المؤلفون: Christoph Klenk, Leif Hommers, Martin J. Lohse

المصدر: Frontiers in Endocrinology, Vol 13 (2022)

مصطلحات موضوعية: GPCRs, parathyroid hormone 1 receptor, matrix metalloproteinase, ectodomain cleavage, biased signaling, Diseases of the endocrine glands. Clinical endocrinology, RC648-665

الوصف: Parathyroid hormone 1 receptor (PTH1R) is a member of the class B family of G protein-coupled receptors, which are characterized by a large extracellular domain required for ligand binding. We have previously shown that the extracellular domain of PTH1R is subject to metalloproteinase cleavage in vivo that is regulated by ligand-induced receptor trafficking and leads to impaired stability of PTH1R. In this work, we localize the cleavage site in the first loop of the extracellular domain using amino-terminal protein sequencing of purified receptor and by mutagenesis studies. We further show, that a receptor mutant not susceptible to proteolytic cleavage exhibits reduced signaling to Gs and increased activation of Gq compared to wild-type PTH1R. These findings indicate that the extracellular domain modulates PTH1R signaling specificity, and that its cleavage affects receptor signaling.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fendo.2022.839351/fullTest; https://doaj.org/toc/1664-2392Test

الوصول الحر: https://doaj.org/article/935fb72434e34706bb014467e30863b4Test

المؤلفون: Ryo Araki, Toru Asari, Hitoshi Kudo, Eiji Sasaki, Ryota Yamauchi, Xizhe Liu, Kanichiro Wada, Gentaro Kumagai, Ayako Sasaki, Ken-Ichi Furukawa, Yasuyuki Ishibashi

المصدر: Journal of Pharmacological Sciences, Vol 145, Iss 1, Pp 23-28 (2021)

مصطلحات موضوعية: Ossification of the posterior longitudinal ligament, Ligamentum flavum, Mesenchymal stem cells, Teriparatide, Parathyroid hormone 1 receptor, Therapeutics. Pharmacology, RM1-950

الوصف: Ossification of the posterior longitudinal ligament (OPLL) within the spinal canal sometimes leads to severe myelopathy. Teriparatide (TPD) is a recombinant human parathyroid hormone (PTH) (1–34), which promotes osteogenesis of mesenchymal stem cells (MSCs) via PTH 1 receptor (PTH1R). Although ligamentum flavum (LF)-MSCs from patients with OPLL have a high osteogenic potency, the effect of TPD on them remains unknown. In this study, we determined PTH1R expression in LF-MSCs from patients with OPLL and investigated whether TPD promotes osteogenic differentiation in them. First, LF-MSCs were isolated from patients with OPLL and cervical spondylotic myelopathy (CSM) (controls). Cultured LF-MSCs were treated with different concentrations of TPD on days 0, 7, and 14. On day 21, osteogenic gene expression was quantified. Mineralization was measured based on optical density after Alizarin Red S staining. LF-MSCs from both groups expressed PTH1R at the same level. TPD did not enhance osteogenic gene expression and mineralization in LF-MSCs from both groups. TPD did not promote the osteogenic differentiation of LF-MSCs from patients with OPLL. Thus, it may be safe for patients with OPLL. However, further confirmation of our results with in vivo studies is necessary.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1347861320301006Test; https://doaj.org/toc/1347-8613Test

الوصول الحر: https://doaj.org/article/6dfe4449ad884af0b1bfba449f1b64d0Test

المؤلفون: Rattana Chaimana, Jarinthorn Teerapornpuntakit, Walailak Jantarajit, Kornkamon Lertsuwan, Saowalak Krungchanuchat, Nattapon Panupinthu, Nateetip Krishnamra, Narattaphol Charoenphandhu

المصدر: Biochemistry and Biophysics Reports, Vol 27, Iss , Pp 101054- (2021)

مصطلحات موضوعية: Anion secretion, Cystic fibrosis transmembrane conductance regulator (CFTR), Parathyroid hormone (PTH), Parathyroid hormone 1 receptor (PTH1R), Phosphoinositide 3-kinase (PI3K), Protein kinase A (PKA), Biology (General), QH301-705.5, Biochemistry, QD415-436

الوصف: Parathyroid hormone (PTH) has previously been shown to enhance the transepithelial secretion of Cl− and HCO3− across the intestinal epithelia including Caco-2 monolayer, but the underlying cellular mechanisms are not completely understood. Herein, we identified the major signaling pathways that possibly mediated the PTH action to its known target anion channel, i.e., cystic fibrosis transmembrane conductance regulator anion channel (CFTR). Specifically, PTH was able to induce phosphorylation of protein kinase A and phosphoinositide 3-kinase. Since the apical HCO3− efflux through CFTR often required the intracellular H+/HCO3− production and/or the Na+-dependent basolateral HCO3− uptake, the intracellular pH (pHi) balance might be disturbed, especially as a consequence of increased endogenous H+ and HCO3− production. However, measurement of pHi by a pH-sensitive dye suggested that the PTH-exposed Caco-2 cells were able to maintain normal pH despite robust HCO3− transport. In addition, although the plasma membrane Na+/K+-ATPase (NKA) is normally essential for basolateral HCO3− uptake and other transporters (e.g., NHE1), PTH did not induce insertion of new NKA molecules into the basolateral membrane as determined by membrane protein biotinylation technique. Thus, together with our previous data, we concluded that the PTH action on Caco-2 cells is dependent on PKA and PI3K with no detectable change in pHi or NKA abundance on cell membrane.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2405580821001485Test; https://doaj.org/toc/2405-5808Test

الوصول الحر: https://doaj.org/article/88d58977020d45c39ffdbe5abae37921Test

المؤلفون: Ryota Yamauchi, Hitoshi Kudo, Xizhe Liu, Yasuyuki Ishibashi, Eiji Sasaki, Ryo Araki, Toru Asari, Gentaro Kumagai, Kanichiro Wada, Ayako Sasaki, Ken-Ichi Furukawa

المصدر: Journal of Pharmacological Sciences, Vol 145, Iss 1, Pp 23-28 (2021)

مصطلحات موضوعية: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Gene Expression, 03 medical and health sciences, Myelopathy, 0302 clinical medicine, Calcification, Physiologic, Osteogenesis, Teriparatide, Gene expression, medicine, Ossification of the posterior longitudinal ligament, Humans, Spinal canal, Receptor, Parathyroid hormone 1 receptor, Cells, Cultured, Aged, Receptor, Parathyroid Hormone, Type 1, Pharmacology, business.industry, Ossification, Heterotopic, Mesenchymal stem cell, lcsh:RM1-950, Cell Differentiation, Middle Aged, medicine.disease, Longitudinal Ligaments, 030104 developmental biology, medicine.anatomical_structure, lcsh:Therapeutics. Pharmacology, Ligamentum flavum, Molecular Medicine, Mesenchymal stem cells, Female, business, 030217 neurology & neurosurgery, medicine.drug, Hormone

الوصف: Ossification of the posterior longitudinal ligament (OPLL) within the spinal canal sometimes leads to severe myelopathy. Teriparatide (TPD) is a recombinant human parathyroid hormone (PTH) (1–34), which promotes osteogenesis of mesenchymal stem cells (MSCs) via PTH 1 receptor (PTH1R). Although ligamentum flavum (LF)-MSCs from patients with OPLL have a high osteogenic potency, the effect of TPD on them remains unknown. In this study, we determined PTH1R expression in LF-MSCs from patients with OPLL and investigated whether TPD promotes osteogenic differentiation in them. First, LF-MSCs were isolated from patients with OPLL and cervical spondylotic myelopathy (CSM) (controls). Cultured LF-MSCs were treated with different concentrations of TPD on days 0, 7, and 14. On day 21, osteogenic gene expression was quantified. Mineralization was measured based on optical density after Alizarin Red S staining. LF-MSCs from both groups expressed PTH1R at the same level. TPD did not enhance osteogenic gene expression and mineralization in LF-MSCs from both groups. TPD did not promote the osteogenic differentiation of LF-MSCs from patients with OPLL. Thus, it may be safe for patients with OPLL. However, further confirmation of our results with in vivo studies is necessary.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6e6960a064023e509554c0aa42725ecdTest
http://www.sciencedirect.com/science/article/pii/S1347861320301006Test

المؤلفون: Tatsuya Tamura, Toru Esaki, Yoshiaki Isshiki, Yoshikazu Nishimura, Yoshiyuki Furuta, 一色 義明, 古田 佳之, 江崎 徹, 田村 達也, 西村 祥和

المصدر: MEDCHEM NEWS. 2017, 27(3):153

المؤلفون: Walailak Jantarajit, Rattana Chaimana, Saowalak Krungchanuchat, Jarinthorn Teerapornpuntakit, Nattapon Panupinthu, Kornkamon Lertsuwan, Nateetip Krishnamra, Narattaphol Charoenphandhu

المصدر: Biochemistry and Biophysics Reports
Biochemistry and Biophysics Reports, Vol 27, Iss, Pp 101054-(2021)

مصطلحات موضوعية: 0301 basic medicine, QH301-705.5, Intracellular pH, Biophysics, Parathyroid hormone, QD415-436, Biochemistry, Cell membrane, 03 medical and health sciences, Parathyroid hormone 1 receptor (PTH1R), 0302 clinical medicine, medicine, Protein kinase A (PKA), Parathyroid hormone (PTH), Biology (General), Na+/K+-ATPase, Protein kinase A, Epithelial polarity, biology, Chemistry, Phosphoinositide 3-kinase (PI3K), respiratory system, Cystic fibrosis transmembrane conductance regulator, Cell biology, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, Cystic fibrosis transmembrane conductance regulator (CFTR), Intracellular, Research Article, Anion secretion

الوصف: Parathyroid hormone (PTH) has previously been shown to enhance the transepithelial secretion of Cl− and HCO3− across the intestinal epithelia including Caco-2 monolayer, but the underlying cellular mechanisms are not completely understood. Herein, we identified the major signaling pathways that possibly mediated the PTH action to its known target anion channel, i.e., cystic fibrosis transmembrane conductance regulator anion channel (CFTR). Specifically, PTH was able to induce phosphorylation of protein kinase A and phosphoinositide 3-kinase. Since the apical HCO3− efflux through CFTR often required the intracellular H+/HCO3− production and/or the Na+-dependent basolateral HCO3− uptake, the intracellular pH (pHi) balance might be disturbed, especially as a consequence of increased endogenous H+ and HCO3− production. However, measurement of pHi by a pH-sensitive dye suggested that the PTH-exposed Caco-2 cells were able to maintain normal pH despite robust HCO3− transport. In addition, although the plasma membrane Na+/K+-ATPase (NKA) is normally essential for basolateral HCO3− uptake and other transporters (e.g., NHE1), PTH did not induce insertion of new NKA molecules into the basolateral membrane as determined by membrane protein biotinylation technique. Thus, together with our previous data, we concluded that the PTH action on Caco-2 cells is dependent on PKA and PI3K with no detectable change in pHi or NKA abundance on cell membrane.
Highlights • Intestinal epithelial-like Caco-2 cells expressed CFTR and PTH1R. • PTH increased anion transport across Caco-2 monolayer as suggested by Vt change. • PTH induced phosphorylation of PKA and PI3K in Caco-2 cells. • Intracellular pH was unaltered despite the presence of PTH-induced HCO3− efflux. • PTH did not change Na+/K+-ATPase abundance in the plasma membrane.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b707a07fbafee378b14ad82fc28281fcTest
http://europepmc.org/articles/PMC8220001Test

المؤلفون: Nishikawa, Nobuyuki, Yago, Rie, Yamazaki, Yuichiro, Negoro, Hiromitsu, Suzuki, Mari, Imamura, Masaaki, Toda, Yoshinobu, Tanabe, Kazunari, Ogawa, Osamu, Kanematsu, Akihiro

المساهمون: 根来, 宏光, 小川, 修

مصطلحات موضوعية: Parathyroid hormone-related peptide, Parathyroid hormone 1 receptor, Bladder compliance, Smooth muscle

الوصف: [Background]To investigate the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor 1 (PTH1R) in clinical specimens of normal and diseased bladders. PTHrP is a unique stretch-induced endogenous detrusor relaxant that functions via PTH1R. We hypothesized that suppression of this axis could be involved in the pathogenesis of bladder disease. [Methods]PTH1R expression in clinical samples was examined by immunohistochemistry. Normal kidney tissue from a patient with renal cancer and bladder specimens from patients undergoing ureteral reimplantation for vesicoureteral reflux or partial cystectomy for urachal cyst were examined as normal control organs. These were compared with 13 diseased bladder specimens from patients undergoing bladder augmentation. The augmentation patients ranged from 8 to 31 years old (median 15 years), including 9 males and 4 females. Seven patients had spinal disorders, 3 had posterior urethral valves and 3 non-neurogenic neurogenic bladders (Hinman syndrome). [Results]Renal tubules, detrusor muscle and blood vessels in normal control bladders stained positive for PTH1R. According to preoperative urodynamic studies of augmentation patients, the median percent bladder capacity compared with the age-standard was 43.6% (range 1.5–86.6%), median intravesical pressure at maximal capacity was 30 cmH2O (range 10–107 cmH2O), and median compliance was 3.93 ml/cmH2O (range 0.05–30.3 ml/cmH2O). Detrusor overactivity was observed in five cases (38.5%). All augmented bladders showed negative stainings in PTH1R expression in the detrusor tissue, but positive staining of blood vessels in majority of the cases. [Conclusions]Downregulation of PTH1R may be involved in the pathogenesis of human end-stage bladder disease requiring augmentation.

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/2433/212494Test; BMC Urology; 15

الإتاحة: http://hdl.handle.net/2433/212494Test

المؤلفون: Nishikawa, Nobuyuki, Yago, Rie, Yamazaki, Yuichiro, Negoro, Hiromitsu, Suzuki, Mari, Imamura, Masaaki, Toda, Yoshinobu, Tanabe, Kazunari, Ogawa, Osamu, Kanematsu, Akihiro

مصطلحات موضوعية: Parathyroid hormone-related peptide, Parathyroid hormone 1 receptor, Bladder compliance, Smooth muscle

الوصف: Background To investigate the expression of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor 1 (PTH1R) in clinical specimens of normal and diseased bladders. PTHrP is a unique stretch-induced endogenous detrusor relaxant that functions via PTH1R. We hypothesized that suppression of this axis could be involved in the pathogenesis of bladder disease. Methods PTH1R expression in clinical samples was examined by immunohistochemistry. Normal kidney tissue from a patient with renal cancer and bladder specimens from patients undergoing ureteral reimplantation for vesicoureteral reflux or partial cystectomy for urachal cyst were examined as normal control organs. These were compared with 13 diseased bladder specimens from patients undergoing bladder augmentation. The augmentation patients ranged from 8 to 31 years old (median 15 years), including 9 males and 4 females. Seven patients had spinal disorders, 3 had posterior urethral valves and 3 non-neurogenic neurogenic bladders (Hinman syndrome). Results Renal tubules, detrusor muscle and blood vessels in normal control bladders stained positive for PTH1R. According to preoperative urodynamic studies of augmentation patients, the median percent bladder capacity compared with the age-standard was 43.6% (range 1.5–86.6%), median intravesical pressure at maximal capacity was 30 cmH 2 O (range 10–107 cmH 2 O), and median compliance was 3.93 ml/cmH 2 O (range 0.05–30.3 ml/cmH 2 O). Detrusor overactivity was observed in five cases (38.5%). All augmented bladders showed negative stainings in PTH1R expression in the detrusor tissue, but positive staining of blood vessels in majority of the cases. Conclusions Downregulation of PTH1R may be involved in the pathogenesis of human end-stage bladder disease requiring augmentation.

العلاقة: http://www.biomedcentral.com/1471-2490/15/2Test

الإتاحة: http://www.biomedcentral.com/1471-2490/15/2Test

المؤلفون: Yamei Wang, Paul D. Miller, Bruce H. Mitlak, Chad L. Deal, Lorraine A. Fitzpatrick

المصدر: Bone Reports
Bone Reports, Vol 11, Iss, Pp-(2019)

مصطلحات موضوعية: musculoskeletal diseases, 0301 basic medicine, ACTIVExtend, ACTIVE extension study, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, Endocrinology, Diabetes and Metabolism, Abaloparatide, Osteoporosis, BMD, bone mineral density, Urology, Parathyroid hormone, Bone density conservation agents, 030209 endocrinology & metabolism, Placebo, ITT, intent-to-treat, Article, PTH1R, parathyroid hormone 1 receptor, 03 medical and health sciences, 0302 clinical medicine, medicine, ACTIVE, Abaloparatide Comparator Trial in Vertebral Endpoints, Orthopedics and Sports Medicine, PTH1, parathyroid hormone 1, Bone regeneration, Femoral neck, Bone mineral, Alendronate, business.industry, medicine.disease, medicine.anatomical_structure, Lumbar spine, Postmenopausal, 030101 anatomy & morphology, lcsh:RC925-935, business

الوصف: Highlights • A significantly greater proportion of abaloparatide/alendronate patients had BMD increases over 0, 3 and 6 percent versus placebo/alendronate. • BMD responses were higher at all anatomic sites and for all thresholds assessed for abaloparatide/alendronate versus placebo/alendronate • This study provides further evidence of cumulative benefit from sequential treatment with an anabolic agent followed by an antiresorptive.
Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor signaling pathway that favors the stimulation of bone formation. Here, we report a prospective, exploratory analysis of bone mineral density (BMD) response rates comparing sequential abaloparatide/alendronate vs placebo/alendronate across the ACTIVE and ACTIVExtend studies. BMD was measured at the lumbar spine, total hip, and femoral neck from the beginning of ACTIVE to the end of ACTIVExtend (18 months of abaloparatide or placebo followed by about 1 month for re-consent, followed by 24 months of alendronate treatment for a total of 43 months). Responders were defined as those patients who had improvements in BMD at 3 anatomic sites—the lumbar spine, total hip, and femoral neck. Three response thresholds, >0%, >3%, and >6%, were evaluated. Five hundred fifty-eight patients in the abaloparatide/alendronate group and 581 patients in the placebo/alendronate group from ACTIVExtend were included in the analysis. At Month 43, a significantly greater proportion of those in the abaloparatide/alendronate group compared with the placebo/alendronate group responded with BMD changes from ACTIVE baseline of >0%, >3%, and >6% at all 3 anatomic sites (p 3% threshold, 60.7% (307/506) vs 24.0% (121/505) of patients experienced BMD increases at all 3 sites in the abaloparatide/alendronate vs placebo/alendronate groups, respectively (p 0%, >3%, and >6% at each individual anatomic site compared with the placebo/alendronate group at 43 months (p

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e5a68b4ce7297e75843717b1c79f322fTest
http://europepmc.org/articles/PMC6883300Test

المؤلفون: Al-Hasan, Maram Maher

المصدر: Theses

مصطلحات موضوعية: Parathyroid hormone 1 receptor (PTH1R), parathyroid hormone like hormone (PTHLH), parathyroid hormone (PTH), gastric epithelium, stem cell, Biotechnology, Molecular Biology

الوصف: In the stomach, the epithelial stem cells are responsible for glandular homeostasis. These stem cells continuously undergo cellular proliferation and differentiation to balance the death of senescent cells. Studies conducted on gastric cancers showed a significant increase in parathyroid hormone-like hormone (PTHLH). Moreover, both PTHLH along with parathyroid hormone (PTH) act as endogenous ligands for parathyroid hormone 1 receptor (PTH1R) which belongs to family B of G- protein-coupled receptors (GPCRs). This receptor functions by mediating many different signaling pathways and the most studied pathway is the stimulation of cyclic adenosine monophosphate (cAMP) as a second messenger. There are very few studies on understanding the normal function of gastric PTH1R. Specifically, how PTH1R and its ligands are associated with gastric cancer. The goal of this project is to investigate the expression of PTH1R in the gastric epithelium and to understand its possible function and signaling in maintaining gastric homeostasis. Firstly, gene expression analysis suggested that PTH1R is expressed in vivo in the normal human stomach, and in mouse forestomach, corpus, and antrum. In vitro studies on HeLa, and human embryonic kidney 293 cells (HEK293), also showed positive expression of PTH1R. However, mouse gastric epithelium progenitor cells (mGEP) and human gastric cancer cell line (AGS) showed no expression of PTH1R. To study the mechanism of PTH1R function, transfection of PTH1R plasmid was successfully conducted in mGEP and AGS cells. Next, we investigated the signaling pathways activated upon PTH1R stimulation. cAMP assay in transfected AGS cells treated with PTH1R agonist suggests activation of Gαs signaling pathway. On the other hand, transfected mGEP cells successfully activated ERK1/2 pathway. Morphological studies suggested a difference in the cell morphology of transfected mGEP cells in which large cell to cell spaces was reported. Furthermore, cell viability results showed statistically a non-significant ...

وصف الملف: application/pdf

العلاقة: https://scholarworks.uaeu.ac.ae/all_theses/794Test; https://scholarworks.uaeu.ac.ae/cgi/viewcontent.cgi?article=1794&context=all_thesesTest

الإتاحة: https://scholarworks.uaeu.ac.ae/all_theses/794Test
https://scholarworks.uaeu.ac.ae/cgi/viewcontent.cgi?article=1794&context=all_thesesTest