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David E C Cole, Francisco H J Yun, Betty Y L Wong, Andrew Y Shuen, Ronald A Booth, Alfredo Scillitani, Svetlana Pidasheva, Xiang Zhou, Lucie Canaff and Geoffrey N Hendy

Introduction The calcium-sensing receptor (CASR) is a plasma membrane G-protein-coupled receptor (GPCR) abundantly expressed in the parathyroid gland and kidney tubule where it plays a key role as the ‘calciostat’, maintaining extracellular fluid

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Caroline M Gorvin

using the cell-surface-expressed calcium-sensing receptor (CASR), a class C G-protein-coupled receptor (GPCR), for which Ca 2+ is the major ligand ( Riccardi & Brown 2010 , Conigrave & Ward 2013 ). Figure 1 Regulation of extracellular calcium at

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Caroline M Gorvin

Discovery of the calcium-sensing receptor The significance of the parathyroid in calcium homeostasis has been recognised for more than 100 years. Early investigations demonstrated that removal of the parathyroid glands induces acute

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Annalisa Terranegra, Anita Ferraretto, Elena Dogliotti, Milena Scarpellini, Sabrina Corbetta, Anna Maria Barbieri, Anna Spada, Teresa Arcidiacono, Francesco Rainone, Andrea Aloia, Daniele Cusi, Giuseppe Vezzoli and Laura Soldati

Introduction The calcium-sensing receptor (CASR) is a G-protein-coupled membrane receptor involved in the regulation of cellular calcium metabolism. The receptor senses changes in extracellular calcium concentration ([Ca 2+ ] o ) and activates

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Fadil M Hannan, Valerie N Babinsky and Rajesh V Thakker

that comprises the calcium-sensing receptor (CaSR), G-protein α-11 (Gα 11 ) subunit and adaptor-related protein complex 2 sigma (AP2σ) subunit ( Pollak et al . 1993 , Nesbit et al . 2013 a , b ). This article will provide an overview of the role of

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D Alvarez-Hernandez, I Santamaria, M Rodriguez-Garcia, P Iglesias, R Delgado-Lillo and JB Cannata-Andia

A novel missense activating mutation in the extracellular calcium-sensing receptor (CaSR) is reported in this work. It was identified in three related subjects with the phenotypic features of autosomal dominant hypocalcemia (ADH). The proband, a 27-year-old woman, diagnosed as having hypoparathyroidism at 7 years of age and a history of seizures, showed the highest penetrance of the mutation. The remaining two affected members presented asymptomatic chronic hypocalcemia despite severe hypoparathyroidism associated with high levels of serum phosphate and calcium urinary excretion. The missense mutation (Glu(604)Lys) affected an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular amino-terminal domain, which seems to be required for the coupling of ligand binding to the activation of intracellular signaling pathways. This genetic change cosegregated with hypocalcemia in all the individuals where the mutation was found. As parathyroid hormone (PTH) secretion is the regulatory target of the CaSR, polymorphism analysis of the PTH gene was carried out. PTH polymorphisms were analyzed in the kindred studied. Affected members for the Glu(604)Lys CaSR mutation which also carried the uncommon PTH alleles showed higher penetrance of the mutation, with more severe autosomal dominant hypocalcemia. These results suggested that the PTH gene could act as a modifier locus of ADH, affecting the penetrance of the activating CaSR mutation described.

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RE Toribio, CW Kohn, CC Capen and TJ Rosol

Parathyroid hormone (PTH) is secreted by the chief cells of the parathyroid gland in response to changes in ionized calcium (Ca(2+)) concentrations. In this study, we measured PTH secretion, and PTH mRNA and calcium-sensing receptor (CaR) mRNA expression by equine parathyroid chief cells in vitro. We also evaluated the effects of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha on PTH secretion, and PTH and CaR mRNA expression. The relationship between PTH and Ca(2+) was inversely related. PTH secretion decreased from 100% (day 0) to 13% (day 30). PTH mRNA expression declined from 100% (day 0) to 25% (day 30). CaR mRNA decreased from 100% (day 0) to 16% (day 30). Chief cells exposed to high (2.0 mM) Ca(2+) concentrations had a lower PTH mRNA expression compared with low Ca(2+) concentrations. Ca(2+) concentrations had no effect on CaR mRNA expression. The inhibitory effect of high Ca(2+) concentrations on PTH secretion also declined over time. After day 10, there was no significant difference in PTH secretion between low and high Ca(2+ )concentrations. IL-1beta decreased both PTH secretion (75%) and PTH mRNA expression (73%), and resulted in a significant overexpression of CaR mRNA (up to 142%). The effects of IL-1beta were blocked by an IL-1 receptor antagonist. IL-1beta decreased the Ca(2+) set-point from 1.4 mM to 1.2 mM. IL-6 decreased PTH secretion (74%), but had no effect on PTH and CaR mRNA expression. TNF-alpha had no effect on PTH secretion, and PTH and CaR mRNA expression. In summary, the decreased responsiveness of parathyroid cells to Ca(2+) from 0 to 30 days can be explained, in part, by the reduced CaR expression. IL-1beta and IL-6 but not TNF-alpha affected parathyroid function in vitro and may be important in influencing PTH secretion in the septic horse.

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Petrine Wellendorph, Lars Dan Johansen, Anders A Jensen, Emilio Casanova, Martin Gassmann, Pierre Deprez, Philippe Clément-Lacroix, Bernhard Bettler and Hans Bräuner-Osborne

receptors also include the metabotropic glutamate (mGlu), γ-aminobutyric acid B (GABA B ), T1R taste and calcium-sensing receptors. Aside from the 7TM domain governing G protein activation, family C receptors also possess a large amino-terminal domain

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Alessandra Mingione, Chiara Verdelli, Stefano Ferrero, Valentina Vaira, Vito Guarnieri, Alfredo Scillitani, Leonardo Vicentini, Gianni Balza, Edoardo Beretta, Annalisa Terranegra, Giuseppe Vezzoli, Laura Soldati and Sabrina Corbetta

increased parathyroid cell proliferation. The parathyroid cell sensitivity to [Ca 2+ ] o is mediated by the calcium-sensing receptor (CASR). CASR is a G-protein-coupled membrane receptor interacting with different intracellular pathways ( Breitwieser 2013

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Cynthia S Ritter, Sangeeta Pande, Irina Krits, Eduardo Slatopolsky and Alex J Brown

. 1996 , Chen & Goodman 2004 ). Chief cells of the parathyroid gland express a cell surface calcium-sensing receptor (CaR) that detects small changes in serum calcium and controls the rate of PTH secretion ( Fukugawa & Kurokawa 2002 , Hofer & Brown 2003