Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor-Mediated Signaling Pathways
Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor-Mediated Signaling Pathways
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DOI：
10.1124/jpet.112.199752
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发表时间：
2013-06-01
影响因子：
3.5
通讯作者：
Thomsen, William J.
中科院分区：
文献类型：
--
作者：
Cupp, Meghan E.;Nayak, Surendra K.;Thomsen, William J.
甲状旁腺激素（PTH）和甲状旁腺相关肽（PTHrP）通过成骨细胞PTH 1受体（PTH 1 R）发挥作用，在骨重建中起重要作用。间歇性给予PTH（1-34）（特立哌齐）导致骨形成，而连续给药反而导致骨吸收。PTH 1 R的激活促进多种信号通路的调节，包括G（s）/cAMP/蛋白激酶A、G（q）/钙/蛋白激酶C、β-抑制蛋白募集和细胞外信号相关激酶（ERK）1/2磷酸化以及受体内化，但它们在促进PTH（1-34）的合成代谢和分解代谢作用中的作用尚不清楚。在本研究中，在正交人PTH 1 R（hPTH 1 R）功能测定中评价了一系列PTH（1-34）和PTHrP（1-34）肽类似物，这些测定捕获G（s）-和G（q）-信号传导、β-抑制蛋白募集、ERK 1/2磷酸化和受体内化，以进一步确定它们刺激的PTH 1 R信号传导模式，并进一步建立有助于激动剂活性的肽结构域。结果表明，PTH和PTHrP的N-和C-末端结构域对于信号通路的激活是至关重要的。然而，两个区域的修饰导致激动剂效力和刺激G（q）-信号传导、β-抑制蛋白募集、ERK 1/2磷酸化和受体内化的功效比刺激G（s）-信号传导的功效更显著降低。肽C-末端结构域在hPTH 1 R信号传导的活化中的实质性贡献表明肽N-末端区域定位到受体J-结构域中的作用。本研究中评估的几种PTH和PTHrP肽促进不同模式的偏向激动剂信号传导，并可作为有用的工具，以进一步阐明成骨细胞中治疗相关的PTH 1 R信号传导。随着对治疗相关信号传导的更好理解，可以设计具有所需信号传导的新型偏向肽，以更安全和更有效地治疗骨质疏松症。
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, beta-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, beta-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, beta-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.