title: β-Arrestin-biased signaling of PTH analogs of the type 1 parathyroid hormone receptor.
abstract: Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gα(s)-, Gα(q)- and β-arrestin-coupled parathyroid hormone receptor type 1 (PTH1R). Pharmacological evidence based on the effect of PTH(7-34), a PTH derivative that is said to preferentially activate β-arrestin signaling through PTH1R, suggests that PTH1R-activated β-arrestin signaling mediates anabolic effects on bone. Here, we performed a thorough evaluation of PTH(7-34) signaling behaviour using quantitative assays for β-arrestin recruitment, Gα(s)- and Gα(q)-signaling. We found that PTH(7-34) inhibited PTH-induced cAMP accumulation, but was unable to induce β-arrestin recruitment, PTH1R internalization and ERK1/2 phosphorylation in HEK293, CHO and U2OS cells. Thus, the β-arrestin bias of PTH(7-34) is not apparent in every cell type examined, suggesting that correlating in vivo effects of PTH(7-34) to in vitro pharmacology should be done with caution.
authors.affiliation: Merck Research Laboratories, Molecular Pharmacology & DMPK, Oss, The Netherlands.
authors.forename: Miranda M C
authors.initials: MM
authors.lastname: van der Lee
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.forename: Jesse W Y
authors.initials: JW
authors.lastname: Wat
authors.forename: Jody
authors.initials: J
authors.lastname: van Offenbeek
authors.forename: Martijn
authors.initials: M
authors.lastname: Timmerman
authors.forename: Lonneke
authors.initials: L
authors.lastname: Voorneveld
authors.forename: Lambertus H C J
authors.initials: LH
authors.lastname: van Lith
authors.forename: Guido J R
authors.initials: GJ
authors.lastname: Zaman
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010281:Parathyroid Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D010766:Phosphorylation; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D000071557:beta-Arrestins; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium