title: A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation.
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 beta-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-Trp(12),Tyr(34))-PTH(7-34) (PTH-betaarr), which activates beta-arrestin but not classic G protein signaling. In mice, PTH-betaarr induces anabolic bone formation, as does the nonselective agonist PTH(1-34), which activates both mechanisms. In beta-arrestin2-null mice, the increase in bone mineral density evoked by PTH(1-34) is attenuated and that stimulated by PTH-betaarr is ablated. The beta-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 beta-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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Gesty-Palmer
authors.forename: Pat
authors.initials: P
authors.lastname: Flannery
authors.forename: Ling
authors.initials: L
authors.lastname: Yuan
authors.forename: Leonor
authors.initials: L
authors.lastname: Corsino
authors.forename: Robert
authors.initials: R
authors.lastname: Spurney
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: Louis M
authors.initials: LM
authors.lastname: Luttrell
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D015519:Bone Density; D001846:Bone Development / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044168:Receptor, Parathyroid Hormone, Type 1; D000071557:beta-Arrestins; D019204:GTP-Binding Proteins