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Regions of PTH(1–34) and PTHrP(1–34) Important for Human PTHR1‐Mediated Signaling
Author(s) -
Thomsen William,
Cupp Meghan,
Nayak Surendra
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb565
Subject(s) - parathyroid hormone , phosphorylation , osteoblast , microbiology and biotechnology , chemistry , signal transduction , bone resorption , mapk/erk pathway , protein kinase c , medicine , in vitro , endocrinology , calcium , biology , biochemistry , organic chemistry
Parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP), acting through osteoblast PTHR1, play important roles in bone remodeling. Activation of osteoblast PTHR1 leads to regulation of multiple signaling pathways including G s /cAMP/PKA, G q /IP/calcium/PKC, and G‐protein‐independent and beta‐arrestin‐mediated Erk1/2 phosphorylation. In vitro and in vivo studies using reported biased PTH peptides have lead to conflicting conclusions regarding which signaling pathway(s) are involved in bone formation and/or resorption. In this study, several PTH and PTHrP peptide analogs were evaluated in parallel assays capturing cAMP accumulation (DiscoveRX HitHunter TM assay), beta‐arrestin recruitment (DiscoveRX PathFinder TM assay), and Erk1/2 phosphorylation (CisBio TRF Cell'erk TM assay) using CHO‐K1 cells stably expressing human PTHR1. The specific aim of this investigation was to determine regions important for activation of these signaling pathways. Collectively our results suggest that both N‐terminal and C‐terminal regions are critical for both stimulation of cAMP accumulation and beta‐arrestin recruitment. In addition, peptide mediated stimulation of Erk1/2 phosphorylation parallels ability to promote beta‐arrestin recruitment.