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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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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.
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physiology and pathophysiology of the Calcium Sensing receptor in the kidney
American Journal of Physiology-renal Physiology, 2010Co-Authors: Daniela Riccardi, Edward M. BrownAbstract:The extracellular Calcium-Sensing receptor (CaSR) plays a major role in the maintenance of a physiological serum ionized Calcium (Ca2+) concentration by regulating the circulating levels of parathyroid hormone. It was molecularly identified in 1993 by Brown et al. in the laboratory of Dr. Steven Hebert with an expression cloning strategy. Subsequent studies have demonstrated that the CaSR is highly expressed in the kidney, where it is capable of integrating signals deriving from the tubular fluid and/or the interstitial plasma. Additional studies elucidating inherited and acquired mutations in the CaSR gene, the existence of activating and inactivating autoantibodies, and genetic polymorphisms of the CaSR have greatly enhanced our understanding of the role of the CaSR in mineral ion metabolism. Allosteric modulators of the CaSR are the first drugs in their class to become available for clinical use and have been shown to treat successfully hyperparathyroidism secondary to advanced renal failure. In addition, preclinical and clinical studies suggest the possibility of using such compounds in various forms of hypercalcemic hyperparathyroidism, such as primary and lithium-induced hyperparathyroidism and that occurring after renal transplantation. This review addresses the role of the CaSR in kidney physiology and pathophysiology as well as current and in-the-pipeline treatments utilizing CaSR-based therapeutics.
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anti parathyroid and anti Calcium Sensing receptor antibodies in autoimmune hypoparathyroidism
Endocrinology and Metabolism Clinics of North America, 2009Co-Authors: Edward M. BrownAbstract:The parathyroid glands are an infrequent target for autoimmunity, the exception being autoimmune polyglandular syndrome type 1, in which autoimmune hypoparathyroidism is the rule. Antibodies that are directed against the parathyroid cell surface Calcium-Sensing receptor (CaSR) have recently been recognized to be present in the serum of patients with autoimmune hypoparathyroidism. In some individuals, these anti-CaSR antibodies have also been shown to produce functional activation of the receptor, suggesting a direct pathogenic role in hypocalcemia. Additionally, a few hypercalcemic patients with autoimmune hypocalciuric hypercalcemia owing to anti-CaSR antibodies that inhibit receptor activation have now been identified. Other novel parathyroid autoantigens are starting to be elucidated, suggesting that new approaches to treatment, such as CaSR antagonists or agonists (calcilytics/calcimimetics), may be worthwhile.
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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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.
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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receptor expression modulates Calcium Sensing receptor mediated intracellular ca2 mobilization
Endocrinology, 2015Co-Authors: Sarah C. Brennan, Heechang Mun, Katherine Leach, Philip W Kuchel, Arthur Christopoulos, Arthur D ConigraveAbstract:Calcium-Sensing receptors (CaSRs) are class C G protein-coupled receptors that respond to physiological activators, including extracellular Ca2+ (Cao2+) and l-amino acids as well as the pharmaceutical calcimimetic, cinacalcet. Unlike Cao2+, which is an orthosteric agonist, l-amino acids and cinacalcet are positive allosteric modulators. CaSR expression levels vary considerably between tissues, but the physiological significance of these differences in expression for the effects of its activators is unknown. To investigate the impact of receptor expression on CaSR-mediated signaling we used a tetracycline-inducible expression system and focused on intracellular Ca2+ (Cai2+) responses in single cells and considered both population and single-cell behavior. Increased receptor expression positively modulated CaSR-mediated Cai2+ mobilization in response to elevated Cao2+, the amino acid l-phenylalanine, or the calcimimetic cinacalcet. It lowered threshold concentrations for the initiation of Cai2+ oscillations...
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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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receptor expression modulates Calcium Sensing receptor mediated intracellular ca2 mobilization
Endocrinology, 2015Co-Authors: Sarah C. Brennan, Heechang Mun, Katherine Leach, Philip W Kuchel, Arthur Christopoulos, Arthur D ConigraveAbstract:Calcium-Sensing receptors (CaSRs) are class C G protein-coupled receptors that respond to physiological activators, including extracellular Ca2+ (Cao2+) and l-amino acids as well as the pharmaceutical calcimimetic, cinacalcet. Unlike Cao2+, which is an orthosteric agonist, l-amino acids and cinacalcet are positive allosteric modulators. CaSR expression levels vary considerably between tissues, but the physiological significance of these differences in expression for the effects of its activators is unknown. To investigate the impact of receptor expression on CaSR-mediated signaling we used a tetracycline-inducible expression system and focused on intracellular Ca2+ (Cai2+) responses in single cells and considered both population and single-cell behavior. Increased receptor expression positively modulated CaSR-mediated Cai2+ mobilization in response to elevated Cao2+, the amino acid l-phenylalanine, or the calcimimetic cinacalcet. It lowered threshold concentrations for the initiation of Cai2+ oscillations...
Fadil M Hannan - 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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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.
