Structure of a parathyroid hormone/parathyroid hormone-related peptide receptor of the human cerebellum and functional expression in human neuroblastoma SK-N-MC cells

Eggenberger, M.; Flühmann, Beat; Muff, Roman; Lauber, Markus; Lichtensteiger, W.; Hunziker, W.; Fischer, Jan A.; Born, Walter

doi:10.1016/0169-328x(95)00253-o

Cited by 21 publications

(6 citation statements)

References 24 publications

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“…functional CaR similar to that originally cloned from bovine parathyroid. Furthermore, there are reports showing expression of transcripts or immunoreactivity for PTHrP in rodent neurons (43) and meningial epithelial cells (38) as well as expression of a functional PTH/PTHrP receptor in human cerebellar neurons (13) and rat astrocytes (19). Thus PTHrP, acting through its receptor, may function in an autocrine/paracrine manner in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Regulation of secretion of PTHrP by Ca²⁺-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Chattopadhyay

Evliyaoglu

Heese

et al. 2000

American Journal of Physiology-Cell Physiology

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Parathyroid hormone-related protein (PTHrP) is the major mediator of the humoral hypercalcemia of malignancy and of malignant osteolysis associated with skeletal metastases of common epithelial cancers. PTHrP secretion is regulated by the extracellular calcium concentration ([Ca(2+)](o)) in several types of normal and malignant cells. Because the [Ca(2+)](o)-sensing receptor (CaR) is a key mediator of [Ca(2+)](o)-regulated hormone secretion [e.g., of parathyroid hormone (PTH) by parathyroid chief cells], we investigated the expression of the CaR and PTHrP in normal and neoplastic glial cells and studied the effects of [Ca(2+)](o) on PTHrP secretion. Our results show that primary embryonic human astrocytes (HPA) express CaR mRNA and protein as detected by RT-PCR and Western analysis, respectively. Furthermore, astrocytomas and meningiomas also express the CaR at similar levels as assessed by RT-PCR and Northern and Western blot analyses. HPA and astrocytomas express transcripts encoding all three known isoforms of PTHrP [PTHrP(139), PTHrP(141), and PTHrP(173), comprising 139, 141, and 173 predicted amino acid residues, respectively] as assessed by RT-PCR, whereas meningiomas express only the first two of these. Finally, elevated levels of [Ca(2+)](o) and other polycationic CaR agonists dose dependently stimulate PTHrP secretion from HPA, astrocytomas, and meningiomas, although both basal and high [Ca(2+)](o)-stimulated rates of PTHrP secretion are approximately 2. 5-fold higher in HPA than in the glial tumors studied here. Therefore, our results show that HPA, astrocytomas, and meningiomas express both the CaR and PTHrP and that CaR agonists stimulate PTHrP secretion.

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Section: Discussionmentioning

confidence: 99%

Regulation of secretion of PTHrP by Ca²⁺-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Chattopadhyay

Evliyaoglu

Heese

et al. 2000

American Journal of Physiology-Cell Physiology

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“…PTHrP and type I PTH/PTHrP receptors are widely distributed in the brain (17)(18)(19)38). Recent studies (39,40) have demonstrated that a PTH2 receptor, which is activated by PTH, but not PTHrP, is abundant in the CNS (19).…”

Section: Discussionmentioning

confidence: 99%

Centrally Administered Parathyroid Hormone (PTH)-Related Protein(1–34) But Not PTH(1–34) Stimulates Arginine-Vasopressin Secretion and Its Messenger Ribonucleic Acid Expression in Supraoptic Nucleus of the Conscious Rats

et al. 1998

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It has been suggested that PTH-related protein (PTHrP) is an endogenous modulator of cardiovascular systems. We have reported that PTHrP(1-34), but not PTH(1-34), causes the release of argininevasopressin (AVP) from the supraoptic nucleus (SON) of the hypothalamus in vitro through a novel receptor distinct from the PTH/ PTHrP receptors (type I or type II) described previously. In this study, we have investigated the in vivo effects of PTHrP(1-34) on AVP secretion and its messenger RNA (mRNA) expression in the SON in conscious rats. Intracerebroventricular (icv) administration of PTHrP(1-34) resulted in an increase in plasma AVP concentration in a dose-dependent manner (0 -400 pmol/rat). The maximal effect was obtained at 15 min after icv administration of PTHrP(1-34). Neither PTHrP(7-34) nor PTH(1-34) had any effect on plasma AVP levels. PTHrP(1-34)-induced AVP secretion was antagonized by pretreatment with PTHrP(7-34) but not by that with PTH(1-34). In addition, in situ hybridization study revealed that AVP mRNA expression in the SON and paraventricular nucleus was significantly increased 30 min after icv administration of PTHrP(1-34) and reached a maximum at 180 min. Furthermore, in Northern blot analyses, AVP mRNA expression in the SON was increased to approximately a 2-fold of basal level by PTHrP(1-34). On the other hand, neither PTHrP(7-34) or PTH(1-34) had any effect on the mRNA expression. The PTHrP(1-34)-stimulated AVP mRNA expression was eliminated by pretreatment with PTHrP(7-34) but not with PTH(1-34). These results suggest that, in the central nervous system, PTHrP(1-34) is involved in AVP secretion through a novel receptor distinct from the PTH/PTHrP receptors reported previously, playing a role in the body water and electrolyte homeostasis. (Endocrinology 139: 383-388, 1998) P TH-RELATED protein (PTHrP) was identified in tumors associated with humoral hypercalcemia of malignancy (HHM) (1-3). Though PTHrP and PTH are expressed by different genes (1), the amino-terminal fragment of PTHrP and PTH interacts with a classical PTH/PTHrP receptor (type I) on bone and kidney because of the amino acid homology (2). These peptides also interact with a nonclassical PTH/PTHrP receptor (type II) on lymphocytes, insulinoma cells, keretinocytes, and squamous carcinoma cells.Since the demonstration of PTHrP protein and messenger RNA (mRNA) and its receptor protein in a variety of tissues associated with the cardiovascular system, it has been suggested that PTHrP functions as an autocrine/paracrine modulator in the cardiovascular tissues (4 -7). PTHrP acts on vascular smooth muscle, where it is produced (8, 9), as a vasorelaxant (10 -12). Iv administration of the amino-terminal PTHrP peptides induces hypotension in a specific manner (7,13,14). PTHrP also acts on heart muscle by increasing heart rate and contractility (4,10,15,16). Furthermore, vasoconstrictor substances, such as angiotensin II, endotheline, and catecholamines stimulate PTHrP mRNA expression in vascular smooth muscle cells (7, 13). These res...

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“…10B ). The K I value of this peptide is reportedly 2 nM 11 , suggesting that PTH-HRP (used at 1.38 nM according to the enzyme immunoassay) has a high affinity for PTHR 1 . Further, PTH-HRP revealed by TMB supported the detection of PTHR 1 s in HOS cells in a statistically significant manner (P < 0.001) with a significant inhibitory effect of the PTH 1–34 excess (P < 0.05; Fig.…”

Section: Resultsmentioning

confidence: 90%

“…This two domain model suggests that the N-terminal domain of PTH will interact with the extracellular domain of the receptor whereas the C-terminal domain of the hormone will interact with the transmembrane domain. A shorter version of intact PTH, PTH 1–34 (teriparatide), can stimulate the PTHR 1 with equivalent affinity (K I of 4 nM vs. 2 nM, respectively, in a radioligand competition assay) 11 . Moreover, the crystal structure of agonist-bound PTHR 1 extracellular domain showed that the C-terminal domain of the hormone does not bind directly with the receptor 12 .…”

Section: Introductionmentioning

confidence: 99%

Production and evaluation of parathyroid hormone receptor1 ligands with intrinsic or assembled peroxidase domains

Charest‐Morin

Poubelle

Marceau

2017

Sci Rep

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Parathyroid hormone (PTH) can be C-terminally extended without significant affinity loss for the PTH1 receptor (PTHR1). We developed fusion protein ligands with enzymatic activity to probe PTHR1s at the cell surface. Two fusion proteins were generated by linking PTH to the N-terminus of either horseradish peroxidase (PTH-HRP) or the genetically modified soybean peroxidase APEX2 (PTH-APEX2). Alternatively, myc-tagged PTH (PTH-myc) was combined with antibodies, some of which HRP-conjugated, in the extracellular fluid. The three PTH-fusion proteins were produced as conditioned mediums (CM) by transfected producer HEK 293a cells. Binding of receptor-bound enzymatic ligands was revealed using widely available substrate/co-substrate systems. The stimulation of recipient HEK 293a expressing PTHR1s with the PTH-myc/antibodies combination or with PTH-APEX2 supported the histochemical or luminescent detection of recombinant PTHR1s (TrueBlueTM or luminol-based reagent). The PTH-HRP construction was the most sensitive and supported all tested peroxidase co-substrates (TrueBlueTM, tetramethylbenzidine (TMB), luminol, biotin-phenol with streptavidin-Qdots); the 3 latter schemes identified endogenous PTHR1 in the osteoblastic HOS cell line. The specificity of the fusion protein binding to PTHR1 was determined by its competition with an excess of PTH1–34. Bifunctional ligands possessing enzymatic activity detect intact receptors with various possible applications, including the screening of drugs that compete for receptor binding.

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Structure of a parathyroid hormone/parathyroid hormone-related peptide receptor of the human cerebellum and functional expression in human neuroblastoma SK-N-MC cells

Cited by 21 publications

References 24 publications

Regulation of secretion of PTHrP by Ca²⁺-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Regulation of secretion of PTHrP by Ca²⁺-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Centrally Administered Parathyroid Hormone (PTH)-Related Protein(1–34) But Not PTH(1–34) Stimulates Arginine-Vasopressin Secretion and Its Messenger Ribonucleic Acid Expression in Supraoptic Nucleus of the Conscious Rats

Production and evaluation of parathyroid hormone receptor1 ligands with intrinsic or assembled peroxidase domains

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Structure of a parathyroid hormone/parathyroid hormone-related peptide receptor of the human cerebellum and functional expression in human neuroblastoma SK-N-MC cells

Cited by 21 publications

References 24 publications

Regulation of secretion of PTHrP by Ca2+-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Regulation of secretion of PTHrP by Ca2+-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Centrally Administered Parathyroid Hormone (PTH)-Related Protein(1–34) But Not PTH(1–34) Stimulates Arginine-Vasopressin Secretion and Its Messenger Ribonucleic Acid Expression in Supraoptic Nucleus of the Conscious Rats

Production and evaluation of parathyroid hormone receptor1 ligands with intrinsic or assembled peroxidase domains

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Regulation of secretion of PTHrP by Ca²⁺-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Regulation of secretion of PTHrP by Ca²⁺-sensing receptor in human astrocytes, astrocytomas, and meningiomas