Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ca2+-sensing receptor (CaR) is a member of the seven-transmembrane domain, G-protein-coupled receptor superfamily. It is expressed in parathyroid, kidney, and other tissues. In parathyroid, activation of the CaR by extracellular Ca2+ negatively regulates the secretion of parathyroid hormone. In the the thick ascending limb of Henle's loop, receptor activation decreases renal reabsorption of Ca2+. Heterozygous inactivating mutations of the CaR cause familial benign hypocalciuric hypercalcemia while homozygous inactivating mutations cause neonatal severe hyperparathyroidism. Conversely, activating mutations of the CaR cause autosomal dominant and sporadic hypoparathyroidism. Affected individuals have hypocalcemia which ranges from mild and asymptomatic to life-threatening. They also show a greater tendency to hypercalciuria than do other patients with hypoparathyroidism. Most, but not all, of the reported activating mutations occur in the amino-terminal, extracellular domain of the receptor. When expressed in cultured cells, mutant receptors can show both increased receptor sensitivity to Ca2+ and increased maximal signal transduction capacity.
Mol Genet Metab 1998 Jul
PMID:Activating mutations of the Ca2+-sensing receptor. 971 29

The regulation of parathyroid hormone secretion by the chief cells of the parathyroid is mediated by a 7-transmembrane (7-TM) Ca2+-sensing receptor (CaR), which signals via activation of pertussis toxin-insensitive G proteins, causing stimulation of phosphatidylinositol-specific phospholipase C (PI-PLC). We have identified the PI-PLC isoforms expressed in two model systems utilized for studying CaR signal transduction, i.e. dispersed bovine parathyroid cells and a human embryonic kidney cell line (HEK 293) stably transfected with the human parathyroid CaR-cDNA. All of the eight PI-PLC isozymes examined in this study were found to be expressed to varying extents in the bovine parathyroid gland and in the CaR-transfected HEK cells as assessed by immunoblotting. We localized the expression of the more abundant isozymes (beta1, beta2, beta3, gamma1, gamma2, delta2) to the chief cells of the bovine parathyroid by immunocytochemistry, while the two less abundant isozymes (delta1, beta4) were not detectable in parathyroid sections. G proteins activated by 7-TM receptors are known to activate mainly PI-PLC of the beta class. Therefore, beta1, beta2, beta3 and beta4, all expressed in the bovine parathyroid, are candidate isozymes for coupling to the CaR. A comparison of the levels of expression of PI-PLC isozymes between CaR-transfected HEK cells and non-transfected HEK cells suggested that the expression of the CaR in this human cell line does not cause a significant up-regulation of any of the PLCbeta and PLCgamma isozymes. PLCdelta2, showing predominantly nuclear localization in the parathyroid, was the sole PI-PLC isozyme with higher levels of expression in CaR-transfected HEK cells.
J Mol Endocrinol 1998 Aug
PMID:Characterization of the phosphatidylinositol-specific phospholipase C isozymes present in the bovine parathyroid and in human kidney HEK293 cells stably transfected with the human parathyroid Ca2+-sensing receptor. 972 59

Pseudohypoparathyroidism (PHP) is a heterogeneous disease complex characterized by resistance to parathyroid hormone (PTH). PHP type Ib has been thought to be caused by abnormalities in PTH/PTH-related protein (PTHrP) receptor. However, previous studies have shown no mutation in the coding region of PTH/PTHrP receptor gene in patients with PHP type Ib. Because patients with PHP type Ib do not have Albright's hereditary osteodystrophy, and because resistance to PTH is most prominent in proximal tubules of the kidney, PHP Ib may be caused by a kidney-specific abnormality in PTH/PTHrP receptor. Cloning of 5' region of human PTH/PTHrP receptor gene revealed that there are at least three untranslated exons, U1, U2 and U3. Exons U1 and U2 and the upstream promoter of exon U1 are used in kidney, but not in skin fibroblasts and osteoblastic cells. The upstream region of exon U1 was highly AT-rich and exhibited kidney-specific promoter activity. However, there was no mutation in these kidney-specific promoter regions and untranslated exons in eight patients with PHP type Ib. These results demonstrate that PHP type Ib is not caused by mutations in PTH/PTHrP receptor gene, at least in the examined patients. Identification and characterization of nuclear proteins that bind to kidney-specific promoter region of human PTH/PTHrP receptor may be necessary for the elucidation of pathogenesis of PHP type Ib.
Mol Cell Endocrinol 1998 Jun 25
PMID:Cloning and characterization of kidney-specific promoter of human PTH/PTHrP receptor gene: absence of mutation in patients with pseudohypoparathyroidism type Ib. 972 84

During human pregnancy, parathyroid hormone-related protein (PTHrP) and parathyroid hormone (PTH)/PTHrP receptor are produced by the uterus, placenta, fetal membranes (amnion and chorion) and developing fetus. PTHrP alternative 3' mRNA splicing results in transcripts which encode three PTHrP isoforms and have been identified in amnion. Uteroplacental PTHrP expression is greatest in amnion and increases dramatically during late pregnancy. The aims of this study were to determine PTH/PTHrP receptor mRNA expression at preterm and term gestations and to determine 3' alternative splicing patterns in placenta, amnion and choriodecidua at preterm and term gestations. Using semiquantitative reverse transcription-polymerase chain reaction, PTHrP and PTH/PTHrP receptor transcripts were identified in preterm (n=5) and term (n=7) gestational tissues. PTH/PTHrP receptor mRNA expression did not differ between tissue types or change with advancing gestation. In contrast, PTHrP expression in the same tissues increased with advancing gestation and was significantly greater in amnion than in placenta and choriodecidua. Thus PTHrP, although produced predominantly in amnion, may act in amnion and other tissues including placenta, choriodecidua and myometrium. In amnion over placenta, transcripts encoding PTHrP 1-139 and 1-173 were detected in some preterm and all term samples and those encoding PTHrP 1-141 were detected in all samples. Similar results were obtained for reflected amnion. In placenta and choriodecidua, PTHrP 1-139 and 1-173 transcripts were undetectable or of low abundance. PTHrP 1-141 transcripts were detected in some placenta and choriodecidua samples. In summary, transcripts encoding PTHrP 1-141 appeared to be more abundantly expressed than those encoding PTHrP 1-139 or 1-173. However, the up-regulation of PTHrP expression in amnion at term may involve each of the alternative 3' mRNA splicing pathways since transcripts for each isoform appeared to be more consistently expressed at term.
J Mol Endocrinol 1998 Oct
PMID:Parathyroid hormone-related protein (PTHrP) mRNA splicing and parathyroid hormone/PTHrP receptor mRNA expression in human placenta and fetal membranes. 980 66

We have investigated the possible acute effect of steroid hormones, including 1alpha,25 dihydroxycholecalciferol (1alpha,25(OH)2D3) and estradiol, on the generation of superoxide anion (O2*-) in bone resorbing osteoclasts. Evidence is presented demonstrating acute non-genomic stimulatory action of 1alpha,25(OH)2D3 on the production of free radicals by rat osteoclasts cultured on calcified matrix. The increase in O2*- production was observed in the range of 6-10 s (n = 5) following exposure of enriched osteoclasts to 1alpha,25(OH)2D3 and was found to be transient with the peak response being in the range of 5-45 s (n = 5). The decline in the transient was much slower than the elevation, time for the decay being in the range 1-5 min (n = 5) and remained above the levels present prior to the addition. The exposure of the osteoclast to dexamethasone was found to have no effect on O2*- generation, whilst estradiol was found to be inhibitory. The mode of stimulation and the kinetics of the transients of O2*- in the bone resorbing osteoclasts produced by 1alpha,25(OH)2D3 were similar to that of parathyroid hormone (PTH) and pertussis. The exposure of the bone resorbing osteoclasts to cholera toxin was found to have no effect, suggesting that the stimulatory action is unlikely to be mediated via cAMP elevation. The importance of these observations is discussed in the context of calcium homeostasis and bone physiology.
Mol Cell Endocrinol 1999 Mar 25
PMID:Direct non-genomic effect of steroid hormones on superoxide anion generation in the bone resorbing osteoclasts. 1037 17

It has been well established that increases in extracellular calcium concentration ([Ca2+]) inhibit parathyroid hormone (PTH) secretion. The effects of [Ca2+] are mediated through a G-protein-coupled receptor that has been cloned and characterized. Additionally, it has been demonstrated in parathyroid cells that an increase in [Ca2+] results in an increase in steady-state levels of intracellular calcium ([Ca2+]i). At present, it has not been fully resolved whether changes in [Ca2+]i are related to changes in PTH secretion. In the current study, the effect of increased [Ca2+] on PTH secretion and the connection regarding changes in concentrations of intracellular calcium [Ca2+]i have been examined in primary cultures of bovine parathyroid cells. PTH secretion was measured by radioimmunoassay and intracellular calcium was determined by single cell calcium imaging. Bovine parathyroid cells pre-incubated with either 0.5 or 1 mM calcium responded to rapid increases in [Ca2+] (> or = 0.5 mM) with an immediate and sustained increase in steady-state levels of [Ca2+]i that persisted for time intervals greater than 15 minutes. Although the magnitude of the sustained increase in [Ca2+]i varied among individual cells (approximately 40% to > 300%), the overall pattern and course of time were similar in all cells examined (n = 142). In all trials, [Ca2+]i immediately returned to baseline levels following the addition of the calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Additional control studies, however, suggest that sustained increases in [Ca2+]i do not correlate with regulation of parathyroid hormone secretion. Sustained elevations of [Ca2+]i were not observed when [Ca2+] was gradually increased by the addition of 0.1 mM increments at 1 minute intervals. Furthermore, the effect on inhibition of PTH secretion was the same regardless of whether [Ca2+] was increased by gradual or rapid addition.
Mol Cell Biol Res Commun 1999 Jun
PMID:Ca2+-induced increases in steady-state concentrations of intracellular calcium are not required for inhibition of parathyroid hormone secretion. 1042 30

To investigate the regulation of parathyroid hormone secretion by phosphatases we examined the effect of okadaic acid, a selective inhibitor of protein phosphatases (PP)-1 and -2A, on isolated, dispersed parathyroid cells. Okadaic acid inhibited secretion from intact bovine, intact human and streptolysin-O permeabilized bovine cells. Approximately 10(-6) M okadaic acid resulted in a 50% decrease in parathyroid hormone (PTH) secretion from both intact and permeabilized cells, consistent with PP-1 being the target of inhibition. Upon subcellular fractionation, PP-1 overlapped but was not identical to either PTH, a marker of the secretory granule, or Na+/K+-ATPase, a plasma membrane marker. In summary, PP-1 activity is involved in Ca2+-dependent but not basal PTH secretion.
Mol Cell Endocrinol 1999 Aug 20
PMID:Inhibition of protein phosphatase 1 decreases PTH secretion from isolated dispersed parathyroid cells. 1050 11

The function of the most numerous cell in bone, the osteocyte, has until recently been mysterious and at times controversial. There is now an emerging consensus that osteocytes modulate signals arising from mechanical loading and so direct the appearance and disappearance of bone tissue at the microscopic level, which allows bone as an organ both to grow and to adapt efficiently to the body's mechanical needs for strength with lightness. Osteocytes appear to use some molecular signalling pathways that are familiar from other tissues, such as the generation of nitric oxide and prostaglandins as well as directing cell-cell communication via gap junctions. They may also direct the removal of damaged or redundant bone through mechanisms linked to their own apoptosis or via the secretion of specialised cellular attachment proteins such as osteopontin. Osteocytes possess receptors for parathyroid hormone/parathyroid hormone related peptide and both oestrogen receptors alpha and beta. They also express molecules which in nerve cells are involved with glutamate neuro-transmission. At least some of these receptors and their ligands may regulate osteocyte apoptosis and modulate osteocyte signalling.
Mol Cell Endocrinol 2000 Jan 25
PMID:Osteocyte function, osteocyte death and bone fracture resistance. 1068 47

Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) receptor are important developmental regulators of cell growth and differentiation in some organs. In lung, both the peptide and the receptor are expressed early in development and in alveolar cells in adults. In adult alveolar cells, PTHrP appears to promote the alveolar type II cell phenotype in vitro. Mice carrying null mutations in genes for either receptor or ligand die at birth of respiratory failure. To determine if absence of the PTH/PTHrP receptor alters morphogenesis or cellular differentiation of the distal lung, we analyzed the morphology and gene expression patterns in PTH/PTHrP receptor null mutant mice right before birth and compared them with wild-type and heterozygous null littermates. Using semiquantitative Northern blots, we observed that messenger RNA (mRNA) for aquaporin-5, the type I cell-specific water channel, was markedly decreased. The abundance of other marker mRNAs for type I and type II cell phenotypes, including T1alpha, surfactant proteins, and others, was unaltered. Gross morphology and lung pattern, assessed by in situ hybridization for surfactant protein C, were normal. We conclude therefore that, although signaling through this receptor may influence expression of specific lung genes, it does not play a major role in the general regulation of lung development and growth.
Am J Respir Cell Mol Biol 2000 Mar
PMID:Aquaporin-5 expression, but not other peripheral lung marker genes, is reduced in PTH/PTHrP receptor null mutant fetal mice. 1069 74

We used site-directed mutagenesis to construct 55 single-site variants of rhPTH, a recombinantly-expressed form of human parathyroid hormone (1-34) containing three amino acid changes compared to the natural sequence (ML8, ML18 and FY34). We identified several mutations, at residues Lys(13), Glu(19), Val(21), Glu(22), Lys(27) and Asp(30), that increase biological activity by up to 2. 5-fold, as measured by stimulation of adenylate cyclase activity in rat UMR-106 cells. We constructed a series of 15 variants in which two to eight substitutions at these positions were combined, and found that the mutations behaved additively, leading to peptides with significantly enhanced potency. The most active combination variant, with six substitutions (KS13, ES19, VQ21, ES22, KQ27 and DN30), is 15 times more active than the parent molecule. However, the extent to which such combinations increase the activity of the peptide depends critically on the identity of the residues at positions 8 and 18. We constructed two of the combination variants in a variety of sequence backgrounds containing different combinations of leucine, methionine and norleucine at positions 8 and 18. Enhancements in potency were significantly reduced when Met or Nle was present at either of these positions, both in UMR-106 cells and human SaOS-2 cells. A corresponding non-additivity was observed in direct measurements of receptor binding affinity on UMR-106 cells. These results suggest that interactions, either direct or indirect, between certain PTH side chains prevent these mutations from behaving in an additive manner.
Mol Cell Endocrinol 2000 Feb 25
PMID:Active variants of human parathyroid hormone (1-34) with multiple amino acid substitutions. 1071 47


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