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Edward M. Brown - One of the best experts on this subject based on the ideXlab platform.
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calcium sensing Receptor version 2020 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2020Co-Authors: Daniel D Bikle, Edward M. Brown, Arthur D Conigrave, Daniela Riccardi, Hans Braunerosborne, Katie Leach, Wenhan Chang, Fadil Hannan, Dolores M Shoback, D T WardAbstract:The Calcium-Sensing Receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [46] and subsequently updated [76]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [77]). While divalent/trivalent cations, polyamines and polycations are CaS Receptor agonists [14, 109], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [35, 46, 60, 107, 108]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full Receptor activation [147, 53]. The sensitivity of the CaS Receptor to primary agonists is increased by elevated extracellular pH [17] or decreased extracellular ionic strength [108]. This Receptor bears no sequence or structural relation to the plant calcium Receptor, also called CaS.
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calcium sensing Receptor version 2019 4 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Daniel D Bikle, Edward M. Brown, Arthur D Conigrave, Daniela Riccardi, Hans Braunerosborne, Katie Leach, Wenhan Chang, Fadil Hannan, Dolores M Shoback, Donald T WardAbstract:The Calcium-Sensing Receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [44]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [74]). While divalent/trivalent cations, polyamines and polycations are CaS Receptor agonists [14, 106], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [34, 44, 58, 104, 105]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full Receptor activation [143, 51]. The sensitivity of the CaS Receptor to primary agonists is increased by elevated extracellular pH [17] or decreased extracellular ionic strength [105]. This Receptor bears no sequence or structural relation to the plant calcium Receptor, also called CaS.
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immune checkpoint inhibitor induced hypoparathyroidism associated with calcium sensing Receptor activating autoantibodies
The Journal of Clinical Endocrinology and Metabolism, 2019Co-Authors: Paramarajan Piranavan, Edward M. Brown, Helen E Kemp, Yan Li, Nitin TrivediAbstract:Context While therapy with immune checkpoint inhibitors such as nivolumab have substantially improved survival in several types of cancer, increased attention has been given to adverse immune events associated with their use, including the development of endocrine autoimmunity. Objectives First, to describe a patient with a two-year history of metastatic small cell lung cancer who had been treated with nivolumab a few months prior to presentation with the signs and symptoms of severe hypocalcemia and hypoparathyroidism. Second, to investigate the etiology of the patient’s hypoparathyroidism, including the presence of activating autoantibodies against the Calcium-Sensing Receptor (CaSR), since humoral and cellular immune responses against the CaSR have been reported in patients with autoimmune hypoparathyroidism. Case and Results A 61-year-old female was admitted with persistent nausea, vomiting, epigastric pain, constipation, and generalized weakness. Laboratory analyses showed low total serum calcium, ionized calcium, and parathyroid hormone (PTH). The patient was diagnosed with severe hypocalcemia as a result of autoimmune hypoparathyroidism after testing positive for CaSR-activating autoantibodies. She was treated with intravenous calcium gluconate infusions followed by a transition to oral calcium carbonate plus calcitriol which normalized her serum calcium. Her serum PTH remained low0 during her hospitalization and initial outpatient follow-up despite adequate repletion of magnesium. Conclusions This case illustrates autoimmune hypoparathyroidism induced by immune checkpoint inhibitor-blockade. As immune checkpoint inhibitors are now used to treat many cancers, clinicians should be aware of the potential risk for hypocalcemia that may be associated with their use.
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the calcium sensing Receptor a promising target for prevention of colorectal cancer
Biochimica et Biophysica Acta, 2015Co-Authors: Abhishek Aggarwal, Edward M. Brown, Romuald Mentaverri, Samawansha Tennakoon, Cedric Boudot, Maximilian Prinzwohlgenannt, Julia Hobaus, Sabina Baumgartnerparzer, Eniko KallayAbstract:The inverse correlation between dietary calcium intake and the risk of colorectal cancer (CRC) is well known, but poorly understood. Expression of the Calcium-Sensing Receptor (CaSR), a calcium-binding G protein-coupled Receptor is downregulated in CRC leading us to hypothesize that the CaSR has tumor suppressive roles in the colon. The aim of this study was to understand whether restoration of CaSR expression could reduce the malignant phenotype in CRC. In human colorectal tumors, expression of the CaSR negatively correlated with proliferation markers whereas loss of CaSR correlated with poor tumor differentiation and reduced apoptotic potential. In vivo, dearth of CaSR significantly increased expression of proliferation markers and decreased levels of differentiation and apoptotic markers in the colons of CaSR/PTH double knock-out mice confirming the tumor suppressive functions of CaSR. In vitro CRC cells stably overexpressing wild-type CaSR showed significant reduction in proliferation, as well as increased differentiation and apoptotic potential. The positive allosteric modulator of CaSR, NPS R-568 further enhanced these effects, whereas treatment with the negative allosteric modulator, NPS 2143 inhibited these functions. Interestingly, the dominant-negative mutant (R185Q) was able to abrogate these effects. Our results demonstrate a critical tumor suppressive role of CaSR in the colon. Restoration of CaSR expression and function is linked to regulation of the balance between proliferation, differentiation, and apoptosis and provides a rationale for novel strategies in CRC therapy.
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deficiency of the calcium sensing Receptor in the kidney causes parathyroid hormone independent hypocalciuria
Journal of The American Society of Nephrology, 2012Co-Authors: Hakan R Toka, Edward M. Brown, Claudine H Kos, Khaldoun I Alromaih, Jacob M Koshy, Salvatore Dibartolo, Stephen J Quinn, Gary C Curhan, David B Mount, Martin R. PollakAbstract:Rare loss-of-function mutations in the Calcium-Sensing Receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)–dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.31±0.03 versus 0.63±0.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na+-K+-2Cl− cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca2+ transport.
Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
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asymmetric activation of the calcium sensing Receptor homodimer
Nature, 2021Co-Authors: Yang Gao, Fadil M Hannan, Rajesh V Thakker, Michael J Robertson, Sabrina N Rahman, Alpay B Seven, Chensong Zhang, Justin G Meyerowitz, Ouliana Panova, Hans BraunerosborneAbstract:The Calcium-Sensing Receptor (CaSR), a cell-surface sensor for Ca2+, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders1. CaSR is a family C G-protein-coupled Receptor2 that functions as an obligate homodimer, with each protomer composed of a Ca2+-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this Receptor.
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calcimimetic and calcilytic therapies for inherited disorders of the calcium sensing Receptor signalling pathway
British Journal of Pharmacology, 2018Co-Authors: Fadil M Hannan, Mie K Olesen, Rajesh V ThakkerAbstract:The Calcium-Sensing Receptor (CaS Receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss-of-function and gain-of-function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS Receptor signal transduction in the parathyroid glands is probably regulated by G-protein subunit α11 (Gα11 ) and adaptor-related protein complex-2 σ-subunit (AP2σ), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS Receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS Receptor, Gα11 or AP2σ proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient-based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS Receptor signalling pathway. LINKED ARTICLES This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.
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calcium sensing Receptor casr mutations and disorders of calcium electrolyte and water metabolism
Best Practice & Research Clinical Endocrinology & Metabolism, 2013Co-Authors: Fadil M Hannan, Rajesh V ThakkerAbstract:The extracellular Calcium-Sensing Receptor (CaSR) is a family C G-protein-coupled Receptor (GPCR) that is expressed at multiple sites, including the parathyroids and kidneys. The human CASR gene, located on chromosome 3q21.1, encodes a 1078 amino acid protein. More than 230 different disease-causing mutations of the CaSR have been reported. Loss-of-function mutations lead to three hypercalcemic disorders, which are familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism and primary hyperparathyroidism. Gain-of-function mutations, on the other hand, result in the hypocalcemic disorders of autosomal dominant hypocalcemia and Bartter syndrome type V. Moreover, autoantibodies directed against the extracellular domain of the CaSR have been found to be associated with FHH in some patients, and also in some patients with hypoparathyroidism that may be part of autoimmune polyglandular syndrome type 1. Studies of disease-causing CASR mutations have provided insights into structure–function relationships and highlighted intra-molecular domains that are critical for ligand binding, intracellular signaling, and Receptor trafficking.
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diseases associated with the extracellular calcium sensing Receptor
Cell Calcium, 2004Co-Authors: Rajesh V ThakkerAbstract:The human Calcium-Sensing Receptor (CaSR) is a 1078 amino acid cell surface protein, which is predominantly expressed in the parathyroids and kidney, and is a member of the family of G protein-coupled Receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q21.1 and loss-of-function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FHH, FBH or FBHH) and neonatal severe primary hyperparathyroidism (NSHPT). However, some individuals with loss-of-function CaSR mutations remain normocalcaemic. In addition, there is genetic heterogeneity amongst the forms of FHH. Thus, the majority of FHH patients have loss-of-function CaSR mutations, and this is referred to as FHH type 1. However, in one family, the causative gene for FHH is located on 19p13, referred to as FHH type 2, and in another family it is located on 19q13, referred to as FHH type 3. Gain-of-function CaSR mutations have been shown to result in autosomal dominant hypocalcaemia with hypercalciuria (ADHH) and Bartter's syndrome type V. CaSR auto-antibodies have been found in FHH patients who did not have loss-of-function CaSR mutations, and in patients with an acquired form (i.e. autoimmune) of hypoparathyroidism. Thus, abnormalities of the CaSR are associated with three hypercalcaemic and three hypocalcaemic disorders.
Olga Kifor - One of the best experts on this subject based on the ideXlab platform.
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the calcium sensing Receptor car is involved in strontium ranelate induced osteoblast proliferation
Biochemical Pharmacology, 2007Co-Authors: Naibedya Chattopadhyay, Stephen J Quinn, Olga Kifor, Edward M. BrownAbstract:Abstract Strontium ranelate has several beneficial effects on bone and reduces the risk of vertebral and hip fractures in women with postmenopausal osteoporosis. We investigated whether Sr2+ acts via a cell surface Calcium-Sensing Receptor (CaR) in HEK293 cells stably transfected with the bovine CaR (HEK-CaR) and rat primary osteoblasts (POBs) expressing the CaR endogenously. Elevating Cao2+ or Sr2+ concentration-dependently activated the CaR in HEK-CaR but not in non-transfected cells, but the potency of Sr2+ varied depending on the biological response tested. Sr2+ was less potent than Cao2+ in stimulating inositol phosphate accumulation and in increasing Cai2+, but was comparable to Cao2+ in stimulating ERK phosphorylation and a non-selective cation channel, suggesting that Ca2+ and Sr2+ have differential effects on specific cellular processes. With physiological concentrations of Cao2+, Sr2+-induced further CaR activation. Neither Sr2+ nor Cao2+ affected the four parameters just described in non-transfected cells. In POB, Sr2+ stimulated cellular proliferation. This effect was CaR-mediated, as transfecting the cells with a dominant negative bovine CaR significantly attenuated Cao2+-stimulated POB proliferation. Finally, Sr2+ significantly increased the mRNA levels of the immediate early genes, c-fos and egr-1, which are involved in POB proliferation, and this effect was attenuated by overexpressing the dominant negative CaR. In conclusion, Sr2+ is a full CaR agonist in HEK-CaR and POB, and, therefore, the anabolic effect of Sr2+ on bone in vivo could be mediated, in part, by the CaR.
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Acquired hypocalciuric hypercalcemia due to autoantibodies against the Calcium-Sensing Receptor.
The New England journal of medicine, 2004Co-Authors: J. Carl Pallais, Olga Kifor, Yi-bin Chen, David M. SlovikAbstract:A complex homeostatic system involving the interplay of bone, the kidneys, and the intestines maintains extracellular calcium levels within a relatively narrow range. This article describes a patient with autoimmune hyperparathyroidism and hypocalciuric hypercalcemia caused by IgG4 autoantibodies directed against the Calcium-Sensing Receptor. The patient's hypercalcemia and elevated parathyroid hormone levels responded to the administration of glucocorticoids.
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activating antibodies to the calcium sensing Receptor in two patients with autoimmune hypoparathyroidism
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Olga Kifor, Robert Butters, Aidan Mcelduff, Meryl S Leboff, Francis D Moore, Thomas Cantor, Imre Kifor, Edward M. BrownAbstract:Autoimmune hypoparathyroidism is thought to result from immune-mediated destruction of the parathyroid glands. We encountered two patients with hypoparathyroidism and other autoimmune conditions (Graves' disease and Addison's disease, respectively) in whom autoimmune destruction of the parathyroid glands had not taken place. In the first, a histologically normal parathyroid gland was observed at the time of subtotal thyroidectomy; and in the second, the hypoparathyroidism remitted spontaneously. Both patients had antibodies that reacted with the cell surface of bovine parathyroid cells and human embryonic kidney (HEK293) cells transfected with the extracellular Calcium-Sensing Receptor (CaR) but not with nontransfected HEK293 cells. The antibodies also reacted with the same bands on Western analysis of extracts of bovine parathyroid tissue and CaR-transfected HEK293 cells that were identified by an authentic, polyclonal, anti-CaR antiserum and reacted with several peptides with sequences from the CaR's extracellular domain. These anti-CaR antibodies activated the Receptor based on their ability to increase inositol phosphate accumulation, activate MAPK, and inhibit PTH secretion. These results, therefore, demonstrate that patients with the biochemical findings of primary hypoparathyroidism can harbor activating antibodies to the CaR, which, in the two cases studied here, did not produce irreversible destruction of the parathyroid glands.
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a familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium sensing Receptor
The New England Journal of Medicine, 1996Co-Authors: Simon H. S. Pearce, Mei Bai, Catherine Williamson, Olga Kifor, Malcolm G Coulthard, Michael A Davies, Nicholas Lewisbarned, David A Mccredie, H R Powell, P KendalltaylorAbstract:BACKGROUND: The Calcium-Sensing Receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the Receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the Calcium-Sensing Receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the Calcium-Sensing-Receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the Calcium-Sensing-Receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant Receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type Receptor. CONCLUSIONS: Gain-of-function mutations in the Calcium-Sensing Receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.
Sarah C. Brennan - One of the best experts on this subject based on the ideXlab platform.
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structural mechanism of ligand activation in human calcium sensing Receptor
eLife, 2016Co-Authors: Yong Geng, Lidia Mosyak, Igor Kurinov, Hao Zuo, Emmanuel Sturchler, Tat Cheung Cheng, Prakash Subramanyam, Alice P Brown, Sarah C. BrennanAbstract:Human Calcium-Sensing Receptor (CaSR) is a G-protein-coupled Receptor (GPCR) that maintains extracellular Ca(2+) homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the Receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate Receptor activation. Our structures reveal multiple binding sites for Ca(2+) and PO4(3-) ions. Both ions are crucial for structural integrity of the Receptor. While Ca(2+) ions stabilize the active state, PO4(3-) ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.
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The extracellular Calcium-Sensing Receptor regulates human fetal lung development via CFTR
Scientific Reports, 2016Co-Authors: Sarah C. Brennan, William J. Wilkinson, Hsiu-er Tseng, Brenda Finney, Bethan Monk, Holly Dibble, Samantha Quilliam, Luis J. V. Galietta, David Warburton, Paul J KempAbstract: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 activating adenylate cyclase and we show that Ca^2+-stimulated type I adenylate cyclase is expressed in the developing human lung. Together, these observations suggest that physiological fetal hypercalcemia, acting on the CaSR, promotes human fetal lung development via cAMP-dependent opening of CFTR. Disturbances in this process would be expected to permanently impact lung structure and might predispose to certain postnatal respiratory diseases.
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calcium sensing Receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma
Science Translational Medicine, 2015Co-Authors: Polina Yarova, Alecia Stewart, Venkatachalem Sathish, Rodney D Britt, Michael A Thompson, Alexander P P Lowe, Michelle R Freeman, Bharathi Aravamudan, Hirohito Kita, Sarah C. BrennanAbstract:Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native Calcium-Sensing Receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyperreactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics.
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calcium sensing Receptor signalling in physiology and cancer
Biochimica et Biophysica Acta, 2013Co-Authors: Sarah C. Brennan, Ursula Thiem, Susanne Roth, Abhishek Aggarwal, Irfete S Fetahu, Samawansha Tennakoon, A R Gomes, Maria Luisa Brandi, Frank J Bruggeman, Romuald MentaverriAbstract:The calcium sensing Receptor (CaSR) is a class C G-protein-coupled Receptor that is crucial for the feedback regulation of extracellular free ionised calcium homeostasis. While extracellular calcium (Ca2 +o) is considered the primary physiological ligand, the CaSR is activated physiologically by a plethora of molecules including polyamines and l-amino acids. Activation of the CaSR by different ligands has the ability to stabilise unique conformations of the Receptor, which may lead to preferential coupling of different G proteins; a phenomenon termed ‘ligand-biased signalling’. While mutations of the CaSR are currently not linked with any malignancies, altered CaSR expression and function are associated with cancer progression. Interestingly, the CaSR appears to act both as a tumour suppressor and an oncogene, depending on the pathophysiology involved. Reduced expression of the CaSR occurs in both parathyroid and colon cancers, leading to loss of the growth suppressing effect of high Ca2 +o. On the other hand, activation of the CaSR might facilitate metastasis to bone in breast and prostate cancer. A deeper understanding of the mechanisms driving CaSR signalling in different tissues, aided by a systems biology approach, will be instrumental in developing novel drugs that target the CaSR or its ligands in cancer.
Arthur D Conigrave - One of the best experts on this subject based on the ideXlab platform.
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calcium sensing Receptor version 2020 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2020Co-Authors: Daniel D Bikle, Edward M. Brown, Arthur D Conigrave, Daniela Riccardi, Hans Braunerosborne, Katie Leach, Wenhan Chang, Fadil Hannan, Dolores M Shoback, D T WardAbstract:The Calcium-Sensing Receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [46] and subsequently updated [76]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [77]). While divalent/trivalent cations, polyamines and polycations are CaS Receptor agonists [14, 109], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [35, 46, 60, 107, 108]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full Receptor activation [147, 53]. The sensitivity of the CaS Receptor to primary agonists is increased by elevated extracellular pH [17] or decreased extracellular ionic strength [108]. This Receptor bears no sequence or structural relation to the plant calcium Receptor, also called CaS.
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phosphate acts directly on the calcium sensing Receptor to stimulate parathyroid hormone secretion
Nature Communications, 2019Co-Authors: Patricia P Centeno, Heechang Mun, Arthur D Conigrave, Amanda Herberger, Edward F Nemeth, Wenhan Chang, D T WardAbstract:Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent secretion of parathyroid hormone (PTH). However, the phosphate-sensing mechanism remains unknown and requires elucidation for understanding the aetiology of secondary hyperparathyroidism in chronic kidney disease (CKD). The Calcium-Sensing Receptor (CaSR) is the main controller of PTH secretion and here we show that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits CaSR activity via non-competitive antagonism. Mutation of residue R62 in anion binding site-1 abolishes phosphate-induced inhibition of CaSR. Further, pathophysiologic phosphate concentrations elicit rapid and reversible increases in PTH secretion from freshly-isolated human parathyroid cells consistent with a Receptor-mediated action. The same effect is seen in wild-type murine parathyroid glands, but not in CaSR knockout glands. By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, explaining the stimulatory effect of phosphate on PTH secretion.
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calcium sensing Receptor version 2019 4 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Daniel D Bikle, Edward M. Brown, Arthur D Conigrave, Daniela Riccardi, Hans Braunerosborne, Katie Leach, Wenhan Chang, Fadil Hannan, Dolores M Shoback, Donald T WardAbstract:The Calcium-Sensing Receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [44]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [74]). While divalent/trivalent cations, polyamines and polycations are CaS Receptor agonists [14, 106], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [34, 44, 58, 104, 105]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full Receptor activation [143, 51]. The sensitivity of the CaS Receptor to primary agonists is increased by elevated extracellular pH [17] or decreased extracellular ionic strength [105]. This Receptor bears no sequence or structural relation to the plant calcium Receptor, also called CaS.
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Towards a structural understanding of allosteric drugs at the human Calcium-Sensing Receptor
Cell Research, 2016Co-Authors: Katie Leach, Arthur D Conigrave, Patrick M Sexton, Karen J Gregory, Irina Kufareva, Elham Khajehali, Anna E Cook, Ruben Abagyan, Arthur ChristopoulosAbstract:Drugs that allosterically target the human Calcium-Sensing Receptor (CaSR) have substantial therapeutic potential, but are currently limited. Given the absence of high-resolution structures of the CaSR, we combined mutagenesis with a novel analytical approach and molecular modeling to develop an “enriched” picture of structure-function requirements for interaction between Ca^2+_o and allosteric modulators within the CaSR's 7 transmembrane (7TM) domain. An extended cavity that accommodates multiple binding sites for structurally diverse ligands was identified. Phenylalkylamines bind to a site that overlaps with a putative Ca^2+_o-binding site and extends towards an extracellular vestibule. In contrast, the structurally and pharmacologically distinct AC-265347 binds deeper within the 7TM domains. Furthermore, distinct amino acid networks were found to mediate cooperativity by different modulators. These findings may facilitate the rational design of allosteric modulators with distinct and potentially pathway-biased pharmacological effects.
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calcium sensing Receptor casr pharmacological properties and signaling pathways
Best Practice & Research Clinical Endocrinology & Metabolism, 2013Co-Authors: Arthur D Conigrave, D T WardAbstract:In this article we consider the mechanisms by which the Calcium-Sensing Receptor (CaSR) induces its cellular responses via the control (activation or inhibition) of signaling pathways. We consider key features of CaSR-mediated signaling including its control of the heterotrimeric G-proteins Gq/11, Gi/o and G12/13 and the downstream consequences recognizing that very few CaSR-mediated cell phenomena have been fully described. We also consider the manner in which the CaSR contributes to the formation of specific signaling scaffolds via peptide recognition sequences in its intracellular C-terminal along with the origins of its high level of cooperativity, particularly for Ca(2+)o, and its remarkable resistance to desensitization. We also consider the nature of the mechanisms by which the CaSR controls oscillatory and sustained Ca(2+)i mobilizing responses and inhibits or elevates cyclic adenosine monophosphate (cAMP) levels dependent on the cellular and signaling context. Finally, we consider the diversity of the Receptor's ligands, ligand binding sites and broader compartment-dependent physiological roles leading to the identification of pronounced ligand-biased signaling for agonists including Sr(2+) and modulators including l-amino acids and the clinically effective calcimimetic cinacalcet. We note the implications of these findings for the development of new designer drugs that might target the CaSR in pathophysiological contexts beyond those established for the treatment of disorders of calcium metabolism.
