RT Journal Article
SR Electronic
T1 Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor-Mediated Signaling Pathways
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.112.199752
DO 10.1124/jpet.112.199752
A1 Meghan E Cupp
A1 Amina S Adem
A1 Surendra K Nayak
A1 William J Thomsen
YR 2013
UL http://jpet.aspetjournals.org/content/early/2013/03/20/jpet.112.199752.abstract
AB Parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP), acting through the osteoblast PTH1R, play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation while continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including Gs/cAMP/PKA, Gq/calcium/PKC, β-arrestin recruitment and ERK1/2 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 hPTH1R functional assays capturing Gs- and Gq-signaling, β-arrestin recruitment, ERK1/2 phosphorylation and receptor internalization to further define patterns of of PTH1R signaling they stimulate and to further establish peptide domains contributing to agonist activity. Results indicate that both N- and C-terminal domains are critical for activation of signaling pathways. However, modifications of both regions leads 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. 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 peptide analogs 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.