Comparable Initial Engagement of Intracellular Signaling Pathways by Parathyroid Hormone Receptor Ligands Teriparatide, Abaloparatide, and Long‐Acting PTH

Sato, Tadatoshi; Verma, Shiv Kumar; Khatri, Ashok; Dean, Thomas R.; Göransson, Olga; Gardella, Thomas J.; Wein, Marc N.

doi:10.1002/jbm4.10441

Cited by 21 publications

(32 citation statements)

References 58 publications

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“…The authors of this study ( 102 ) indicated that their findings of no subtle differences between PTH (1–34) and abaloparatide in early actions that have been previously reported ( 98 – 100 ) might relate to limitations in design and sensitivity of assays. They also consider the possibility that the differences noted by others in clinical studies might be related to pharmacokinetic or other factors ( 102 ).…”

Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 69%

“…The lack of prolonged effect on cAMP production by PTHrP (1–36) or abaloparatide was considered to be due to reduced internalization of receptor, and faster recycling possibly caused by endosomal pH sensitivity ( 99 , 100 ). Abaloparatide, which had been developed as a new analog ( 101 ) for therapeutic use in osteoporosis, is identical to PTHrP in its first 21 residues, but has 8 residues different from PTHrP between 22 and 34, and is equipotent with PTH peptides in the standard bioassay of total cell cAMP generation in target cells ( 79 , 100 , 102 ).…”

Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 99%

“…These views of differences in modes of interaction with receptor might need reconsideration in light of a further study of signaling events with peptide engagement of PTH1R. In comparing actions of PTH (1–34) and abaloparatide in an osteocyte cell line, a number of assays were used that showed that PTH (1–34) and abaloparatide were indistinguishable in their early receptor-related effects ( 102 ). They induced intracellular calcium equally and were equipotent in a standard cAMP response assay with full phosphodiesterase inhibition, as has been shown many times ( 100 , 104 ).…”

Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 99%

“…This revealed no difference in phosphorylation of substrates between the two ligands, PTH (1–34) and abaloparatide. Further, PTH (1–34), abaloparatide and M-PTH showed comparable effects on salt inducible kinase (SIK2) phosphorylation, substrate dephosphorylation and downstream gene expression ( 102 ). All of these findings suggest equivalent signaling effects of PTH (1–34) and abaloparatide.…”

Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 99%

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PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway

Martın

2022

Front. Endocrinol.

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After the initial signaling action of parathyroid hormone (PTH) on bone was shown to be activation of adenylyl cyclase, its target was found to be cells of the osteoblast lineage, to the exclusion of osteoclasts and their precursors. This led to the view that the osteoblast lineage regulated osteoclast formation, a proposal that was established when the molecular mechanisms of osteoclast formation were discovered. This is in addition to the effect of PTH1Rv signaling throughout the osteoblast differentiation process to favour the formation of bone-forming osteoblasts. Initial signaling in the PTH target cells through cAMP and protein kinase A (PKA) activation is extremely rapid, and marked by an amplification process in which the later event, PKA activation, precedes cAMP accumulation in time and is achieved at lower concentrations. All of this is consistent with the existence of “spare receptors”, as is the case with several other peptide hormones. PTH-related protein (PTHrP), that was discovered as a cancer product, shares structural similarity with PTH in the amino-terminal domain that allows the hormone, PTH, and the autocrine/paracrine agent, PTHrP, to share actions upon a common G protein coupled receptor, PTH1R, through which they activate adenylyl cyclase with equivalent potencies. Studies of ligand-receptor kinetics have revealed that the PTH/PTH1R ligand-receptor complex, after initial binding and adenylyl cyclase activation at the plasma membrane, is translocated to the endosome, where adenylyl cyclase activation persists for a further short period. This behavior of the PTH1R resembles that of a number of hormones and other agonists that undergo such endosomal translocation. It remains to be determined whether and to what extent the cellular effects through the PTH1R might be influenced when endosomal is added to plasma membrane activation.

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Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 69%

Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 99%

Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 99%

Section: Persistent Activation Of Adenylyl Cyclase In Endosome By Pth and Pthrp Peptidesmentioning

confidence: 99%

See 2 more Smart Citations

PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway

Martın

2022

Front. Endocrinol.

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“…Pleiotropic in its downstream coupling, PTH1R signals primarily via Gs, but can also couple to Gq 18 , G12/13 19 and Gi 20 , and interacts with and signals via β-arrestins 21,22 . The two endogenous agonists, parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), trigger PTH1R activation with similar kinetics and specificity for the various intracellular pathways [23][24][25] . However, PTH can induce prolonged signalling from intracellular sites, while PTHrP signals exclusively from the cell surface 26 .…”

Section: Introductionmentioning

confidence: 99%

Functional modulation of PTH1R activation and signalling by RAMP2

Nemec

Schihada

Kleinau

et al. 2021

Preprint

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Receptor-activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that associate with different G protein-coupled receptors (GPCRs) including the parathyroid hormone 1 receptor (PTH1R), a class B GPCR, and an important modulator of mineral ion homeostasis and bone metabolism. However, it is unknown whether and how RAMP proteins may affect PTH1R function. Using different optical biosensors to measure the activation of PTH1R and its downstream signalling, we describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique pre-activated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signalling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signalling sensitivity. Additionally, RAMP2 increases both PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R. Employing homology modelling we describe the putative structural molecular basis underlying our functional findings. These data uncover a critical role of RAMPs in the activation and signalling of a GPCR that may provide a new venue for highly specific modulation of GPCR function and advanced drug design.

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Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

et al. 2022

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Consistent with a vital role of parathyroid hormone (PTH) receptor type 1 (PTH1R) in skeletal development, homozygous loss‐of‐function PTH1R mutations in humans results in neonatal lethality (Blomstrand chondrodysplasia), whereas such heterozygous mutations cause a primary failure of tooth eruption (PFE). Despite a key role of PTH1R in calcium and phosphate homeostasis, blood mineral ion levels are not altered in such cases of PFE. Recently, two nonlethal homozygous PTH1R mutations were identified in two unrelated families in which affected members exhibit either dental and skeletal abnormalities (PTH1R‐V204E) or hypocalcemia and hyperphosphatemia (PTH1R‐R186H). Arg186 and Val204 map to the first transmembrane helix of the PTH1R, and thus to a critical region of this class B G protein‐coupled receptor. We used cell‐based assays and PTH and PTH‐related protein (PTHrP) ligand analogs to assess the impact of the R186H and V204E mutations on PTH1R function in vitro. In transiently transfected HEK293 cells, PTH1R‐R186H mediated cyclic adenosine monophosphate (cAMP) responses to PTH(1‐34) and PTHrP(1‐36) that were of comparable potency to those observed on wild‐type PTH1R (PTH1R‐WT) (half maximal effective concentrations [EC50s] = 0.4nM to 1.2nM), whereas the response‐maxima were significantly reduced for the PTH1R‐V204E mutant (maximum effect [Emax] = 81%–77% of PTH1R‐WT, p ≤ 0.004). Antibody binding to an extracellular hemagglutinin (HA) tag was comparable for PTH1R‐R186H and PTH1R‐WT, but was significantly reduced for PTH1R‐V204E (maximum binding level [Bmax] = 44% ± 11% of PTH1R‐WT, p = 0.002). The potency of cAMP signaling induced by a PTH(1‐11) analog was reduced by ninefold and threefold, respectively, for PTH1R‐R186H and PTH1R‐V204E, relative to PTH1R‐WT, and a PTH(1‐15) radioligand analog that bound adequately to PTH1R‐WT exhibited little or no specific binding to either mutant receptor. The data support a general decrease in PTH1R surface expression and/or function as a mechanism for PFE and a selective impairment in PTH ligand affinity as a potential PTH1R‐mutation‐based mechanism for pseudohypoparathyroidism. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Comparable Initial Engagement of Intracellular Signaling Pathways by Parathyroid Hormone Receptor Ligands Teriparatide, Abaloparatide, and Long‐Acting PTH

Cited by 21 publications

References 58 publications

PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway

PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway

Functional modulation of PTH1R activation and signalling by RAMP2

Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

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