Inhibition of the in vivo parathyroid hormone-mediated calcemic response in rats by a synthetic hormone antagonist.

Doppelt, Samuel H.; Neer, Robert M.; Nussbaum, Samuel R.; Federico, P; Potts, John T.; Rosenblatt, Michael

doi:10.1073/pnas.83.19.7557

Cited by 26 publications

(10 citation statements)

References 16 publications

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“…Others have demonstrated that smaller C-PTH fragments do not react with the PTH/PTHrP receptor, and that region 69 -84 has to be intact to react with the C-PTH receptor (15). The anticalcemic and antiphosphaturic effects of this PTH peptide in vivo were demonstrated at higher molar concentrations and were mediated by an inhibition of hPTH-(1-34) binding to the PTH/PTHrP receptor and of ligand-induced cAMP production (42,43). This last point was also demonstrated in a recent study (40).…”

Section: Discussionmentioning

confidence: 99%

Synthetic Carboxyl-Terminal Fragments of Parathyroid Hormone (PTH) Decrease Ionized Calcium Concentration in Rats by Acting on a Receptor Different from the PTH/PTH-Related Peptide Receptor

et al. 2001

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Even if the carboxyl-terminal (C-) fragments/intact (I-) PTH ratio is tightly regulated by the ionized calcium (Ca(2+)) concentration in humans and animals, in health and in disease, the physiological roles of C-PTH fragments and of the C-PTH receptor remain elusive. To explore these issues, we studied the influence of synthetic C-PTH peptides of various lengths on Ca(2+) concentration and on the calcemic response to human (h) PTH-(1-34) and hPTH-(1-84) in anesthetized thyroparathyroidectomized (TPTX) rats. We also looked at the capacity of these PTH preparations to react with the PTH/PTHrP receptor and with a receptor for the carboxyl (C)-terminal portion of PTH (C-PTH receptor) in rat osteosarcoma cells, ROS 17/2.8. The Ca(2+) concentration was reduced by 0.19 +/- 0.03 mmol/liter over 2 h in all TPTX groups. Infusion of solvent over 2 more h had no further effect on the Ca(2+) concentration (-0.01 +/- 0.01 mmol/liter), whereas infusion of hPTH-(7-84) or a fragment mixture [10% hPTH-(7-84) and 45% each of hPTH-(39-84) and hPTH-(53-84)] 10 nmol/h further decreased the Ca(2+) concentration by 0.18 +/- 0.02 (P<0.001) and 0.07+/-0.04 mmol/liter (P< 0.001), respectively. Infusion of hPTH-(1-84) or hPTH-(1-34) (1 nmol/h) increased the Ca(2+) concentration by 0.16 +/- 0.03 (P < 0.001) and 0.19 +/- 0.03 mmol/liter (P < 0.001), respectively. Adding hPTH-(7-84) (10 nmol/h) to these preparations prevented the calcemic response and maintained Ca(2+) concentrations equal to or below levels observed in TPTX animals infused with solvent alone. Adding the fragment mixture (10 nmol/h) to hPTH-(1-84) did not prevent a normal calcemic response, but partially blocked the response to hPTH-(1-34), and more than 3 nmol/h hPTH-(7-84) prevented it. Both hPTH-(1-84) and hPTH-(1-34) stimulated cAMP production in ROS 17/2.8 clonal cells, whereas hPTH-(7-84) was ineffective in this respect. Both hPTH-(1-84) and hPTH-(1-34) displaced (125)I-[Nle(8,18),Tyr(34)]hPTH-(1-34) amide from the PTH/PTHrP receptor, whereas hPTH-(7-84) had no such influence. Both hPTH-(1-84) and hPTH-(7-84) displaced (125)I-[Tyr(34)]hPTH-(19-84) from the C-PTH receptor, the former preparation being more potent on a molar basis, whereas hPTH-(1-34) had no effect. These results suggest that C-PTH fragments, particularly hPTH-(7-84), can influence the Ca(2+) concentration negatively in vivo and limit in such a way the calcemic responses to hPTH-(1-84) and hPTH-(1-34) by interacting with a receptor different from the PTH/PTHrP receptor, possibly a C-PTH receptor.

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Section: Discussionmentioning

confidence: 99%

Synthetic Carboxyl-Terminal Fragments of Parathyroid Hormone (PTH) Decrease Ionized Calcium Concentration in Rats by Acting on a Receptor Different from the PTH/PTH-Related Peptide Receptor

et al. 2001

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“…Deletion of residues 1–6 from the PTH(1–34) scaffold produced analogues that no longer activate signalling via the cAMP–PKA pathway, but instead, function as competitive antagonists of PTHR1-mediated cAMP signalling. 36 Further modification of the PTH(7–34) scaffold at residue position 12 produced an analogue, DTrp 12 -PTH(7–34), which in addition to competitively antagonizing cAMP signalling at PTHR1, 37 also acts as an inverse agonist and consequently reduces basal cAMP signalling at certain constitutively active PTHR1 variants. 38 Other PTH and PTHrP ligand analogues modified at residue position 1 have been developed that preferentially activate Gα S -cAMP signalling over Gα q -PLC-β signalling.…”

Section: Altered Signalling Of Pthr1 Ligandsmentioning

confidence: 99%

PTH receptor-1 signalling—mechanistic insights and therapeutic prospects

et al. 2015

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Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR) that regulates skeletal development, bone turnover and mineral ion homeostasis. PTHR1 transduces stimuli from PTH and PTHrP into the interior of target cells to promote diverse biochemical responses. Evaluation of the signalling properties of structurally modified PTHR1 ligands has helped to elucidate determinants of receptor function and mechanisms of downstream cellular and physiological responses. Analysis of PTHR1 responses induced by structurally modified ligands suggests that PTHR1 can continue to signal through a G-protein-mediated pathway within endosomes. Such findings challenge the longstanding paradigm in GPCR biology that the receptor is transiently activated at the cell membrane, followed by rapid deactivation and receptor internalization. Evaluation of structurally modified PTHR1 ligands has further led to the identification of ligand analogues that differ from PTH or PTHrP in the type, strength and duration of responses induced at the receptor, cellular and organism levels. These modified ligands, and the biochemical principles revealed through their use, might facilitate an improved understanding of PTHR1 function in vivo and enable the treatment of disorders resulting from defects in PTHR1 signalling. This Review discusses current understanding of PTHR1 modes of action and how these findings might be applied in future therapeutic agents.

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“…Combined removal of Ser/Ala 1 and Val 2 virtually eliminates adenylyl cyclase activation. Peptides lacking the first three to six amino acids are inhibitors of PTH action (23,42).…”

Section: Effects Of Pth On Receptor Activation and Receptor Turnovermentioning

confidence: 99%

PTH(1–84)/PTH(7–84): a balance of power

Friedman¹,

Goodman²

2006

American Journal of Physiology-Renal Physiology

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This review considers many new basic and clinical aspects of parathyroid hormone (PTH). We focus especially on the identification of PTH fragments and how they may relate to renal failure, diagnosis, and treatment of secondary hyperparathyroidism and renal osteodystrophy. The biosynthesis and metabolism of PTH, measurement of circulating forms of PTH, the effects of PTH on receptor activation and turnover, the relationship between PTH levels and bone turnover in renal failure in humans, and the involvement of PTH in experimental models of renal failure are discussed. Despite these developments in understanding the etiology of renal failure and the availability of new assays for bioactive PTH, no adequate surrogate for bone biopsy and quantitative bone histomorphometry has been developed.

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Inhibition of the in vivo parathyroid hormone-mediated calcemic response in rats by a synthetic hormone antagonist.

Cited by 26 publications

References 16 publications

Synthetic Carboxyl-Terminal Fragments of Parathyroid Hormone (PTH) Decrease Ionized Calcium Concentration in Rats by Acting on a Receptor Different from the PTH/PTH-Related Peptide Receptor

Synthetic Carboxyl-Terminal Fragments of Parathyroid Hormone (PTH) Decrease Ionized Calcium Concentration in Rats by Acting on a Receptor Different from the PTH/PTH-Related Peptide Receptor

PTH receptor-1 signalling—mechanistic insights and therapeutic prospects

PTH(1–84)/PTH(7–84): a balance of power

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