Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion

2020 ◽  
Author(s):  
Centeno PP ◽  
Herberger A ◽  
Mun H.
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Secretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism

2005 ◽  
Vol 153 (4) ◽  
pp. 587-594 ◽  
Author(s):  
Takehisa Kawata ◽  
Yasuo Imanishi ◽  
Keisuke Kobayashi ◽  
Takao Kenko ◽  
Michihito Wada ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Primary Hyperparathyroidism ◽  
Secondary Hyperparathyroidism ◽  
Murine Model ◽  
Hormone Secretion ◽  
Suppressive Effect ◽  
Receptor Expression ◽  
Parathyroid Glands ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet’s effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93–99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.

Association of Polymorphic Alleles of the Calcium-Sensing Receptor Gene with Parathyroid Hormone Secretion in Hemodialysis Patients

Nephron ◽  
2000 ◽  
Vol 85 (4) ◽  
pp. 317-323 ◽  
Author(s):  
Shozo Yano ◽  
Toshitsugu Sugimoto ◽  
Michiko Kanzawa ◽  
Tatsuo Tsukamoto ◽  
Tetsuya Hattori ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Receptor Gene ◽  
Hormone Secretion ◽  
Hemodialysis Patients ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Calcium Sensing Receptor Gene

scholarly journals A Novel Calcium-Sensing Receptor Antagonist Transiently Stimulates Parathyroid Hormone Secretion in Vivo

Endocrinology ◽  
2005 ◽  
Vol 146 (4) ◽  
pp. 2015-2022 ◽  
Author(s):  
Brian J. Arey ◽  
Ramakrishna Seethala ◽  
Zhengping Ma ◽  
Aberra Fura ◽  
Jennifer Morin ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Receptor Antagonist ◽  
Hormone Secretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals Calcium-Sensing Receptor Expression and Parathyroid Hormone Secretion in Hyperplastic Parathyroid Glands from Humans

2005 ◽  
Vol 16 (7) ◽  
pp. 2190-2197 ◽  
Author(s):  
Sagrario Cañadillas ◽  
Antonio Canalejo ◽  
Rafael Santamaría ◽  
Maria E. Rodríguez ◽  
Jose C. Estepa ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Secretion ◽  
Receptor Expression ◽  
Parathyroid Glands ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Patricia P. Centeno ◽  
Amanda Herberger ◽  
Hee-Chang Mun ◽  
Chialing Tu ◽  
Edward F. Nemeth ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Secretion ◽  
Phosphate Concentration ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Mediated Action ◽  
Calcium Sensing ◽  
Competitive Antagonism ◽  
Phosphate Sensing ◽  
Phosphate Sensor

Abstract 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.

scholarly journals The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion

2009 ◽  
Vol 297 (4) ◽  
pp. E915-E923 ◽  
Author(s):  
Lakshmi Kantham ◽  
Steven J. Quinn ◽  
Ogo I. Egbuna ◽  
Khanjan Baxi ◽  
Robert Butters ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Secretion ◽  
The Other ◽  
Constant Infusion ◽  
Calcium Sensing Receptor ◽  
Double Knockout ◽  
Deficient Diet ◽  
Direct Role ◽  
Serum Calcitonin ◽  
Calcium Sensing

The calcium-sensing receptor (CaSR) controls parathyroid hormone (PTH) secretion, which, in turn, via direct and indirect actions on kidney, bone, and intestine, maintains a normal extracellular ionized calcium concentration (Ca2+o). There is less understanding of the CaSR's homeostatic importance outside of the parathyroid gland. We have employed single and double knockout mouse models, namely mice lacking PTH alone (CaSR+/+ PTH−/−, referred to as C+P−), lacking both CaSR and PTH (CaSR−/− PTH−/−, C−P−) or wild-type (CaSR+/+ PTH+/+, C+P+) mice to study CaSR-specific functions without confounding CaSR-mediated changes in PTH. The mice received three hypercalcemic challenges: an oral Ca2+ load, injection or constant infusion of PTH via osmotic pump, or a phosphate-deficient diet. C−P− mice show increased susceptibility to developing hypercalcemia with all three challenges compared with the other two genotypes, whereas C+P− mice defend against hypercalcemia similarly to C+P+ mice. Reduced renal Ca2+ clearance contributes to the intolerance of the C−P− mice to Ca2+ loads, as they excrete less Ca2+ at any given Ca2+o than the other two genotypes, confirming the CaSR's direct role in regulating renal Ca2+ handling. In addition, C+P+ and C+P−, but not C−P−, mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)2D3 in C−P− mice, in contrast, was similar to those in C+P− and C+P+ mice during an oral Ca2+ load, indicating that increased 1,25(OH)2D3 production cannot account for the oral Ca2+-induced hypercalcemia in the C−P− mice. Thus, CaSR-stimulated PTH release serves as a “floor” to defend against hypocalcemia. In contrast, high-Ca2+o-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca2+o-stimulated, CaSR-mediated CT secretion and renal Ca2+ excretion, and perhaps other factors, serve as a “ceiling” to limit hypercalcemia resulting from various types of hypercalcemic challenges.

scholarly journals Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor

2021 ◽  
Vol 7 (23) ◽  
pp. eabg1483
Author(s):  
Tianlei Wen ◽  
Ziyu Wang ◽  
Xiaozhe Chen ◽  
Yue Ren ◽  
Xuhang Lu ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Bound States ◽  
Hormone Secretion ◽  
Allosteric Modulation ◽  
Full Length ◽  
Structural Basis ◽  
Endocrine Disorders ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Class C

Calcium-sensing receptor (CaSR) is a class C G protein–coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo–electron microscopy structures of full-length CaSR in distinct ligand-bound states. Ligands (Ca2+ and l-tryptophan) bind to the extracellular domain of CaSR and induce large-scale conformational changes, leading to the closure of two heptahelical transmembrane domains (7TMDs) for activation. The positive modulator (evocalcet) and the negative allosteric modulator (NPS-2143) occupy the similar binding pocket in 7TMD. The binding of NPS-2143 causes a considerable rearrangement of two 7TMDs, forming an inactivated TM6/TM6 interface. Moreover, a total of 305 disease-causing missense mutations of CaSR have been mapped to the structure in the active state, creating hotspot maps of five clinical endocrine disorders. Our results provide a structural framework for understanding the activation, allosteric modulation mechanism, and disease therapy for class C GPCRs.

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