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The American Journal of Medicine Jun 1974
Review
Topics: Amino Acid Sequence; Animals; Binding Sites, Antibody; Cattle; Chromatography, Gel; Dogs; Epitopes; Humans; Hydrolysis; Iodine Radioisotopes; Kinetics; Metabolic Clearance Rate; Parathyroid Hormone; Peptide Fragments; Radioimmunoassay; Structure-Activity Relationship
PubMed: 4133938
DOI: 10.1016/0002-9343(74)90805-5 -
Science (New York, N.Y.) Apr 2019The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and...
The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the cryo-electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.
Topics: Amino Acid Motifs; Cryoelectron Microscopy; Humans; Parathyroid Hormone; Protein Binding; Protein Domains; Receptor, Parathyroid Hormone, Type 1
PubMed: 30975883
DOI: 10.1126/science.aav7942 -
Advances in Nephrology From the Necker... 1994The current understanding of the cellular mode of action of PTH has undergone deep changes during the last decade and the major acquisitions can be summarized as... (Review)
Review
The current understanding of the cellular mode of action of PTH has undergone deep changes during the last decade and the major acquisitions can be summarized as follows. First, results from biochemical and cell biology studies suggest the existence of at least two receptor types coupled to two distinct intracellular signaling pathways by G proteins: the phospholipase C-calcium-protein kinase C pathway would be coupled to high-affinity receptors, whereas the adenylate cyclase-cAMP-protein kinase A pathway would be coupled to low-affinity receptors. Until now, only one type of PTH receptor has been identified at the molecular level. It is very likely that additional PTH receptor types will be evidenced. Second, both PTH receptor-coupled transduction pathways are involved in the inhibitory effect of the hormone on the activity of two transport systems of the apical membrane of proximal tubular cells: Na-Pi cotransport and Na-H exchanger. These effects are the cellular basis for PTH inhibition of Pi and bicarbonate reabsorption. Which proteins are the targets of the different protein kinases remains to be established. Concerning the other effects of PTH on the proximal tubule (stimulation of neoglucogenesis and of calcitriol synthesis, and Na, K-ATPase inhibition), protein kinase C seems to play a major role. Third, in Henle's loop, PTH stimulates reabsorption of divalent cations through a dual effect under the dependence of protein kinase A, i.e., enhanced epithelial potential difference and opening of paracellular pathway. Finally, stimulation of distal calcium reabsorption results from multiple events: membrane insertion of apical calcium channels, opening of basolateral chloride channels resulting in cellular hyperpolarization, and modulation of Ca-ATPase. Again, while it is commonly acknowledged that both transduction systems are involved, their precise molecular targets remain to be identified (Table 1). The elucidation of the cellular mode of action of PTH, some examples of which have been reviewed, holds major interest far beyond the field of cell or organ physiology. It is the basis for understanding and, ultimately, for comprehensive treatment of genetic diseases characterized by functional abnormalities of molecules involved in the cascade of events leading to the effect of PTH on its cellular targets (hormone receptors, G proteins, and kinases). The second perspective is pharmacologic: molecular and structural identification of PTH-receptor interactions will be a prelude to design and synthesis of new selective, nonpeptidic hormonal analogs and antagonists that are easier to handle. The high incidence and severity of secondary hyperparathyroidism during chronic renal failure highlights the importance of this research.
Topics: Animals; Humans; Kidney Tubules, Proximal; Parathyroid Hormone; Receptors, Parathyroid Hormone
PubMed: 8154358
DOI: No ID Found -
Endocrinology Nov 1986The biologically active PTH fragment 1-34 induces mononuclear leukocytes to produce a substance(s) capable of increasing bone resorption, as assayed in an organ culture...
The biologically active PTH fragment 1-34 induces mononuclear leukocytes to produce a substance(s) capable of increasing bone resorption, as assayed in an organ culture system. The onset of the effect is evident at 2 days and lasts at least 7 days. The cell responsible for this effect appears to be an activated nonadherent lymphocyte (probably T-cell). PTH-(1-34) induces these cells to secrete this factor(s). The presence of adherent mononuclear leukocytes or appropriate conditioned medium appears to augment this response. Secretion of this factor(s) is specific for PTH-(1-34); it is not induced by biologically inactive PTH fragments, nor can it be induced by incubating mononuclear leukocytes with other hormones, including human PRL or lysine vasopressin. On the other hand, PTH-(1-34), human PRL, and lysine vasopressin all activate mononuclear leukocytes, as determined by [3H]thymidine incorporation. Biologically inactive PTH fragments do not. Thus, while lymphocyte activation may be a necessary prerequisite to lymphocyte modulation of bone resorption, it is not sufficient of itself. The PTH fragment 1-34 activates mononuclear leukocytes and specifically induces nonadherent lymphocytes to produce a substance(s) capable of increasing bone resorption. Preliminary characterization of this substance(s) shows that cellular components of the organ culture are necessary to demonstrate the increased resorptive capacity of PTH-stimulated lymphocyte supernatants. Secondly, this resorptive capacity is heat sensitive. Finally, this substance(s) appears to have a nominal molecular radius greater than 14,000 daltons, but less than 50,000 daltons.
Topics: Bone Resorption; Cell Adhesion; Culture Media; Humans; Indomethacin; Lymphocytes; Molecular Weight; Organ Culture Techniques; Parathyroid Hormone; Peptide Fragments; Teriparatide; Thymidine; Time Factors
PubMed: 3769872
DOI: 10.1210/endo-119-5-2333 -
Endocrinology Nov 1995
Review
Topics: Animals; Humans; Parathyroid Hormone; Peptide Fragments
PubMed: 7588199
DOI: 10.1210/endo.136.11.7588199 -
The Journal of Endocrinology Sep 1997
Review
Topics: Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Parathyroid Hormone; Receptors, Parathyroid Hormone; Structure-Activity Relationship
PubMed: 9379133
DOI: No ID Found -
Contributions To Nephrology 1980Circulating immunoreactive PTH consists primarily of intact hormone and a biologically inactive C-terminal fragment. About half of the intact PTH is removed by the... (Review)
Review
Circulating immunoreactive PTH consists primarily of intact hormone and a biologically inactive C-terminal fragment. About half of the intact PTH is removed by the kidney and half by other mechanisms. In contrast, the kidney appears almost solely responsible for removal of the C-terminal fragment. There have as yet not been definitive answers to the following questions: Where in the body is the long-lived C-terminal fragment produced? What is the quantitative relation between the disappearance half-time of the C-terminal fragment and some measure of the stage of kidney dysfunction? What is the true prevalence of ectopic PTH production?
Topics: Amino Acid Sequence; Animals; Chemical Phenomena; Chemistry; Hormones, Ectopic; Humans; Parathyroid Hormone; Radioimmunoassay; Time Factors
PubMed: 6995011
DOI: 10.1159/000384950 -
Biochemical Society Transactions Aug 2007Over the years, the association of peptide ligands to Family B GPCRs (G-protein coupled receptors) has been characterized by a number of experimental and theoretical... (Review)
Review
Over the years, the association of peptide ligands to Family B GPCRs (G-protein coupled receptors) has been characterized by a number of experimental and theoretical techniques. For the PTH (parathyroid hormone) ligand-receptor system, important insight has been provided by photoaffinity labelling experiments and the elucidation of direct contact points between ligand and receptor. Our research has focused on the structural elucidation of the receptor domains shown to be involved in the binding of PTH. Employing a combination of carefully designed receptor domains, solution-state NMR carried out in the presence of membrane mimetics and extensive computer simulations, we have obtained a well-resolved model of the ligand-receptor complex for PTH. Here, we review the development of this model and highlight some inherent limitations of the methods employed and their consequences on interpretation of the ligand-receptor model.
Topics: Animals; Humans; Ligands; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Protein Binding; Protein Structure, Tertiary; Receptor, Parathyroid Hormone, Type 1
PubMed: 17635133
DOI: 10.1042/BST0350721 -
Bone Oct 2000
Review
Topics: Animals; Bone Resorption; Humans; Mice; Osteoblasts; Parathyroid Hormone; Peptide Fragments
PubMed: 11033440
DOI: 10.1016/s8756-3282(00)00364-1 -
BMJ Open Jan 2018Fracture healing is a complex physiological process. Impaired healing will increase the need for care and cause serious complications. Thus, identifying strategies to... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Fracture healing is a complex physiological process. Impaired healing will increase the need for care and cause serious complications. Thus, identifying strategies to accelerate the rate of healing, preventing delayed unions and non-unions, is essential. Parathyroid hormone (PTH) is a key systemic regulator of calcium and phosphate metabolism. It has been determined that intermittent administration of PTH and its analogue can exert anabolic effect on bone, increase bone mass and reduce bone loss, leading to an increase in bone formation. Owing to their anabolic effect, there is an increasing interest in its potential in promoting the process of fracture healing. However, in clinical studies, the results are in conflict. This objective of this study is to determine the role of PTH analogues for fracture healing in adults.
METHODS AND ANALYSIS
MEDLINE, EMBASE and Cochrane databases will be searched to identify all randomised controlled trials (RCTs) and quasi-RCTs that compare the different effects between PTH analogues and any other treatments in adults with any type of fracture. The primary outcome is the functional recovery. And the secondary outcomes are fracture union and adverse events. The meta-analysis will be performed using a random effects model. Heterogeneity will be assessed by the P values and I² statistic. And subgroup analyses and sensitivity analyses will be used to explore the heterogeneity. Risk of bias will be assessed using the Cochrane tool and the quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.
ETHICS AND DISSEMINATION
Ethical approval is not required because this proposed systematic review and meta-analysis is based on published data, without including confidential personal data or data on interventions on patients. The findings of this study will be published in a peer-reviewed journaland presented at a relevant conference.
PROSPERO REGISTRATION NUMBER
CRD42017062093.
Topics: Adult; Bone Density; Fracture Healing; Fractures, Bone; Humans; Parathyroid Hormone; Randomized Controlled Trials as Topic; Systematic Reviews as Topic
PubMed: 29362267
DOI: 10.1136/bmjopen-2017-019291