title: Parathyroid hormone (PTH) and PTH-related peptide domains contributing to activation of different PTH receptor-mediated signaling pathways.
abstract: Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), acting through the osteoblast PTH1 receptor (PTH1R), play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation, whereas continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including G(s)/cAMP/protein kinase A, G(q)/calcium/protein kinase C, β-arrestin recruitment, and extracellular signal-related kinase (ERK)1/2 phosphorylation, as well as receptor internalization, but their role in promoting anabolic and catabolic actions of PTH(1-34) are unclear. In the present investigation, a collection of PTH(1-34) and PTHrP(1-34) peptide analogs were evaluated in orthogonal human PTH1R (hPTH1R) functional assays capturing G(s)- and G(q)-signaling, β-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization to further define the patterns of PTH1R signaling that they stimulate and further establish peptide domains contributing to agonist activity. Results indicate that both N- and C-terminal domains of PTH and PTHrP are critical for activation of signaling pathways. However, modifications of both regions lead to more substantial decreases in agonist potency and efficacy to stimulate G(q)-signaling, β-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization than to stimulate G(s)-signaling. The substantial contribution of the peptide C-terminal domain in activation of hPTH1R signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain. Several PTH and PTHrP peptides evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts. With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis.
authors.affiliation: Center for Cancer and Metabolic Diseases, SRI International, 140 Research Drive, Harrisonburg, VA 22802, USA.
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Cupp
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Nayak
authors.forename: Amina S
authors.initials: AS
authors.lastname: Adem
authors.forename: William J
authors.initials: WJ
authors.lastname: Thomsen
mesh_terms: D000465:Algorithms; D000818:Animals; D019393:Arrestin / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D010281:Parathyroid Hormone / Q000737:chemistry / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019393:Arrestin; D050071:Bone Density Conservation Agents; D007295:Inositol Phosphates; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D044183:Receptor, Parathyroid Hormone, Type 2; C054296:parathyroid hormone-related protein (1-34); D000242:Cyclic AMP; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs