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.

The calcium-sensing receptor as a nutrient sensor

2005 ◽  
Vol 33 (1) ◽  
pp. 316-320 ◽  
Author(s):  
D. Riccardi ◽  
D. Maldonado-Perez
Keyword(s):  
G Protein ◽  
Cell Fate ◽  
Aromatic Amino Acids ◽  
Cell Types ◽  
Extracellular Calcium ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Sense And Respond ◽  
Acute Changes ◽  
G Protein Coupled

Critical to cell fate in many cell types is the ability to sense and respond to acute changes in free ionized extracellular calcium concentration ([Ca2+]o). Such tight control is mediated by the activation of a protein known as the extracellular-calcium-sensing receptor (CaR). CaR belongs to the ‘family C’ of G-protein-coupled receptors and was the first G-protein-coupled receptor to be identified to have an inorganic cation, calcium, as its ligand. While calcium is the physiological agonist of the receptor, several other polyvalent cations and polycations can also modulate CaR function as do certain L-aromatic amino acids, polyamines, salinity and pH. This feature renders the CaR uniquely capable of generating cell- and tissue-specific responses, and of integrating inputs deriving from changes in the Ca2+o concentration with signals deriving from the local metabolic environment. Here we address the role of the CaR in physiology and disease, the range of CaR modulators and the potential roles of the CaR as a metabolic sensor in a variety of physiological (and pathological) scenarios.

scholarly journals The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to l-phenylalanine in acutely isolated intestinal I cells

2011 ◽  
Vol 300 (4) ◽  
pp. G538-G546 ◽  
Author(s):  
Alice P. Liou ◽  
Yoshitatsu Sei ◽  
Xilin Zhao ◽  
Jianying Feng ◽  
Xinping Lu ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Fluorescent Protein ◽  
Direct Detection ◽  
Hormone Secretion ◽  
Extracellular Calcium ◽  
Calcium Flux ◽  
Specific Response ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
I Cells

The extracellular calcium-sensing receptor (CaSR) has recently been recognized as an l-amino acid sensor and has been implicated in mediating cholecystokinin (CCK) secretion in response to aromatic amino acids. We investigated whether direct detection of l-phenylalanine (l-Phe) by CaSR results in CCK secretion in the native I cell. Fluorescence-activated cell sorting of duodenal I cells from CCK-enhanced green fluorescent protein (eGFP) transgenic mice demonstrated CaSR gene expression. Immunostaining of fixed and fresh duodenal tissue sections confirmed CaSR protein expression. Intracellular calcium fluxes were CaSR dependent, stereoselective for l-Phe over d-Phe, and responsive to type II calcimimetic cinacalcet in CCK-eGFP cells. Additionally, CCK secretion by an isolated I cell population was increased by 30 and 62% in response to l-Phe in the presence of physiological (1.26 mM) and superphysiological (2.5 mM) extracellular calcium concentrations, respectively. While the deletion of CaSR from CCK-eGFP cells did not affect basal CCK secretion, the effect of l-Phe or cinacalcet on intracellular calcium flux was lost. In fact, both secretagogues, as well as superphysiological Ca2+, evoked an unexpected 20–30% decrease in CCK secretion compared with basal secretion in CaSR−/− CCK-eGFP cells. CCK secretion in response to KCl or tryptone was unaffected by the absence of CaSR. The present data suggest that CaSR is required for hormone secretion in the specific response to l-Phe by the native I cell, and that a receptor-mediated mechanism may inhibit hormone secretion in the absence of a fully functional CaSR.

Calcium-sensing receptor-dependent activation of CREB phosphorylation in HEK293 cells and human parathyroid cells

2013 ◽  
Vol 304 (10) ◽  
pp. E1097-E1104 ◽  
Author(s):  
Vimesh A. Avlani ◽  
Wenting Ma ◽  
Hee-Chang Mun ◽  
Katie Leach ◽  
Leigh Delbridge ◽  
...  
Keyword(s):  
Epithelial Transport ◽  
Shape Change ◽  
Hormone Secretion ◽  
Control Cell ◽  
Cell Types ◽  
Hek293 Cells ◽  
Calcium Sensing Receptor ◽  
Bias Analysis ◽  
Creb Phosphorylation ◽  
Calcium Sensing

In addition to its acute effects on hormone secretion, epithelial transport, and shape change, the calcium-sensing receptor (CaSR) modulates the expression of genes that control cell survival, proliferation, and differentiation as well as the synthesis of peptide hormones and enzymes. In the present study, we investigated the impacts of a CaSR agonist and several CaSR modulators on phosphorylation of transcription factor CREB residue Ser133 in CaSR-expressing HEK293 (HEK-CaSR) cells and human adenomatous parathyroid cells. Elevated Ca2+o concentration had no effect on CREB phosphorylation (p-CREB) in control HEK293 cells but stimulated p-CREB in both HEK-CaSR cells and human parathyroid cells. In addition, p-CREB was stimulated by the positive modulator cinacalcet and inhibited by the negative modulator NPS 2143 in both CaSR-expressing cell types. Two positive modulators that bind in the receptor's Venus Fly Trap domain, l-phenylalanine and S-methylglutathione, had no effect on p-CREB in HEK-CaSR cells, demonstrating the existence of pronounced signaling bias. Analysis of the signaling pathways using specific inhibitors demonstrated that phosphoinositide-specific phospholipase C and conventional protein kinase C isoforms make major contributions to Ca2+o-induced p-CREB in both cell-types, suggesting key roles for Gq/11. In addition, in parathyroid cells but not HEK-CaSR cells, activation of p-CREB was dependent on Gi/o, demonstrating the existence of cell type-specific signaling.

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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