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Research ArticleCellular and Molecular

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Meghan E. Cupp, Surendra K. Nayak, Amina S. Adem and William J. Thomsen
Journal of Pharmacology and Experimental Therapeutics June 2013, 345 (3) 404-418; DOI: https://doi.org/10.1124/jpet.112.199752
Meghan E. Cupp
Center for Neuroscience and Metabolic Diseases, SRI International, Harrisonburg, Virginia
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Surendra K. Nayak
Center for Neuroscience and Metabolic Diseases, SRI International, Harrisonburg, Virginia
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Amina S. Adem
Center for Neuroscience and Metabolic Diseases, SRI International, Harrisonburg, Virginia
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William J. Thomsen
Center for Neuroscience and Metabolic Diseases, SRI International, Harrisonburg, Virginia
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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 Gs/cAMP/protein kinase A, Gq/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 Gs- and Gq-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 Gq-signaling, β-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization than to stimulate Gs-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.

Footnotes

    • Received September 6, 2012.
    • Accepted March 14, 2013.
  • dx.doi.org/10.1124/jpet.112.199752.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 3
1 Jun 2013
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Research ArticleCellular and Molecular

Domains of PTH and PTHrP Mediating PTH1R Signaling

Meghan E. Cupp, Surendra K. Nayak, Amina S. Adem and William J. Thomsen
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 404-418; DOI: https://doi.org/10.1124/jpet.112.199752

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Research ArticleCellular and Molecular

Domains of PTH and PTHrP Mediating PTH1R Signaling

Meghan E. Cupp, Surendra K. Nayak, Amina S. Adem and William J. Thomsen
Journal of Pharmacology and Experimental Therapeutics June 1, 2013, 345 (3) 404-418; DOI: https://doi.org/10.1124/jpet.112.199752
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