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      Amino Alcohol- (NPS-2143) and Quinazolinone-Derived Calcilytics (ATF936 and AXT914) Differentially Mitigate Excessive Signalling of Calcium-Sensing Receptor Mutants Causing Bartter Syndrome Type 5 and Autosomal Dominant Hypocalcemia

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          Abstract

          Introduction

          Activating calcium sensing receptor (CaSR) mutations cause autosomal dominant hypocalcemia (ADH) characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS) type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics) on activating CaSR mutants.

          Methods

          All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca 2+] o). To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca 2+] o in the presence or absence of NPS-2143, ATF936 or AXT914.

          Results

          All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca 2+] o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants.

          Conclusion

          The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations.

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          Most cited references27

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          Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

          Maintenance of a stable internal environment within complex organisms requires specialized cells that sense changes in the extracellular concentration of specific ions (such as Ca2+). Although the molecular nature of such ion sensors is unknown, parathyroid cells possess a cell surface Ca(2+)-sensing mechanism that also recognizes trivalent and polyvalent cations (such as neomycin) and couples by changes in phosphoinositide turnover and cytosolic Ca2+ to regulation of parathyroid hormone secretion. The latter restores normocalcaemia by acting on kidney and bone. We now report the cloning of complementary DNA encoding an extracellular Ca(2+)-sensing receptor from bovine parathyroid with pharmacological and functional properties nearly identical to those of the native receptor. The novel approximately 120K receptor shares limited similarity with the metabotropic glutamate receptors and features a large extracellular domain, containing clusters of acidic amino-acid residues possibly involved in calcium binding, coupled to a seven-membrane-spanning domain like those in the G-protein-coupled receptor superfamily.
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            Extracellular calcium sensing and signalling.

            Ca2+ is well established as an intracellular second messenger. However, the molecular identification of a detector for extracellular Ca2+--the extracellular calcium-sensing receptor--has opened up the possibility that Ca2+ might also function as a messenger outside cells. Information about the local extracellular Ca2+ concentration is conveyed to the interior of many cell types through this unique G-protein-coupled receptor. Here, we describe new emerging concepts concerning the signalling function of extracellular Ca2+, with particular emphasis on the extracellular calcium-sensing receptor.
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              Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.

              Defects in the human Ca(2+)-sensing receptor gene have recently been shown to cause familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism. We now demonstrate that a missense mutation (Glu128Ala) in this gene causes familial hypocalcaemia in affected members of one family. Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor. We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                15 December 2014
                : 9
                : 12
                : e115178
                Affiliations
                [1 ]Division of Endocrinology and Diabetes, Department of Medicine I, Universitätsklinikum Erlangen, Erlangen, Germany
                [2 ]Endocrine Practice, Heidelberg, Germany
                [3 ]Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
                University of Bari Aldo Moro, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SL BM CS. Performed the experiments: SL. Analyzed the data: SL BH BM CS. Contributed reagents/materials/analysis tools: CH ES KFR FR. Wrote the paper: SL BH BM CS. Contributed human genetic and clinical data: CH ES KFR FR.

                Article
                PONE-D-14-23046
                10.1371/journal.pone.0115178
                4266668
                25506941
                71345ac2-1032-4986-959e-076a706c8bfd
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 May 2014
                : 19 November 2014
                Page count
                Pages: 11
                Funding
                Christof Schöfl was supported by institutional grants from the Friedrich-Alexander University Erlangen-Nuremberg (AZ 08.12.18.1). We acknowledge support by Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) within the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Endocrine System
                Parathyroid
                Biochemistry
                Metabolism
                Bone and Mineral Metabolism
                Proteins
                Transmembrane Receptors
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signaling Cascades
                Calcium Signaling Cascade
                Calcium Signaling
                Endocrine Signaling
                Calcium-Mediated Signal Transduction
                Physiology
                Endocrine Physiology
                Medicine and Health Sciences
                Endocrinology
                Nephrology
                Mineral Metabolism and the Kidney
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.

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                Uncategorized

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