Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications

Saidak, Zuzana; Brazier, Michel; Kamel, Saı̈d; Mentaverri, Romuald

doi:10.1124/mol.109.058784

Cited by 90 publications

(79 citation statements)

References 142 publications

(193 reference statements)

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“…(28) Several calcilytics have been reported to reduce the sensitivity of CaSR to extracellular Ca 2þ , and cause a rightward shift of the extracellular Ca 2þ -tointracellular Ca 2þ concentration curve. (29,30) JTT-305 (also known as MK-5442), a short-acting calcilytic, transiently elevates the endogenous PTH secretion, and increases bone mineral density (BMD) in rats. (31) Because activating mutations of CaSR cause ADH, and because calcilytics suppress the enhanced sensitivity of CaSR to extracellular Ca 2þ , there is a possibility that JTT-305/MK-5442 may become a new therapeutic agent to reverse most of the abnormalities in Ca metabolism in ADH patients caused by activating mutations of CaSR.…”

Section: Introductionmentioning

confidence: 99%

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

Dong

Endo

Ohnishi

et al. 2015

Journal of Bone and Mineral Research

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Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D 3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca 2þ of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a novel therapeutic agent for ADH.

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Section: Introductionmentioning

confidence: 99%

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

Dong

Endo

Ohnishi

et al. 2015

Journal of Bone and Mineral Research

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“…Much has been learned from studies of lingual nutrient detection due to identification of the G protein family, which couples with nutrient-sensitive G protein coupled receptors located in the taste buds on the tongue and in the intestine (26,27). The CaR, a G protein-coupled receptor, is best known and understood for its control of PTH synthesis and secretion in response to changes in Ca, Mg, Sr, and La (17,18). CaRs are distributed along most of the gastrointestinal tract, from the stomach to the large intestine (23,28).…”

Section: Discussionmentioning

confidence: 99%

“…CaRs are distributed along most of the gastrointestinal tract, from the stomach to the large intestine (23,28). The physiologic role of CaRs is the maintenance of constant blood Ca 2 + levels (1.1-1.3 mM) through continuous adjustments of PTH release from the parathyroid chief cells, which are highly sensitive to the slightest changes in extracellular Ca ion concentrations (17,18). In the present study, we showed that Mg, La, or Sr, which are CaR agonists, can partially substitute for dietary Ca.…”

Section: Discussionmentioning

confidence: 99%

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Effect of dietary components on renal inorganic phosphate (Pi) excretion induced by a Pi-depleted diet

et al. 2014

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“…To date, four groups of ligands have been identified for the CaS receptor: the endogenous cations [93] , the L-amino acids (such as L-phenylalanine and L-tryptophan [94] ), the calcimimetics and the calcilytics [95] . Except for the cations, the latter three groups are all allosteric modulators.…”

Section: Cas Receptors -First Clinical Successmentioning

confidence: 99%

Structure and ligand recognition of class C GPCRs

2012

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The G-protein-coupled receptors (GPCRs) are one of the largest super families of cell-surface receptors and play crucial roles in virtually every organ system. One particular family of GPCRs, the class C GPCRs, is distinguished by a characteristically large extracellular domain and constitutive dimerization. The structure and activation mechanism of this family result in potentially unique ligand recognition sites, thereby offering a variety of possibilities by which receptor activity might be modulated using novel compounds. In the present article, we aim to provide an overview of the exact sites and structural features involved in ligand recognition of the class C GPCRs. Furthermore, we demonstrate the precise steps that occur during the receptor activation process, which underlie the possibilities by which receptor function may be altered by different approaches. Finally, we use four typical family members to illustrate orthosteric and allosteric sites with representative ligands and their corresponding therapeutic potential.

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Agonists and Allosteric Modulators of the Calcium-Sensing Receptor and Their Therapeutic Applications

Abstract: The calcium-sensing receptor (CaR) belongs to the G proteincoupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain.

Cited by 90 publications

References 142 publications

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

Effect of dietary components on renal inorganic phosphate (Pi) excretion induced by a Pi-depleted diet

Structure and ligand recognition of class C GPCRs

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