Optimal fetal lung growth requires anion-driven fluid secretion into the lumen of the developing organ. The fetus is hypercalcemic compared to the mother and here we show that in the developing human lung this hypercalcaemia acts on the extracellular calcium-sensing receptor, CaSR, to promote fluid-driven lung expansion through activation of the cystic fibrosis transmembrane conductance regulator, CFTR. Several chloride channels including TMEM16, bestrophin, CFTR, CLCN2 and CLCA1, are also expressed in the developing human fetal lung at gestational stages when CaSR expression is maximal. Measurements of Cl−-driven fluid secretion in organ explant cultures show that pharmacological CaSR activation by calcimimetics stimulates lung fluid secretion through CFTR, an effect which in humans, but not mice, was also mimicked by fetal hypercalcemic conditions, demonstrating that the physiological relevance of such a mechanism appears to be species-specific. Calcimimetics promote CFTR opening by ...

Experiments performed in mice in which expression of the extracellular calcium-sensing receptor (CaSR) was completely nullified specifically in parathyroid cells, chondrocytes, or cells of the osteoblast lineage have identified phenotypes that indicate a key role for the CaSR in embryonic development of the skeleton, postnatal bone formation, and osteoblast differentiation that are independent of the calcitropic hormone axis. These long-awaited studies further clarify the signaling relationships between the parathyroid gland, kidney, and metabolic bone disease in patients with mutations in the gene encoding the CaSR, and they provide new insights into understanding the signaling pathways involving the CaSR in skeletal cells.. ...

The demonstration that the rare disorder, familial hypocalciuric hypercalcemia (FHH), was caused by inactivating mutations in the gene for the calcium-sensing receptor (CaSR, sometimes referred to as CaR) had two major consequences; it explained the

immune Uncategorized EXT1, LY 2183240 Recently we reported that calcium-sensing receptor (CaSR) is a receptor for substances which enhance the intensities of salty sweet and umami LY 2183240 tastes. CaSR-expressing taste cells are a different subset of cells from your T1R3-expressing umami or lovely taste receptor cells. These observations show that CaSR-expressing taste cells are the main detectors of substances and that they are an independent population from your influenced basic taste receptor cells at least in the case of lovely and umami. Intro The extracellular calcium-sensing receptor CaSR is definitely a classic seven-transmembrane-spanning G protein-coupled receptor (GPCR) belonging to Family C of the superfamily of GPCRs [1]. CaSR has been identified in several cells and tissue like the parathyroid kidney and gland. It has a central function in extracellular calcium mineral homeostasis in mammals [2]. A rise in the bloodstream calcium mineral level is normally sensed by CaSR which ...

Methylation Status of the CpG Islands in Vitamin D and Calcium-Sensing Receptor Gene Promoters Does Not Explain the Reduced Gene Expressions in Parathyroid Aden

Background/aim: Sagliker syndrome (SS) develops as a continuation of chronic kidney disease and secondary hyperparathyroidism conditions. It was thought that there are some genetic predisposition factors leading to SS. The calcium-sensing receptor (CaSR) is essential for calcium homeostasis in the body. We aimed to examine SS patients for chromosome aberrations (CAs) and CaSR gene abnormalities in exons 2 and 3. ...

The drugs cinacalcet and etelcalcetide are allosteric modifiers of the calcium-sensing receptor.[14] They are classified as a calcimimetics, binding to the calcium-sensing receptor and decreasing parathyroid hormone release. Calcilytic drugs, which block CaSR, produce increased bone density in animal studies and have been researched for the treatment of osteoporosis. Unfortunately clinical trial results in humans have proved disappointing, with sustained changes in bone density not observed despite the drug being well tolerated.[15][16] More recent research has shown the CaSR receptor to be involved in numerous other conditions including Alzheimers disease, asthma and some forms of cancer,[17][18][19][19][20] and calcilytic drugs are being researched as potential treatments for these. Recently it has been shown that biomimetic bone like apatite inhibits formation of bone through endochondral ossification pathway via hyperstimulation of extracellular calcium sensing receptor[21]. ...

Author Summary Mice with homozygous deletion of the calcium-sensing receptor (CaR) mimic the syndrome of neonatal severe hyperparathyroidism (NSHPT) in humans with very high circulating parathyroid hormone (PTH) and severe life-threatening hypercalcemia. To determine effects of CaR deficiency on skeletal development and interactions between CaR and 1,25(OH)2D3 or PTH on calcium and skeletal homeostasis, we compared the skeletal phenotypes of homozygous CaR-deficient mice to those of double homozygous CaR- and 1,25(OH)2D3-deficient mice or those of double homozygous CaR- and PTH-deficient mice. CaR-deficient mice had hypercalcemia, hypophosphatemia, hyperparathyroidism, severe skeletal growth retardation, and abnormalities; and most died within 2 weeks of age. Deletion of 1,25(OH)2D3 in CaR-deficient mice resulted in a longer lifespan, normocalcemia, lower serum phosphorus, greater elevation in PTH, and slight improvement in skeletal growth. Deletion of PTH in CaR-deficient mice resulted in rescue of

Title: Recent Updates on the Calcium-Sensing Receptor as a Drug Target. VOLUME: 15 ISSUE: 2. Author(s):Ritu Trivedi, Ambrish Mithal and Naibedya Chattopadhyay. Affiliation:Division of Endocrinology, C.D.R.I., Lucknow, India.. Keywords:Calcimimetic, calcilytic, phenylakylamine, G-protein coupled receptors, calcium homeostasis. Abstract: Parathyroid hormone (PTH) secreted from parathyroid cells is a key regulator of circulating levels of calcium ion, which is maintained within a narrow physiological range mainly by the action of a cell surface Ca2+-sensing receptor (CaSR) residing on parathyroid cells. The CaSR belongs to the family C of G-protein-coupled receptors (GPCRs), all members of which have a large extra cellular domain called Venus flytrap, akin to bacterial nutrient sensor. Promiscuity of the CaSR is reflected in its binding to several physiologically relevant di- or polyvalent cations that could elicit cellular signaling, yet the ligand specificity remains poor. This problem has been ...

Role of Calcium-Sensing Receptors in Bone and Mineral Metabolism Dr. Shobacks laboratory is working on how extracellular calcium-sensing receptors (CaSRs) sense changes in the extracellular calcium in the serum and in the bone microenvironment to alter cellular functions. These receptors play critical roles in parathyroid and kidney function that have been well-established through human, animal and cell-based studies. Our group is investigating the role of this receptor in the control of parathyroid hormone (PTH) secretion in mouse models and the interactions between the vitamin D receptor (VDR) and its systemically and locally generated (within the parathyroid gland itself) ligand 1,25-dihydroxyvitamin D (1,25-D) in the control of parathyroid function, systemic calciotropic hormone secretion, and mineral balance. Most of our work is in conditional and generalized knockout mouse models with selected work experiments in vitro in parathyroid gland organ culture and in cultured osteoblast and bone ...

The calcium-sensing receptor (CaR) is a membrane-bound, G-protein-coupled receptor present on parathyroid cells which monitors the level of extracellular calcium (Ca2+o) and transduces signals involved in serum calcium regulation. Expression of CaR protein in tissues with functions unrelated to syst …

Genetic testing for the CASR gene, which is associated with benign familial hypocalciuric hypercalcemia (BFHH), neonatal severe hyperparathyroidism (NSHPT), familial isolated hyperparathyroidism (FIHP), and autosomal dominant hypocalcemia (ADH).

TY - JOUR. T1 - Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects. AU - Martin, Kevin J.. AU - Bell, Gregory. AU - Pickthorn, Karen. AU - Huang, Saling. AU - Vick, Andrew. AU - Hodsman, Peter. AU - Peacock, Munro. PY - 2014/2. Y1 - 2014/2. N2 - ContextVelcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease - mineral and bone disorder.ObjectiveTo assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers. Methods. The study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18-45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to ...

Butters RR, Chattopadhyay N, Nielsen P, Smith CP, Mithal A, Kifor O, Bai M, Quinn S, Goldsmith P, Hurwitz S, Krapcho K, Busby J, Brown EM. Cloning and characterization of a calcium-sensing receptor from the hypercalcemic New Zealand white rabbit reveals unaltered responsiveness to extracellular calcium. J Bone Miner Res. 1997 Apr; 12(4):568-79 ...

Zhai T Y, Cui B H, Zou L, et al. Expression And RoleOf The Calcium-Sensing Receptor In Rat Peripheral Blood Polymorphonuclear Neutrophils[J]. Oxidative Medicine and Cellular Longevity, 2017.

The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017 ...

Our study highlights the expression of the CaSR in ASM and identifies a fundamental pathophysiological role for this receptor in the context of asthma. The fact that inflammatory cationic proteins known to correlate with asthma severity can activate the CaSR expressed by ASM cells at physiologically relevant concentrations to elevate [Ca2+]i and increase the contractility of the ASM nonspecifically provides both a rational explanation for the genesis of nonspecific AHR in asthma and a basis for the direct mechanistic link between this phenomenon and airway inflammation. These findings raise the possibility that the CaSR directly influences mechanisms involved in inflammatory cell recruitment and activation. In turn, production of asthma-relevant cytokines can further increase CaSR expression, thereby generating a positive feedback loop. Thus, locally delivered calcilytics would have the advantage of breaking this cycle by reducing inflammation and by blunting ASM hyperresponsiveness. Indeed, in ...

Extracellular calcium-sensing receptors (CaRs) and metabotropic or type B gamma-aminobutyric acid receptors (GABA-B-Rs), two closely related members of family C of the G protein-coupled receptor superfamily, dimerize in the formation of signaling and membrane-anchored receptor complexes. We tested w …

Taken together, these results showed that in human colon epithelium-derived CBS cells, either Ca2+ or 1,25(OH)2D3 stimulated CaSR promoter activity and CaSR protein expression. In addition, a combination of Ca2+ and 1,25(OH)2D3 enhanced both CaSR promoter activities and protein expression. We hypothesized that extracellular Ca2+ and 1,25(OH)2D3 are both stimulators of CaSR expression in the normal colonic crypt. It is attractive to speculate that a concentration gradient of Ca2+ and/or 1,25(OH)2D3 exists between the base and apex of the crypt, and that a higher concentration of Ca2+ and/or 1,25(OH)2D3 (to which the colonic epithelium is exposed) at the apex is responsible for CaSR expression and concomitant expression of differentiated cell features. Because the blood Ca2+ level is tightly controlled (1), the Ca2+ concentration in the intestinal extracellular fluid may be a critical source of this agonist. Water reabsorption in the colon could be expected to increase the Ca2+ concentration. ...

Etelcalcetide (formerly velcalcetide, trade name Parsabiv) is a calcimimetic drug for the treatment of secondary hyperparathyroidism in patients undergoing hemodialysis. It is administered intravenously at the end of each dialysis session. Etelcalcetide functions by binding to and activating the calcium-sensing receptor in the parathyroid gland. Parsabiv is currently owned by Amgen and Ono Pharmaceuticals in Japan. Etelcalcetide is used for the treatment of secondary hyperparathyroidism in people with chronic kidney disease (CKD) on hemodialysis. Hyperparathyroidism is the condition of elevated parathyroid hormone (PTH) levels and is often observed in people with CKD. Etelcalcetide functions by binding to and activating the calcium-sensing receptor (CaSR) in the parathyroid gland as an allosteric activator, resulting in PTH reduction and suppression. Etelcalcetide functions in a first order elimination, with a half life of 19 hours. No interaction studies in humans were conducted. Studies in ...

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Dr Roderick Clifton-Bligh is Head of the Department of Endocrinology at Royal North Shore Hospital, and conjoint associate professor in Medicine at the University of Sydney. He completed a PhD in the genetics of thyroid disorders at the University of Cambridge. He now supervises dual research groups, one of which focuses on the genetics of endocrine neoplasms, and the other on metabolic bone disease.. The Cancer Genetics Unit studies the molecular bases of thyroid cancer, phaechromocytoma/paraganglioma syndromes, adrenal cancer, and pituitary neoplasms. The Metabolic Bone Research Unit studies calcium-sensing receptor gene mutations and FGF23 biology.. His scope of clinical practice remains broad. He has co-supervised 8 completed PhDs, including five Endocrinologists. He maintains a strong involvement in teaching and mentoring young physicians.. ...

View and buy high purity Cinacalcet hydrochloride from Tocris Bioscience. Allosteric Calcium-sensing receptor (CaSR) agonist; also CYP2D2 inhibitor and Ca2+ channel blocker; orally bioavailable.

Recruitment of macrophages to sites of cell death is critical for induction of an immunologic response. Calcium concentrations in extracellular fluids vary markedly, and are particularly high at sites of injury or infection. We hypothesized that extracellular calcium participates in modulating the immune response, perhaps acting via the seven-transmembrane calcium-sensing receptor (CaR) on mature monocytes/macrophages. We observed a dose-dependent increase in monocyte chemotaxis in response to extracellular calcium or the selective allosteric CaR activator NPS R-467. In contrast, monocytes derived from mice deficient in CaR lacked the normal chemotactic response to a calcium gradient. Notably, CaR activation of monocytes bearing the receptor synergistically augmented the transmigration response of monocytes to the chemokine MCP-1 in association with increased cell-surface expression of its cognate receptor, CCR2. Conversely, stimulation of monocytes with MCP-1 or SDF-1α reciprocally increased ...

The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated ...

CAR-mediated induction of CYP2B6 mRNA was strongly potentiated by the activation of p38 MAPK in HepG2 cells as effectively as that in human primary hepatocytes. In addition, p38 MAPK is constitutively activated in human primary hepatocytes but not in human hepatoma cell lines including HepG2 cells. Thus, p38 MAPK may play a role in the CAR-mediated CYP2B6 induction in human primary hepatocytes. Only one set of CAR-regulated genes requires p38 MAPK for their activation: this set includes genes such as CYP2A7 and CYP2C9, in addition to CYP2B6. In contrast, p38 MAPK plays no role in CAR activation of the CYP3A4 or UGT1A1 genes. Various cell signaling has been shown to regulate activation of CAR and CAR-mediated transcription of a target gene. Growth factor-activated extracellular signal-related kinase 1/2 signaling represses CAR activation and nuclear translocation (Koike et al., 2007). cAMP and early growth response 1 synergize CAR-mediated transcription of CYP2B6 genes in HepG2 cells (Ding et ...

Ischemia-reperfusion (I/R) injury is a multifactorial process triggered when an organ is subjected to transiently reduced blood supply. The result is a cascade of pathological complications and organ damage due to the production of reactive oxygen species following reperfusion. The present study aims to evaluate the role of activated calcium-sensing receptor (CaR)-cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in I/R injury. Firstly, an I/R rat model with CSE knockout was constructed. Transthoracic echocardiography, TTC and HE staining were performed to determine the cardiac function of rats following I/R Injury, followed by TUNEL staining observation on apoptosis. Besides, with the attempt to better elucidate how CaR-CSE/H2S affects I/R, in-vitro culture of human coronary artery endothelial cells (HCAECs) was conducted with gadolinium chloride (GdCl3, a CaR agonist), H2O2, siRNA against CSE (siCSE), or W7 (a CaM inhibitor). The interaction between CSE and CaM was subsequently ...

Our lab is interested in the biology and therapeutic potential of targeting Class C G protein-coupled receptors (GPCRs). We are predominantly focussed on two class members: metabotropic glutamate receptor subtype 5 (mGlu5) and the calcium-sensing receptor (CaSR). mGlu5 is an exciting new target for schizophrenia, Alzheimers disease, autism spectrum disorders and depression, whereas modulators of the CaSR are already in the clinic for hyperparathyroidism and are putative therapeutics for osteoporosis, calcium handling disorders, asthma and idiopathic pulmonary arterial hypertension. We are pursuing a novel class of therapeutics, called allosteric modulators, to selectively target these receptors. To facilitate rational drug design and discovery efforts, a better understanding of the functional consequences and structural basis of allosteric modulation is needed.. Available projects examine ...

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score | -2.5) and low BMD relative to an age- and gender-matched cohort (Z score | -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1alpha), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin,

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score | -2.5) and low BMD relative to an age- and gender-matched cohort (Z score | -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1α), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin,

When calcium levels are high, activation of the calcium-sensing receptors is increased, causing secretion of PTH to be suppressed. Conversely, when calcium levels are low, receptor activation is reduced, causing PTH release to rise. ...

Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, P Lowe AP, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ, T Ward JP, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med. 2015 Apr 22; 7(284):284ra60 ...

The idea that electric cars are lowering demand is ridiculous. Electric cars havent made a dent, just a small scratch in oil demand. Electric cars are only 0.2% of light-duty vehicles, and cost so much only the upper 5% can afford them, even with subsidies. I suspect the peak oil demand idea is ...

Termination of cyclic adenosine monophosphate (cAMP) signaling via the extracellular Ca(2+)-sensing receptor (CaR) was visualized in single CaR-expressing human embryonic kidney (HEK) 293 cells using ratiometric fluorescence resonance energy transfer-dependent cAMP sensors based on protein kinase A and Epac. Stimulation of CaR rapidly reversed or prevented agonist-stimulated elevation of cAMP through a dual mechanism involving pertussis toxin-sensitive Galpha(i) and the CaR-stimulated increase in intracellular [Ca2+]. In parallel measurements with fura-2, CaR activation elicited robust Ca2+ oscillations that increased in frequency in the presence of cAMP, eventually fusing into a sustained plateau. Considering the Ca2+ sensitivity of cAMP accumulation in these cells, lack of oscillations in [cAMP] during the initial phases of CaR stimulation was puzzling. Additional experiments showed that low-frequency, long-duration Ca2+ oscillations generated a dynamic staircase pattern in [cAMP], whereas higher

CASR: The Calcium Gene The Calcium sensing receptor (CASR) gene is associated with the synthesis of Calcium sensing receptor, a receptor that […]. ...

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Muscle cars are loud, proud, and in your face, with no other pretensions than to be just that. They may be simple, even crude, but for roaring, pumping, tire-smoking standing starts, they are the business.. Muscle cars are a quintessentially North American phenomenon, owing their outrageous existence to a very simple formula. Take a mid-sized American sedan, nothing too complicated, upmarket, or fancy, then add the biggest, raunchiest V8 that it is possible to squeeze under the hood, and there it is!. Pontiac was first, with the legendary GTO, then Ford invented a new class of car with the the pony car, the Mustang, then every other American manufacturer got in on the act, producing the legendary Hemi, Camaro, Firebird and Trans-Am, among many others. This book covers them all, as well as all the excitement of Trans-Am/NASCAR racing. Muscle cars are loud, proud and in your face, with no other pretensions than to be just that. They may be simple, even crude, but for roaring, pumping, tire-smoking ...

Yes, its true: The promise of self-driving cars zooming around while their human operators doze off, read, or watch movies is not quite here yet. But who said that had to happen right now or weve missed our chance at driverless vehicles forever? On Monday, The Outline published an article titled The self-driving car that will never arrive, calling self-driving cars delusional and part of our grossest capitalistic dreams. Its just the latest from those who believe driverless cars and other artificial intelligence innovations are an unrealistic pipe dream.. But innovation happens incrementally, step by step. Just because its not instantaneous doesnt mean it will never happen. Read more…. More about Autonomous Vehicles, Self Driving Cars, Waymo, Tech, and Transportation ...

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TY - JOUR. T1 - Exaggerated cyclic AMP response to parathyroid hormone in familial hypocalciuric hypercalcemia. AU - Marx, S. J.. AU - Spiegel, Allen M.. AU - Sharp, M.. PY - 1979. Y1 - 1979. UR - http://www.scopus.com/inward/record.url?scp=0018428626&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=0018428626&partnerID=8YFLogxK. M3 - Article. AN - SCOPUS:0018428626. VL - 27. JO - Journal of Investigative Medicine. JF - Journal of Investigative Medicine. SN - 1081-5589. IS - 2. ER - ...

Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. ...

Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. ...

A quantitative PCR (Q-PCR) method has been established to measure the mRNA expression levels of parathyroid hormone-related protein (PTHrP), parathyroid hormone receptor type 1 (PTHR1), and calcium-sensing receptor (CaSR) in sea bream (Sparus aurata), using the housekeeping gene, beta-actin, as endogenous control. TaqMan primers and probes were designed using the Primer Express program, according to the published/unpublished sequences of the three target genes and beta-actin of sea bream. Different tissues including gill, kidney, duodenum, hindgut, rectum, liver, heart, brain, pituitary, skin, muscle, and gonad were removed and immediately snap-frozen from three juvenile sea bream (100-150 g) cultured in sea water. The mRNAs were extracted and reverse-transcribed into cDNAs, which were subsequently examined by the ABI 5700 system using an optimized Q-PCR method. Triplicate measures of each sample indicated consistency of the technique. However, the mRNA expression levels for each transcript in ...

Calcium-sensing receptor: The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. In the parathyroid gland, the calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). [Source: Wikipedia] ...

Familial multiple endocrine neoplasia type 1 (MEN1), familial hypocalciuric (or familial benign) hypercalcemia (FHH), hyperparathyroidism jaw tumor syndrome (HPT-JT), other causes of familial isolated hyperparathyroidism (FIH), and pseudohypoparathyroidism (PHP) are disorders of metabolism that are generally inherited in an autosomal dominant fashion. MEN1 is characterized by overgrowth and hyperfunction of the parathyroids, anterior pituitary and gastrointestinal endocrine tissue. MEN1, p15, p18, p21, and p27 are identified genes for MEN 1- like states. FHH is characterized by a usually benign syndrome sometimes mistaken for typical primary hyperparathyroidism, which may result in unnecessary and unsuccessful parathyroid surgery. The CASR gene for the calcium-sensing receptor of the parathyroid cell is mutated in of most FHH kindreds;a minority of kindreds with FHH have mutation of the GA11 or AP2S gene. HPT-JT is a distinctive subtype of familial isolated hyperparathyroidism that has ...

Croft, Wayne D., Hills, Claire E., McCann, Eilish Clare, Bond, Michael, Esparza-Franco, Manuel A. , Bennett, Jeanette, Rand, D. A. (David A.), Davey, John and Ladds, Graham. (2013) A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity. Journal of Biological Chemistry, Volume 288 (Number 38). pp. 27327-27342. ISSN 0021-9258 Bland, Rosemary, Zehnder, Daniel, Bennett, Jeanette, Markovic, Danijela and Hewison, Martin. (2012) Calcium sensing receptor-mediated regulation of vitamin D metabolism in a human proximal tubule cell line. Bone, Vol.51 (No.6). Article no.S29. ISSN 8756-3282 Hills, Claire E., Younis, Mustafa Y. G., Bennett, Jeanette, Siamantouras, Eleftherios, Liu, Kuo-Kang and Squires, Paul E.. (2012) Calcium-sensing receptor activation increases cell-cell adhesion and ß-cell function. Cellular Physiology and Biochemistry, Vol.30 (No.3). pp. 575-586. ISSN 1015-8987 Hills, Claire E., Bland, Rosemary, ...

BACKGROUND: The kidney is one of the affected organs involved in the clinical symptoms of parathyroid hormone (PTH)-related disorders, like primary hyperparathyroidism and familial hypocalciuric hypercalcemia. The molecular mechanism(s) underlying alterations in renal Ca(2+) handling in these disorders is poorly understood. METHODS: Parathyroidectomized and PTH-supplemented rats and mice infused with the calcimimetic compound NPS R-467 were used to study the in vivo effect of PTH on the expression of renal transcellular Ca(2+) transport proteins, including the epithelial Ca(2+) channel transient receptor potential, vanilloid, member 5 (TRPV5), calbindins, and the Na(+)/Ca(2+)-exchanger (NCX1). In addition, the effect of PTH on transepithelial Ca(2+) transport in rabbit connecting tubule/cortical collecting duct (CNT/CCD) primary cultures was determined. RESULTS: Decreased PTH levels in parathyroidectomized rats or NPS R-467-infused mice, resulted in reduced expression of these proteins, which is ...

Familial hypocalciuric hypercalcemia (HHC) is a heritable disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. HHC is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone (PTH; {168450}) level. Hypermagnesemia is typically present. Individuals with HHC are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults (summary by {17:Hannan et al., 2010 ...

The H2-receptor antagonist cimetidine is an antiulcer drug also used for the treatment of cancer due to its antiangiogenic effect. However, this drug has caused structural changes in the seminiferous tubules. Vitamin B12 has been used as a therapeutic agent for the treatment of male infertility. The supplementation of rats with vitamin B12 during cimetidine treatment has recovered the damaged seminiferous tubules, but how this vitamin restores the seminiferous epithelium has not been clarified. In this study, we evaluated whether vitamin B12 improves the number of spermatogonia, spermatocytes, and sperm concentration in cimetidine-treated rats. Adult male rats were treated for 50 days as follows: cimetidine group received 100 mg kg−1 b.w. of cimetidine, cimetidine-B12 group received cimetidine and 3 μg of vitamin B12-hydroxocobalamin, B12 group received only 3 μg of vitamin, and control group received saline. Sperm concentration was calculated and historesin-embedded testes sections were ...

Time courses of translocation of fluorescently conjugated proteins to the plasma membrane were simultaneously measured in thousands of individual rat basophilic leukemia cells. We found that the C2 domain-a calcium-sensing, lipid-binding protein module that is an essential regulator of protein kinase C and numerous other proteins-targeted proteins to the plasma membrane transiently if calcium was released from internal stores, and persistently in response to entry of extracellular calcium across the plasma membrane. The C2 domain translocation time courses of stimulated cells clustered into only two primary modes. Hence, the reversible recruitment of families of signaling proteins from one cellular compartment to another is a rapid bifurcation mechanism for inducing discrete states of cellular signaling networks. ...

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional. ...

Heterotrimeric G proteins play critical roles in transducing extracellular signals generated by 7-transmembrane domain receptors. Somatic gain-of-function mutations in G protein α subunits are associated with a variety of diseases. Recently, we identified gain-of-function mutations in Gα11 in patients with autosomal-dominant hypocalcemia type 2 (ADH2), an inherited disorder of hypocalcemia, low parathyroid hormone (PTH), and hyperphosphatemia. We have generated knockin mice harboring the point mutation GNA11 c.C178T (p.Arg60Cys) identified in ADH2 patients. The mutant mice faithfully replicated human ADH2. They also exhibited low bone mineral density and increased skin pigmentation. Treatment with NPS 2143, a negative allosteric modulator of the calcium-sensing receptor (CASR), increased PTH and calcium concentrations in WT and mutant mice, suggesting that the gain-of-function effect of GNA11(R6OC) is partly dependent on coupling to the CASR. Treatment with the Gα11/q-specific inhibitor ...

OBJECTIVES: Associations between calcium-sensing receptor (CaSR) polymorphisms and serum calcium, PTH and bone mineral density (BMD) have been reported by six studies. However, three other studies have failed to detect such associations. We therefore further investigated three CaSR coding region polymorphisms (Ala986Ser, Arg990Gly and Gln1011Glu) for associations with indices of calcium homeostasis and BMD and for alterations in receptor function. PATIENTS AND DESIGN: One hundred and ten adult, Caucasian, female, dizygotic twin pairs were investigated for associations between the three CaSR polymorphisms and serum calcium, albumin, PTH, 25-hydroxyvitamin D(3) (25OHD(3)), 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], urinary calcium excretion and BMD. Each polymorphic CaSR was also transfected into HEK293 cells and functionally evaluated. RESULTS: There was a lack of association between each of these three CaSR polymorphisms and serum calcium corrected for albumin, PTH, 25OHD(3), 1,25(OH)(2)D(3), urinary

Hang XM, Power DM, Flik G, Balment RJ. Measurement of PTHrP, PTHR1, and CaSR expression levels in tissues of sea bream (Sparus aurata) using quantitative PCR. Ann N Y Acad Sci. 2005;1040:340-4. doi:10.1196/annals.1327.056 ...

The calcium-sensing receptor is a multimodal, multimetabolic sensor that mediates the feedback-dependent control of whole body calcium metabolism. Remarkably, in addition to its role in Ca(2+)(o) (extracellular Ca(2+)) sensing, the CaR (Ca(2+)-sensing receptor) also responds to L-amino acids. L-amino acids appear to activate, predominantly, a signalling pathway coupled with intracellular Ca(2+) mobilization, require a threshold concentration of Ca(2+)(o) for efficacy and sensitize the receptor to activation by Ca(2+)(o). Here, we review the evidence that the CaR, like other closely related members of the class 3 GPCR (G-protein-coupled receptor) family including GPRC6A, is a broad-spectrum amino acid-sensing receptor, consider the nature of the signalling response to amino acids and discuss its physiological significance.

mGluRs together with the γ-aminobutyric acid type B receptor (Kaupmann et al., 1997), the parathyroid calcium-sensing receptors (Brown et al., 1993), and the vomeronasal receptors (Bargmann, 1997) form a separate family within the superfamily of GPCRs (Conn and Pin, 1997). The most striking difference between the mGluR family and most other GPCR resides in their ligand-binding domain. In the latter group numerous studies of structure-function relationships indicated that ligands either interact directly with amino acid residues in the TM domain or in addition with residues in the extracellular domains. For instance, monoamines and other small ligands are bound directly in a pocket formed within the TM segments, whereas the binding sites for neuropeptides and chemokines are defined by complex interactions with residues in the N-terminal extracellular domain, the extracellular loops, and TM segments (Betancur et al., 1997). In contrast, the ligand-binding site of mGluRs is thought to be located ...

Calcimimetic Agents (1) • Small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR) in the PARATHYROID GLANDS and other tissues. They lower the threshold for CaSR activation by extracellular calcium ions and diminish PARATHYROID HORMONE (PTH) release from parathyroid cells. MeSH. Calcineurin Inhibitors (4) • Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN. MeSH. Calcium Antagonists, Exogenous (0) see Calcium Channel Blockers. Calcium Channel Agonists (8) • Agents that increase calcium influx into calcium channels of excitable tissues. This causes vasoconstriction in VASCULAR SMOOTH MUSCLE and/or CARDIAC MUSCLE cells as well as stimulation of insulin release from pancreatic islets. Therefore, tissue-selective calcium agonists have the potential to combat cardiac failure and endocrinological disorders. They have been used primarily in experimental studies in cell and tissue culture. MeSH. Calcium Channel Blockers (117) • A ...

We demonstrate that systemic activation of the CaR with the type-II calcimimetic, cinacalcet, at doses producing physiologically relevant reductions in blood iCa2+ and PTH acutely increases blood pressure in both anesthetized uremic and nonuremic rats. The increase in blood pressure was mediated by vasoconstriction as evidenced by increases in resistance in vascular beds perfused by the carotid, mesenteric, and hindlimb systemic arteries. Acute increases in blood pressure produced by i.v. infusion of cinacalcet in anesthetized rats were similar to those produced by another type-II calcimimetic, R-568, administered s.c. in conscious telemetry-instrumented rats (Odenwald et al., 2006), thus, acute increases in blood pressure may represent a class effect of calcimimetic agents in the rat.. Although, in previous studies, the mechanism responsible for acute increases in blood pressure produced by CaR activation with R-568 was not fully characterized, Odenwald et al. (2006) hypothesized that R-568 ...

View our personal injury video: Electric Cars are Killers! Some electric car makers claim that their vehicles are the safest ones on the road. Is that true?

I confess to being fascinated by the sudden advance in technology over the last few years in driverless (aka. autonomous) cars. Unlike personal jetpacks (which frankly Ive been waiting for since 1984 when some dude flew into the opening ceremony of Los Angeles Olympics) driverless cars are a real thing that is highly likely to available for sale within five years. One of the reasons to expect driverless cars on our roads in the near future is that we have not one but multiple major car companies saying they will have autonomous cars on the market by 2020, if not sooner. Yes, there was a tragic fatal accident recently involving a test driver of a Tesla autonomus car, but already there is significant evidence to suggest that driverless car are very likely to be more safe on the road than human driven ones - after all, most accidents on roads are caused by human error.. So what advantages would driverless cars offer people with impairments? Several benefits immediately spring to mind. Firstly, ...

For the most part, auto insurance rates are based primarily on personal factors including the insureds gender, age, location, and driving record. For example, it will cost more to insure cars for young adults than middle-aged adults. Once these factors are taken into account, the particular vehicle the insured motorist plans to drive is considered.. Insurance companies review the past claims records of all brands and models of cars on the road. They are then able to determine which cars are more likely to be damaged in the event of a crash and to what extent they may cause damage to other vehicles and property.. Also measured is the likelihood and extent of injuries that may be suffered by people involved in accidents with any particular vehicles. Researchers are also able to determine which cars are more likely to be stolen or crashed and which have higher (or lower) injury claims.. All other factors being equal, the most expensive vehicle models will generally be the most expensive to insure; ...

Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988). Required to bridge the calcium-sensing proteins MICU1 and MICU2 with the calcium-conducting subunit MCU (PubMed:24231807). Plays a central role in regulating the uniplex complex response to intracellular calcium signaling (PubMed:27099988). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988).

Buying a used car can mean taking a chance. Unlike new cars, used cars are often not under manufacturers warranty. That means you risk having to sink money for costly fixes into an automobile.Fortunately, many used cars are better than they have been in the past. Some car brands are known to hold up for many years, even decades. Buying a used car can be easier than before.. Getting a deal on used cars is also easier than before, if you know when to shop. There are specific instances when youre much more likely to net a deal and pay the Kellys blue book value for a vehicle. Though these times may seem like random occurrences, there are a very good reason why used car deals take place at certain times and places.. Slow Days Make for Better SalesSaturday is one of the most crowded days of car lots. People who work during the week normally spend their Saturday negotiating the price of a new vehicle. During the week, car lots are most likely to be empty. For this reason, shopping for a used car at ...

The term of muscle car can be described as a car with large body size and oversized engine.One good example is the Chevrolet Chevelle SS,the body size is huge compared to average sportscars.Most known muscle cars are American cars.All muscle cars are rear wheel drive and most of them are coupes and convertibles,rather than four door. ...

The term of muscle car can be described as a car with large body size and oversized engine.One good example is the Chevrolet Chevelle SS,the body size is huge compared to average sportscars.Most known muscle cars are American cars.All muscle cars are rear wheel drive and most of them are coupes and convertibles,rather than four door. ...

QUT road safety expert Professor Andry Rakotonirainy says as cars become more connected, they are at a real risk of being hacked.

In Ruritania all the cars are made by a single firm and vary only in their colouring. Six different colours are available. The same numbers of cars are painted in each of the six colours. Assuming that, when travelling on the roads, the colours of the cars occur in random order, determine the probability that ...

Ive been used to luxury and honestly this VW is not bad. Asian cars are always skimpy on features, and performance. German cars are just as reliable, have tons of technology in them, but do cost way more to maintain. I got it with 78K and put 10K mo

MaxCyte®, ExPERT®, CARMA®, MaxCyte STx®, MaxCyte ATx®, MaxCyte GT®, MaxCyte VLX®, Flow Transfection®, Flow Electroporation®, Any Cell. Any Molecule. Any Scale®, GTx®, ATx®, and STx® logos are trademarks of MaxCyte, Inc. registered in the U.S. Patent and Trademark Office. ExPERT ATx™, ExPERT GTx™, ExPERT STx™, ExPERT VLx ™, MaxCyte GTx™ , VLx™ and Carma Cell Therapies™ are trademarks of MaxCyte, Inc ...

Many variants exist due to the wide variety of liquids and gases transported. Tank cars can be pressurized or non-pressurized, insulated or non-insulated, and designed for single or multiple commodities. Non-pressurized cars have various fittings on the top and may have fittings on the bottom. Some of the top fittings are covered by a protective housing. Pressurized cars have a pressure plate, with all fittings, and a cylindrical protective housing at the top. Loading and unloading are done through the protective housing. Tank cars are specialized pieces of equipment. As an example, the interior of the car may be lined with a material, such as glass, or other specialized coatings to isolate the tank contents from the tank shell. Care is taken to ensure that tank contents are compatible with tank construction. As a result of this specialization, tank cars have generally been one-way cars. Other cars, like boxcars, can easily be reloaded with other goods for the return trip. Combinations of the ...

The Cheng labs approach is like testing small damages in car parts, one at a time. For example, a mutant car headlight is known not to work when a certain connector is missing. Taking a normally functioning connector out of a working headlight and replacing it with a connector damaged in a specific way -- a cracked wire casing or a corroded wire connector, for example -- can show whether the damage matters. If the light works, then that mutation makes no difference on the function of the headlight. If the light does not work, the mutation has an effect ...

Watertown Man Arrested for OUI After Driving Car on Rims - Free download as Word Doc (.doc), PDF File (.pdf), Text File (.txt) or read online for free.

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NCALD antibody (neurocalcin delta) for IHC-P, WB. Anti-NCALD pAb (GTX121264) is tested in Human, Mouse, Rat samples. 100% Ab-Assurance.

People have an over-attachment to their cars: where is Auckland transport going?Aucklanders are driving more than ever and its bad for their health - but efforts to get them out of their cars are failing Traffic in Auckland, New Zealand. The citys residents own more cars on a per capita basis than ever before. Photograph: Greg Bowker/AFP/Getty Images

Run far, far away from the Wilson Bridge this weekend. Apparently there are delays anywhere from 90 minutes to 2 hours. In Maryland, cars are backed up about six miles to the east of the bridge. Unless you enjoy sitting in a car on a hot day and waiting two hours to get where youre going, find another way to get there. Or hitch a ride on a helicopter.. ...

AA Car Finance and AA Cars are trading names of Used Car Sites Limited. Registered address: Fanum House, Basing View, Basingstoke, Hampshire, RG21 4EA. Used Car Sites Limited is authorised and regulated by the Financial Conduct Authority (firm reference number 671360). AA Cars introduces AA Car Finance customers to Evolution Funding Limited. Evolution Funding Limited is authorised and regulated by the Financial Conduct Authority (firm reference number 823324). Registered address: Thompson Close, Whittington Moor, Chesterfield, Derbyshire, S41 9AZ. Evolution Funding Limited and Used Car Sites Limited are credit brokers not lenders. Evolution Funding Limited is only able to offer a range of finance products from a group of carefully selected credit providers, which may be suitable for you and they will explain the key features of these products to you. AA Cars receives payment from Evolution Funding for introducing you to them. The amount AA Cars receives does not impact the amount that you pay ...

Expression of CASR (FHH, GPRC2A, HHC, HHC1, NSHPT) in cancer tissue. The cancer tissue page shows antibody staining of the protein in 20 different cancers.

20 year old cars are common now but they werent in the fifties. We are really spoiled and dont realize how lucky we are. Late model cars will go for an astonishingly long time with minimal upkeep compared to the Model A era.. At the end of WW2 all cars were at least 3 years old and cars 10 years old or more were common. But as soon as new cars were available the old ones got junked. The interest in old cars was practically nil. Just today an old friend, who is not into antique cars, told me how they used buy cars from the junk yards for a few dollars, thirties cars that were being scrapped because they had a dented fender or bald tires, most of them were driven to the junkyard by their owners or by used car lots who just wanted rid of them. Including coupes , roadsters and touring cars that would be worth a fortune today. He said there were lots of Packards but nobody cared about them. Fords, Chevs, Dodges and the like they considered the best buys. You could keep them going with odds and ends ...

If you are wondering how to sell my car then following tips will prove helpful. Everyday millions of used vehicles are sold so there is always a demand for such cars. Selling a used car is not difficult; the difficult part is selling your car at the price you want. Popular cars are easy to sell while it can take many months to sell collectors cars. There are some ways you can use to sell your car fast. Get Your Car Inspected Any machine that runs regularly undergoes wears and tears. It is true about car as well. It has lots of moving parts. Other parts of the car also undergo changes over time. Regular maintenance is needed to keep a vehicle in good condition. If you have maintained your vehicle in good condition then you can expect high price. Back up your claims with professional inspection reports. This way, prospective buyers will take your claims seriously. It is important to repair the parts that need servicing and replace defective parts. While you can sell your car in ??as is ...

In time for Independence Day and summer car sales, American made cars are gaining in quality and notoriety. The most American cars according to Made

Expect cars of the future to be more closely scrutinizing your fingerprints, heart and breathing rates, iris and pupils in the years to come.

Scrap Cars in in Golden Pages. In Bulgaria, old cars are not just scrapped. They are dissembled and all the parts that can be used again are sold out to car owners looking for original parts at discount prices.

I prefer a motorbike because I cant drive a car. I think that motorcycles are faster than cars sometimes. When cars are stuck in traffic jam, motorbike can mov

Sports Technology Formula 1s 2022 cars may look completely new, but what about the illegal ideas that are returning for[...] Sports Technology Formula 1s 2022 cars may look completely new, but what about the illegal ideas that are returning for the new wave of F1 machines. Credit Autosport

DETROIT (AP) - Hot cars are a danger to children, particularly in a sweltering summer like this one. There are some devices on the market - built into cars as well as child seats - that can help prevent kids from being left behind. So far this year, 26 children in the U.S. have died after they...

In the recent times, the new models of car are being launched frequently in the market. This left people in confusion, especially in understanding the worth of their vehicle and whether it is a wise decision to trade in the car to buy a new one. If you have decided to trade in or sell […]

Automotive enthusiasts are in for a long-awaited treat, as American muscle cars are made available for purchase for the very first time at Cars@Duplication with online viewing exclusively available on Carmudi.lk.

Three nautical-inspired vehicles named the Rolls-Royce Boat Tail are being made as part of Rolls-Royces inaugural Coachbuild project. The cars are estimated to go for $25 million each, making them the most expensive new cars ever sold. ...