TY - JOUR 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 SP - 404 LP - 418 DO - 10.1124/jpet.112.199752 VL - 345 IS - 3 AU - Meghan E. Cupp AU - Surendra K. Nayak AU - Amina S. Adem AU - William J. Thomsen Y1 - 2013/06/01 UR - http://jpet.aspetjournals.org/content/345/3/404.abstract N2 - 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. ER -