: Ling
authors: L
authors: Yuan
authors: Bronwen
authors: B
authors: Martin
authors: William H
authors: WH
authors: Wood
authors: Mi-Hye
authors: MH
authors: Lee
authors: Michael G
authors: MG
authors: Janech
authors: Lam C
authors: LC
authors: Tsoi
authors: W Jim
authors: WJ
authors: Zheng
authors: Louis M
authors: LM
authors: Luttrell
authors: Stuart
authors: S
authors: Maudsley
mesh_terms: D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015519:Bone Density; D001846:Bone Development; D001842:Bone and Bones / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts; D010012:Osteogenesis; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D019379:Teriparatide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C058350:parathyroid hormone (7-34); D019379:Teriparatide; C035748:parathyroid hormone (1-34)amide