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 Recent advances in understanding the extracellular calcium-sensing receptor

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2535 ◽  
Author(s):  
Matilde Colella ◽  
Andrea Gerbino ◽  
Aldebaran M. Hofer ◽  
Silvana Curci
Keyword(s):  
G Protein ◽  
Calcium Homeostasis ◽  
Body Fluids ◽  
Extracellular Calcium ◽  
G Protein Coupled Receptor ◽  
Calcium Sensing Receptor ◽  
Endogenous Ligands ◽  
Calcium Sensing ◽  
Intracellular Signals ◽  
G Protein Coupled

The extracellular calcium-sensing receptor (CaR), a ubiquitous class C G-protein-coupled receptor (GPCR), is responsible for the control of calcium homeostasis in body fluids. It integrates information about external Ca2+ and a surfeit of other endogenous ligands into multiple intracellular signals, but how is this achieved? This review will focus on some of the exciting concepts in CaR signaling and pharmacology that have emerged in the last few years.

scholarly journals Functional Desensitization of the Extracellular Calcium-Sensing Receptor Is Regulated via Distinct Mechanisms: Role of G Protein-Coupled Receptor Kinases, Protein Kinase C and β-Arrestins

Endocrinology ◽  
2007 ◽  
Vol 148 (5) ◽  
pp. 2398-2404 ◽  
Author(s):  
Stephan Lorenz ◽  
Romy Frenzel ◽  
Ralf Paschke ◽  
Gerda E. Breitwieser ◽  
Susanne U. Miedlich
Keyword(s):  
G Protein ◽  
Inositol Phosphate ◽  
Phosphorylation Site ◽  
Extracellular Calcium ◽  
Receptor Internalization ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Kinase C ◽  
Inositol Phosphate Accumulation ◽  
G Protein Coupled

The extracellular calcium-sensing receptor (CaR) senses small fluctuations of the extracellular calcium (Ca2+e) concentration and translates them into potent changes in parathyroid hormone secretion. Dissecting the regulatory mechanisms of CaR-mediated signal transduction may provide insights into the physiology of the receptor and identify new molecules as potential drug targets for the treatment of osteoporosis and/or hyperparathyroidism. CaR can be phosphorylated by protein kinase C (PKC) and G protein-coupled receptor kinases (GRKs), and has been shown to bind to β-arrestins, potentially contributing to desensitization of CaR, although the mechanisms by which CaR-mediated signal transduction is terminated are not known. We used a PKC phosphorylation site-deficient CaR, GRK and β-arrestin overexpression or down-regulation to delineate CaR-mediated desensitization. Fluorescence-activated cell sorting was used to determine whether receptor internalization contributed to desensitization. Overexpression of GRK 2 or 3 reduced Ca2+e-dependent inositol phosphate accumulation by more than 70%, whereas a GRK 2 mutant deficient in Gαq binding (D110A) was without major effect. Overexpression of GRK 4–6 did not reduce Ca2+e-dependent inositol phosphate accumulation. Overexpression of β-arrestin 1 or 2 revealed a modest inhibitory effect on Ca2+e-dependent inositol phosphate production (20–30%), which was not observed for the PKC phosphorylation site-deficient CaR. Agonist-dependent receptor internalization (10–15%) did not account for the described effects. Thus, we conclude that PKC phosphorylation of CaR contributes to β-arrestin-dependent desensitization of CaR coupling to G proteins. In contrast, GRK 2 predominantly interferes with G protein-mediated inositol-1,4,5-trisphosphate formation by binding to Gαq.

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 OR07-06 The Roles of GNAQ and GNA11 in Calcium-Sensing Receptor (CaSR) Signalling

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Anna K Gluck ◽  
Mark Stevenson ◽  
Sara Falcone ◽  
Asuka Inoue ◽  
Gerda E Breitwieser ◽  
...  
Keyword(s):  
Protein Expression ◽  
G Protein ◽  
Extracellular Calcium ◽  
Luciferase Reporter ◽  
Reporter Construct ◽  
Calcium Sensing Receptor ◽  
Luciferase Reporter Construct ◽  
Response Element ◽  
Calcium Sensing

Abstract The G-protein subunits Gα 11 and Gα q, which share >90% peptide sequence identity and are encoded by the GNA11 and GNAQ genes, respectively, mediate signalling by the calcium-sensing receptor (CaSR), a class C G-protein coupled receptor (GPCR) that regulates extracellular calcium (Ca2+e) homeostasis. Germline Gα 11 inactivating and activating mutations cause familial hypocalciuric hypercalcaemia type-2 (FHH2) and autosomal dominant hypocalcaemia type-2 (ADH2), respectively, but such Gα q mutations have not been reported. We therefore investigated the DiscovEHR cohort database, which has exomes from 51,289 patients with matched phenotyping data, for such GNAQ mutations. The DiscovEHR cohort was examined for rare GNAQ variants, which were transiently expressed in CaSR-expressing HEK293A Gα q/11 knockout cells, and their effects on CaSR-mediated intracellular calcium (Ca2+i) release and MAPK activity, in response to increasing concentrations of extracellular calcium were assessed using a nuclear factor of activated T-cells response element (NFAT-RE) luciferase reporter construct and a serum response element (SRE) luciferase reporter construct, respectively. Responses were compared to those of wild-type (WT), inactivating FHH2-associated GNA11 mutations (Leu135Gln and Phe220Ser), and engineered GNAQ mutations that were equivalent to the FHH2-causing GNA11 mutations. Gα q/11 protein expression was confirmed by Western blot analysis. Six rare missense GNAQ variants (Arg19Trp, Ala110Val, Gln299His, Ala302Ser, Ala331Thr, Val344Ile) were identified in DiscovEHR individuals, all of whom had mean plasma calcium values in the normal range (8.30–10.00 mg/dL). Functional characterisation of all six Gα q variants showed no significant difference to WT Gα q responses, thereby indicating that these variants are unlikely to be disease-causing mutations. In addition, the FHH2-causing GNA11 mutations (Leu135Gln and Phe220Ser) had significantly reduced responses, compared to WT Gα 11; however, this could be compensated by WT Gα q. GNAQ Leu135Gln and Phe220Ser, in contrast to their Gα 11 counterparts, showed no differences in protein expression or signalling responses when compared to WT Gα q. Our study, which provides mechanistic insights into the differences between Gα q and Gα 11, indicates that Gα q, unlike Gα 11, does not play a major role in the pathogenesis of FHH2 or ADH2.

G protein-coupled calcium-sensing receptor is a crucial mediator of MTA-induced biological activities

Biomaterials ◽  
2017 ◽  
Vol 127 ◽  
pp. 107-116 ◽  
Author(s):  
Jin Man Kim ◽  
Seulki Choi ◽  
Kyu Hwan Kwack ◽  
Sun-Young Kim ◽  
Hyeon-Woo Lee ◽  
...  
Keyword(s):  
G Protein ◽  
Biological Activities ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
G Protein Coupled

scholarly journals Positive and Negative Allosteric Modulators Promote Biased Signaling at the Calcium-Sensing Receptor

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1232-1241 ◽  
Author(s):  
Anna E. Davey ◽  
Katie Leach ◽  
Celine Valant ◽  
Arthur D. Conigrave ◽  
Patrick M. Sexton ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Allosteric Modulators ◽  
G Protein Coupled Receptor ◽  
Calcium Sensing Receptor ◽  
Quantitative Evidence ◽  
Membrane Ruffling ◽  
Beneficial Effects ◽  
Calcium Sensing ◽  
G Protein Coupled

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor whose function can be allosterically modulated in a positive or negative manner by calcimimetics or calcilytics, respectively. Indeed, the second-generation calcimimetic, cinacalcet, has proven clinically useful in the treatment of chronic kidney disease patients with secondary hyperparathyroidism but is not widely used in earlier stages of renal disease due to the potential to predispose such patients to hypocalcaemia and hyperphosphatemia. The development of a biased CaSR ligand that is more selective for specific signaling pathway(s) leading only to beneficial effects may overcome this limitation. The detection of such stimulus-bias at a G protein-coupled receptor requires investigation across multiple signaling pathways and the development of methods to quantify the effects of allosteric ligands on orthosteric ligand affinity and cooperativity at each pathway. In the current study, we determined the effects of the calcimimetics, NPS-R568 or cinacalcet, and the calcilytic, NPS-2143, on Cao2+-mediated intracellular Ca2+ mobilization, ERK1/2 phosphorylation, and plasma membrane ruffling in a stably transfected human embryonic kidney 293-TREx c-myc-CaSR cell line and applied a novel analytical model to quantify these modulator effects. We present quantitative evidence for the generation of stimulus bias by both positive and negative allosteric modulators of the CaSR, manifested as greater allosteric modulation of intracellular Ca2+ mobilization relative to ERK1/2 phosphorylation, and a higher affinity of the modulators for the state of the CaSR mediating plasma membrane ruffling relative to the other two pathways. Our findings provide the first evidence that an allosteric modulator used in clinical practice exhibits stimulus bias.

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