β-Arrestin-biased signaling of PTH analogs of the type 1 parathyroid hormone receptor

• Published in: Cellular signalling 2013-02, Vol.25 (2), p.527-538
• Main Authors: van der Lee, Miranda M.C., Verkaar, Folkert, Wat, Jesse W.Y., van Offenbeek, Jody, Timmerman, Martijn, Voorneveld, Lonneke, van Lith, Lambertus H.C.J., Zaman, Guido J.R.
• Format: Article
• Language: English
• Subjects: Activation; Animals; Arrestins - metabolism; beta-Arrestins; Biased agonist; Bones; Calcium - metabolism; Cell Line; Cellular; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP - metabolism; Derivatives; Hormones; Humans; Low molecular weight; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Parathyroid Hormone - analogs & derivatives; Parathyroid Hormone - pharmacology; Parathyroid hormone receptor; Phosphorylation; PTH(7–34); PTHβarr; Receptor, Parathyroid Hormone, Type 1 - agonists; Receptor, Parathyroid Hormone, Type 1 - metabolism; Receptors; Recruitment; Signal Transduction - drug effects; Signalling; β-Arrestin
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2012.11.012

Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gαs-, Gαq- 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, Gαs- and Gαq-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. ► We made a platform to measure PTH1R signaling to cAMP, Ca2+ and β-arrestin. ► Our assays provide opportunities for identifying biased ligands for PTH1R. ► A presumed β-arrestin-biased PTH derivative (PTH(7–34)) did not activate β-arrestin. ► PTH(7–34)-mediated β-arrestin signaling may be cell type-specific.