scholarly journals L-phenylalanine Increased Gut Hormone Secretion through Calcium-Sensing Receptor in the Porcine Duodenum

Animals ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 476 ◽  
Author(s):  
Jiangyin Feng ◽  
Cuicui Kang ◽  
Chao Wang ◽  
Liren Ding ◽  
Weiyun Zhu ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mrna Expression ◽  
Hormone Secretion ◽  
Calcium Sensing Receptor ◽  
Downstream Signaling ◽  
Protein Levels ◽  
Calcium Sensing ◽  
Gut Hormone ◽  
Gip Release ◽  
Underlying Mechanisms

Luminal amino acids have a pivotal role in gut hormone secretion, and thereby modulate food intake and energy metabolism. However, the mechanisms by which amino acids exert this effect remains unknown. The purpose of this research was to investigate the response of L-phenylalanine (L-Phe) to gut hormone secretion and its underlying mechanisms by perfusing the pig duodenum. Eighty mM L-Phe and extracellular Ca2+ stimulated cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) release, and upregulated the mRNA expression of the calcium-sensing receptor (CaSR), CCK, and GIP. Western blotting results showed that L-Phe also elevated the protein levels of CaSR, the inositol 1,4,5-triphosphate receptor (IP3R), and protein kinase C (PKC). However, the CaSR inhibitor NPS 2143 reduced the mRNA expression of CaSR, CCK, and GIP, and the secretion of CCK and GIP, as well as the protein level of CaSR, IP3R, and PKC. These results indicated that Phe stimulated gut secretion through a CaSR-mediated pathway and its downstream signaling molecules, PKC and IP3R.

Taste Receptors in the Gastrointestinal Tract II.l-Amino acid sensing by calcium-sensing receptors: implications for GI physiology

2006 ◽  
Vol 291 (5) ◽  
pp. G753-G761 ◽  
Author(s):  
Arthur D. Conigrave ◽  
Edward M. Brown
Keyword(s):  
Amino Acid ◽  
Gastrointestinal Tract ◽  
Epithelial Transport ◽  
Hormone Secretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Gut Hormone ◽  
Protein Ingestion ◽  
Amino Acid Sensing ◽  
Amino Acid Sensor

The extracellular calcium-sensing receptor (CaR) is a multimodal sensor for several key nutrients, notably Ca2+ions and l-amino acids, and is expressed abundantly throughout the gastrointestinal tract. While its role as a Ca2+ion sensor is well recognized, its physiological significance as an l-amino acid sensor and thus, in the gastrointestinal tract, as a sensor of protein ingestion is only now coming to light. This review focuses on the CaR’s amino acid sensing properties at both the molecular and cellular levels and considers new and putative physiological roles for the CaR in the amino acid-dependent regulation of gut hormone secretion, epithelial transport, and satiety.

scholarly journals Emerging roles of the extracellular calcium-sensing receptor in nutrient sensing: control of taste modulation and intestinal hormone secretion

2014 ◽  
Vol 111 (S1) ◽  
pp. S16-S22 ◽  
Author(s):  
Sarah C. Brennan ◽  
Thomas S. Davies ◽  
Martin Schepelmann ◽  
Daniela Riccardi
Keyword(s):  
Amino Acids ◽  
Hormone Secretion ◽  
Nutrient Sensing ◽  
The Body ◽  
Hormone Release ◽  
Gi Tract ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Ca Ions ◽  
Taste Modulation

The extracellular Ca-sensing receptor (CaSR) is a sensor for a number of key nutrients within the body, including Ca ions (Ca2+) and l-amino acids. The CaSR is expressed in a number of specialised cells within the gastrointestinal (GI) tract, and much work has been done to examine CaSR's role as a nutrient sensor in this system. This review article examines two emerging roles for the CaSR within the GI tract – as a mediator of kokumi taste modulation in taste cells and as a regulator of dietary hormone release in response to l-amino acids in the intestine.

scholarly journals Calcium-Sensing Receptor in Adipose Tissue: Possible Association with Obesity-Related Elevated Autophagy

2020 ◽  
Vol 21 (20) ◽  
pp. 7617
Author(s):  
Pamela Mattar ◽  
Sofía Sanhueza ◽  
Gabriela Yuri ◽  
Lautaro Briones ◽  
Claudio Perez-Leighton ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Body Fat ◽  
Structural Equation ◽  
Equation Model ◽  
Mrna Levels ◽  
Calcium Sensing Receptor ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Calcium Sensing

Autophagy is upregulated in adipose tissue (AT) from people with obesity. We showed that activation of the calcium-sensing receptor (CaSR) elevates proinflammatory cytokines through autophagy in preadipocytes. Our aim is to understand the role of CaSR on autophagy in AT from humans with obesity. We determined mRNA and protein levels of CaSR and markers of autophagy by qPCR and western blot in human visceral AT explants or isolated primary preadipocytes (60 donors: 72% female, 23–56% body fat). We also investigated their association with donors’ anthropometric variables. Donors’ % body fat and CaSR mRNA expression in AT were correlated (r = 0.44, p < 0.01). CaSR expression was associated with mRNA levels of the autophagy markers atg5 (r = 0.37, p < 0.01), atg7 (r = 0.29, p < 0.05) and lc3b (r = 0.40, p < 0.01). CaSR activation increased becn and atg7 mRNA expression in AT. CaSR activation also upregulated LC3II by ~50%, an effect abolished by the CaSR inhibitor. Spermine (CaSR agonist) regulates LC3II through the ERK1/2 pathway. Structural equation model analysis suggests a link between donors’ AT CaSR expression, AT autophagy and expression of Tumor Necrosis Factor alpha TNF-α. CaSR expression in visceral AT is directly associated with % body fat, and CaSR activation may contribute to obesity-related disruption in AT autophagy.

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.

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.

scholarly journals Illuminating the allosteric modulation of the calcium-sensing receptor

2020 ◽  
Vol 117 (35) ◽  
pp. 21711-21722
Author(s):  
Hongkang Liu ◽  
Ping Yi ◽  
Wenjing Zhao ◽  
Yuling Wu ◽  
Francine Acher ◽  
...  
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Membrane Receptors ◽  
Allosteric Modulators ◽  
Active Conformation ◽  
Calcium Sensing Receptor ◽  
Single Receptor ◽  
Calcium Sensing

Many membrane receptors are regulated by nutrients. However, how these nutrients control a single receptor remains unknown, even in the case of the well-studied calcium-sensing receptor CaSR, which is regulated by multiple factors, including ions and amino acids. Here, we developed an innovative cell-free Förster resonance energy transfer (FRET)-based conformational CaSR biosensor to clarify the main conformational changes associated with activation. By allowing a perfect control of ambient nutrients, this assay revealed that Ca2+alone fully stabilizes the active conformation, while amino acids behave as pure positive allosteric modulators. Based on the identification of Ca2+activation sites, we propose a molecular basis for how these different ligands cooperate to control CaSR activation. Our results provide important information on CaSR function and improve our understanding of the effects of genetic mutations responsible for human diseases. They also provide insights into how a receptor can integrate signals from various nutrients to better adapt to the cell response.

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

PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation

2003 ◽  
Vol 284 (2) ◽  
pp. E435-E442 ◽  
Author(s):  
R. John MacLeod ◽  
Naibedya Chattopadhyay ◽  
Edward M. Brown
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Hormone Secretion ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Hek Cells

Increases in extracellular calcium concentration ([Ca2+]o) stimulate from normal and malignant cells secretion of parathroid hormone-related protein (PTHrP), a major mediator of humoral hypercalcemia of malignancy. Because the calcium-sensing receptor (CaR) is a determinant of calcium-regulated hormone secretion, we examined whether HEK cells stably transfected with human CaR secreted PTHrP in response to CaR stimulation. Increases in [Ca2+]o or neomycin and Gd3+ all substantially increased PTHrP secretion in CaR-HEK cells but had no effect on nontransfected cells. CaR activation likewise increased PTHrP transcripts. PD-098059 and U-0126, inhibitors of the mitogen-activated protein kinase kinase MEK1/2, abolished CaR-stimulated secretion but had no effect on basal secretion. An inhibitor of p38 MAP kinase, SB-203580, also attenuated CaR-stimulated secretion. Western analysis revealed that CaR activation caused a robust increase in MEK1/2 and p38 MAP kinase phosphorylation. A Src family kinase inhibitor, PP2, blocked both basal and CaR-stimulated secretion. We conclude that CaR specifically mediates the effect of increasing [Ca2+]o on PTHrP synthesis and secretion and that activated MEK1/2 and p38 MAP kinases are determinants of the CaR's stimulation of PTHrP secretion.

scholarly journals The calcium-sensing receptor couples to Gαs and regulates PTHrP and ACTH secretion in pituitary cells

2009 ◽  
Vol 204 (3) ◽  
pp. 287-297 ◽  
Author(s):  
Ramanaiah Mamillapalli ◽  
John Wysolmerski
Keyword(s):  
Hormone Secretion ◽  
Cell Types ◽  
Extracellular Calcium ◽  
Pituitary Cells ◽  
Camp Production ◽  
Calcium Sensing Receptor ◽  
Acth Secretion ◽  
Calcium Sensing ◽  
Malignant Breast ◽  
Cell Growth And Differentiation

The calcium-sensing receptor (CaR or CASR as listed in the MGI Database) is a G protein-coupled receptor that binds and signals in response to extracellular calcium and other polycations. It is highly expressed on parathyroid and kidney cells, where it participates in the regulation of systemic calcium homeostasis. It is also expressed on many other cell types and is involved in a wide array of biological functions such as cell growth and differentiation, ion transport, and hormone secretion. It has been described to couple to several different G proteins including Gαi/0, Gαq/11, and Gα12/13. Recently, it has also been shown to stimulate cAMP production by coupling to Gαs in immortalized or malignant breast cells. The CaR is expressed on cells in the anterior pituitary and had previously been described to stimulate cAMP production in these cells. In this report, we examined signaling from the CaR in murine pituitary corticotroph-derived, AtT-20 cells. We found that CaR activation led to the stimulation of cAMP production, and PTH-related protein (PTHrP or PTHLH as listed in the MGI Database) and ACTH secretion from these cells. Furthermore, manipulation of cAMP levels was able to modulate PTHrP and ACTH secretion independent of changes in extracellular calcium. Finally, we demonstrated that the CaR couples to Gαs in AtT-20 cells. Therefore, in pituitary corticotroph-like cells, as in breast cancer cells, the CaR utilizes Gαs and activates cAMP production to stimulate hormone secretion.

scholarly journals The Corpuscles of Stannius, Calcium-Sensing Receptor, and Stanniocalcin: Responses to Calcimimetics and Physiological Challenges

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3002-3010 ◽  
Author(s):  
Michael P. Greenwood ◽  
Gert Flik ◽  
Graham F. Wagner ◽  
Richard J. Balment
Keyword(s):  
Mrna Expression ◽  
Broad Band ◽  
Plasma Concentrations ◽  
Immunoblot Analysis ◽  
Pcr Analysis ◽  
Endocrine Regulation ◽  
Calcium Sensing Receptor ◽  
Corpuscles Of Stannius ◽  
Calcium Sensing

This study has examined whether the calcium-sensing receptor (CaSR) plays a role in control of stanniocalcin-1 (STC-1), the dominant calcium regulatory hormone of fish, comparable with that demonstrated for CaSR in the mediation of ionized calcium regulation of PTH secretion in mammals. In a previous study, we have cloned flounder STC-1 from the corpuscles of Stannius (CS). Here, we report the cloning and characterization of the CS CaSR, and the in vivo responses of this system to altered salinity, EGTA induced hypocalcemia, and calcimimetic administration. Quantitative PCR analysis demonstrated, for the first time, that the CS are major sites of CaSR expression in flounder. Immunoblot analysis of CS proteins with CaSR-specific antibodies revealed a broad band of approximately 215–300 kDa under nonreducing conditions, and bands of approximately 215–300 kDa and approximately 120–150 kDa under reducing conditions. There were no differences in CS CaSR mRNA expression or plasma STC-1 levels between seawater and freshwater (FW)-adapted fish, although CS STC-1 mRNA expression was lower in FW animals. Immunoblots showed that glycosylated monomeric forms of the CaSR migrated at a lower molecular mass in CS samples from FW animals. The ip administration of EGTA rapidly induced hypocalcemia, and a concomitant lowering of plasma STC-1. Calcimimetic administration (1 mg/kg R-568) rapidly increased plasma STC-1 levels, and reduced plasma concentrations of calcium, phosphate, and magnesium when compared with S-568-treated controls. Together, these findings support an evolutionary conserved role for the CaSR in the endocrine regulation of calcium before the appearance of parathyroid glands in tetrapods.

Sign in / Sign up

Export Citation Format

Share Document