The role of the calcium-sensing receptor in human disease

Ward, Bryan K.; Magno, Aaron L.; Walsh, John P.; Ratajczak, Thomas

doi:10.1016/j.clinbiochem.2012.03.034

Cited by 97 publications

(74 citation statements)

References 164 publications

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“…The influence of biological factors, such as pH, oxygen availability and serum protein content, on the Ca 2+ sensitivity of the CaSR in utero and at birth remains to be clarified. In differentiated tissues, such as the mucosa of the gastro-intestinal tract, the CaSR participates in the modulation of cell proliferation and differentiation (Ward et al, 2012). The human colonic epithelium, for example, manifests a rising [Ca 2+ ] e gradient from the base to the top of the crypt, which correlates with an increasing expression of the CaSR as epithelial cells migrate and differentiate towards the apex of the crypt.…”

Section: Discussionmentioning

confidence: 99%

Activation of the calcium-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane

Jouret

Hull

et al. 2013

Journal of Cell Science

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SummaryThe Ca 2+ -sensing receptor (CaSR) belongs to the G-protein-coupled receptor superfamily and plays essential roles in divalent ion homeostasis and cell differentiation. Because extracellular Ca 2+ is essential for the development of stable epithelial tight junctions (TJs), we hypothesized that the CaSR participates in regulating TJ assembly. We first assessed the expression of the CaSR in Madin-Darby canine kidney (MDCK) cells at steady state and following manipulations that modulate TJ assembly. Next, we examined the effects of CaSR agonists and antagonists on TJ assembly. Immunofluorescence studies indicate that endogenous CaSR is located at the basolateral pole of MDCK cells. Stable transfection of human CaSR in MDCK cells further reveals that this protein co-distributes with b-catenin on the basolateral membrane. Switching MDCK cells from low-Ca 2+ medium to medium containing a normal Ca 2+ concentration significantly increases CaSR expression at both the mRNA and protein levels. Exposure of MDCK cells maintained in low-Ca 2+ conditions to the CaSR agonists neomycin, Gd 3+ or R-568 causes the transient relocation of the tight junction components ZO-1 and occludin to sites of cell-cell contact, while inducing no significant changes in the expression of mRNAs encoding junction-associated proteins. Stimulation of CaSR also increases the interaction between ZO-1 and the F-actin-binding protein I-afadin. This effect does not involve activation of the AMP-activated protein kinase. By contrast, CaSR inhibition by NPS-2143 significantly decreases interaction of ZO-1 with I-afadin and reduces deposition of ZO-1 at the cell surface following a Ca 2+ switch from 5 mM to 200 mM [Ca 2+ ] e . Pre-exposure of MDCK cells to the cell-permeant Ca 2+ chelator BAPTA-AM, similarly prevents TJ assembly caused by CaSR activation. Finally, stable transfection of MDCK cells with a cDNA encoding a human disease-associated gain-of-function mutant form of the CaSR increases the transepithelial electrical resistance of these cells in comparison to expression of the wild-type human CaSR. These observations suggest that the CaSR participates in regulating TJ assembly.

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Section: Discussionmentioning

confidence: 99%

Activation of the calcium-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane

Jouret

Hull

et al. 2013

Journal of Cell Science

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“…CaR is a G protein-coupled receptor activated by millimolar concentrations of calcium, which results in the release of calcium from intracellular stores via IP 3 R (for review, see Ward et al, 2012). The role of CaR in the EDH-mediated response was demonstrated in rat mesenteric arteries where activation of CaR in ECs induced a hyperpolarization of the VSMCs, which was abolished by the IK Ca inhibitor TRAM34 or by denudation of the endothelium .…”

Section: B Potassium and Calcium Channels: A Case For The Endotheliumentioning

confidence: 99%

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

et al. 2014

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“…CaSR appears to play a tumor suppressor role in CRC and has a critical role in the maintenance of calcium homeostasis (Sarkar and Kumar, 2012;Ward et al, 2012) by modulating parathyroid hormone (PTH) secretion from the parathyroid glands (Saidak et al, 2009). In recent years, the relationship between CaSR gene polymorphisms and CRC risk has garnered a great deal of attention and association studies of CaSR gene rs1801725 (A986S) variant have been performed to investigate its implication with CRC risk, but despite the biological plausibility the results are inconsistent (Speer et al, 2002;Fuszek et al, 2004;Bacsi et al, 2008;Dong et al, 2008;Jenab et al, 2009) and the role of this gene in the etiology of CRC is still equivocal.…”

Section: Introductionmentioning

confidence: 99%

Parathyroid Hormone Gene rs6256 and Calcium Sensing Receptor Gene rs1801725 Variants are not Associated with Susceptibility to Colorectal Cancer in Iran

Mahmoudi¹,

Karimi²,

Arkani³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Substantial evidence from epidemiological studies has suggested that increased levels of calcium may play a protective role against colorectal cancer (CRC). Given the vital role of calcium sensing receptor (CaSR) and parathyroid hormone (PTH) in the maintenance of calcium homeostasis, we explored whether the rs1801725 (A986S) variant located in exon 7 of the CaSR gene and the rs6256 variant located in exon 3 of PTH gene might be associated with CRC risk. Materials and Methods: In this study 860 subjects including 350 cases with CRC and 510 controls were enrolled and genotyped using PCR-RFLP methods. Results: We observed no significant difference in genotype or allele frequencies between the cases with CRC and controls for both CaSR and PTH genes either before or after adjustment for confounding factors including age, BMI, sex, smoking status, and family history of CRC. Furthermore, no evidence for effect modification of any association of rs1801725 and rs6256 variants and CRC by BMI, sex, or tumor site was observed. In addition, there was no significant difference in genotype and allele frequencies between the normal weight (BMI <25 kg/m 2 ) cases and overweight/ obese (BMI ≥25 kg/m 2 ) cases for the two SNPs. Conclusions: These data indicated that the CaSR gene A986S variant is not a genetic contributor to CRC risk in the Iranian population. Furthermore, our results suggest for the first time that PTH gene variant does not affect CRC risk. Nonetheless, further studies with larger sample size are needed to validate these findings.

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The role of the calcium-sensing receptor in human disease

Cited by 97 publications

References 164 publications

Activation of the calcium-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane

Activation of the calcium-sensing receptor induces deposition of tight junction components to the epithelial cell plasma membrane

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

Parathyroid Hormone Gene rs6256 and Calcium Sensing Receptor Gene rs1801725 Variants are not Associated with Susceptibility to Colorectal Cancer in Iran

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