The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development.
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ABSTRACT:
SUBMITTER: Chang W
PROVIDER: S-EPMC3538864 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
Publications
The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development.
Chang Wenhan W Tu Chialing C Chen Tsui-Hua TH Bikle Daniel D Shoback Dolores D
Science signaling 20080902 35
The extracellular Ca(2+)-sensing receptor (CaSR) plays a nonredundant role in the functions of the parathyroid gland (PTG) and the kidney. Severe hyperparathyroidism, premature death, and incomplete gene excision in Casr(-/-) mice have precluded the assessment of CaSR function in other tissues. We generated mice with tissue-specific deletion of Casr in the PTG, bone, or cartilage. Deletion of Casr in the PTG or bone resulted in profound bone defects, whereas deletion of Casr in chondrocytes (car ...[more]
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Project description:In vertebrates, the extracellular calcium-sensing receptor (CaSR) plays a key role in calcium homeostasis by sensing slight changes in extracellular Ca2+. CaSR is also expressed in mammals including rodent taste cells and is involved in sensing kokumi, a rich, savory quality that enhances the intensities of salty, sweet, and umami tastes. In this study, we focused on chicken CaSR (cCaSR) since calcium is an essential nutrient that is necessary for making eggshell and for the extremely rapid initial growth of bones. First we confirmed that cCaSR is expressed in taste cells. Next we cloned the cCaSR gene from kidney and transiently transfected human embryonic kidney 293 T (HEK293T) cells with the recombinant cCaSR, or empty vector and looked for the agonists and allosteric modulators (including kokumi substances) of cCaSR by Ca2+ imaging. We found that cCaSR was activated by extracellular Ca2+ and Mg2+ in a dose dependent manner. Several L-amino acids and kokumi substances such as glutathione enhanced the response of cCaSR. In addition, NPS2143 as a negative allosteric modulator of human CaSR negatively modulated the response of cCaSR. These results suggest that cCaSR can sense extracellular Ca2+ and Mg2+ as well as positive and negative allosteric modulators. Taken together, the results imply that CaSR might be a multifunctional receptor for calcium, amino acids, and kokumi substances in chicken. The present finding that functional CaSR is expressed in the chicken oral tissues will allow us to further elucidate the physiological role of CaSR in the chickens' taste sense, and to create new feeds that will contribute to the poultry industry.
| S-EPMC9588031 | biostudies-literature
Project description:Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo. The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR-transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR-transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression.
| S-EPMC5884663 | biostudies-literature
Project description:ObjectIschemic brain injury is the leading cause for death and long-term disability in patients who suffer cardiac arrest and embolic stroke. Excitotoxicity and subsequent Ca(2+)-overload lead to ischemic neuron death. We explore a novel mechanism concerning the role of the excitatory extracellular calcium-sensing receptor (CaSR) in the induction of ischemic brain injury.MethodMice were exposed to forebrain ischemia and the actions of CaSR were determined after its genes were ablated specifically in hippocampal neurons or its activities were inhibited pharmacologically. Since the CaSR forms a heteromeric complex with the inhibitory type B γ-aminobutyric acid receptor 1 (GABABR1), we compared neuronal responses to ischemia in mice deficient in CaSR, GABABR1, or both, and in mice injected locally or systemically with a specific CaSR antagonist (or calcilytic) in the presence or absence of a GABABR1 agonist (baclofen).ResultsBoth global and focal brain ischemia led to CaSR overexpression and GABABR1 downregulation in injured neurons. Genetic ablation of Casr genes or blocking CaSR activities by calcilytics rendered robust neuroprotection and preserved learning and memory functions in ischemic mice, partly by restoring GABABR1 expression. Concurrent ablation of Gabbr1 gene blocked the neuroprotection caused by the Casr gene knockout. Coinjection of calcilytics with baclofen synergistically enhanced neuroprotection. This combined therapy remained robust when given 6 h after ischemia.InterpretationOur study demonstrates a novel receptor interaction, which contributes to ischemic neuron death through CaSR upregulation and GABABR1 downregulation, and feasibility of neuroprotection by concurrently targeting these two receptors.
| S-EPMC4265057 | biostudies-literature
Project description:ObjectiveAlthough evidence suggests an inverse association between calcium intake and the risk of colorectal cancer, the mechanisms remain unclear. The calcium-sensing receptor (CASR) is expressed abundantly in normal colonic epithelium and may influence carcinogenesis. We hypothesized that calcium intake might be associated with lower risk of CASR-positive, but not CASR-negative, colorectal cancer.DesignWe assessed tumour CASR protein expression using immunohistochemistry in 779 incident colon and rectal cancer cases that developed among 136 249 individuals in the Nurses' Health Study and Health Professionals Follow-Up Study. Duplication method Cox proportional hazards regression analysis was used to assess associations of calcium intake with incidence of colorectal adenocarcinoma subtypes by CASR status.ResultsTotal calcium intake was inversely associated with the risk of developing colorectal cancer (ptrend=0.01, comparing ≥1200 vs <600 mg/day: multivariable HR=0.75, 95% CI 0.60 to 0.95). For the same comparison, higher total calcium intake was associated with a lower risk of CASR-positive tumours (ptrend=0.003, multivariable HR=0.67, 95% CI 0.51 to 0.86) but not with CASR-negative tumours (ptrend=0.67, multivariable HR=1.15, 95% CI 0.75 to 1.78; pheterogeneity=0.06 between the CASR subtypes). The stronger inverse associations of calcium intake with CASR-positive but not CASR-negative tumours generally appeared consistent regardless of sex, tumour location and source of calcium.ConclusionsOur molecular pathological epidemiology data suggest a causal relationship between higher calcium intake and lower colorectal cancer risk, and a potential role of CASR in mediating antineoplastic effect of calcium.
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Project description:BACKGROUND:There is scarce data on CASR associations with dyslipidemia. We investigated in hemodialysis (HD) patients whether CASR single nucleotide polymorphisms (SNPs) rs7652589 and rs1801725 have associations with dyslipidemia and show epistatic interactions with SNPs of the energy homeostasis-associated gene (ENHO), retinoid X receptor α gene (RXRA), and liver X receptor α gene (LXRA). METHODS:The study included 1208 HD subjects. For diagnosis of dyslipidemia, both K/DOQI criteria and atherogenic index ≥3.8 were used. CASR rs1801725 was genotyped by TaqMan SNP Genotyping Assay, other SNPs - by high-resolution melting curve analysis or polymerase chain reaction-restriction fragment length polymorphism, as appropriate. Relative transcript levels of CASR, ENHO, RXRA, and LXRA were measured in peripheral blood mononuclear cells. The occurrence of dyslipidemic phenotypes concerning tested polymorphisms was compared using models of inheritance. Haplotypes were estimated using the Haploview 4.2 software. Epistatic interactions between tested SNPs were analyzed using the logistic regression and epistasis option in the PLINK software. RESULTS:Rs7652589 indicated a greater probability of atherogenic dyslipidemia in the dominant inheritance model (OR 1.4, 95%CI 1.0-2.0, P = 0.026), principally because of increased triglyceride (TG) levels. The rs1801725 variant allele was associated with a decreased probability of dyslipidemia characterized by non-HDL-cholesterol ≥130 mg/dL and TG ≥200 mg/dL (OR 0.6, 0.4-0.9, P = 0.012). There were no epistatic interactions between CASR and RXRA, LXRA, and ENHO regarding dyslipidemia. Both rs7652589 and rs1801725 SNPs were not in linkage disequilibrium (D' = 0.091, r2 = 0.003 for the entire HD group) and their haplotypes did not correlate with dyslipidemia. Relative CASR transcript was lower at a borderline significance level in patients harboring the rs1801725 variant allele compared with homozygotes of the major allele (0.20, 0.06-7.80 vs. 0.43, 0.04-5.06, P = 0.058). CASR transcript correlated positively with RXRA transcript (adjusted P = 0.001), LXRA transcript (adjusted P = 0.0009), ENHO transcript (borderline significance, adjusted P = 0.055), dry body weight (adjusted P = 0.035), and renal replacement therapy duration (adjusted P = 0.013). CONCLUSIONS:CASR polymorphisms (rs7652589, rs1801725) are associated with dyslipidemia in HD patients. CASR correlates with RXRA, LXRA, and ENHO at the transcript level. Further investigations may elucidate whether other CASR SNPs contribute to associations shown in this study.
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Project description:Calcium and 1,25-dihydroxyvitamin D3 (1,25D3), through the actions of their respective receptors, the Ca2+-sensing receptor (CaSR) and the vitamin D receptor (VDR), potentiate keratinocyte differentiation. VDR regulates epidermal keratinocyte proliferation and differentiation by modulating gene transcription, whereas the CaSR, a member of the family C G-protein coupled receptor, calcium mobilizes intracellular calcium and induces the formation of cell-cell junctions. 1,25D3 augments the sensitivity of the prodifferentiating actions of calcium by increasing the expression of CaSR. CaSR- and VDR-deficient keratinocytes share common characteristics such as abnormal intercellular adhesion and sphigolipid metabolism. Both CaSR and VDR are abundantly expressed in epidermal stem cell populations including CD34 expressing bulge keratinocytes in hair follicles and basal cells in interfollicular epidermis. To delineate the role of CaSR- and VDR-dependent pathways in regulating epidermal development and functions in physiological state, we generated conditional CaSR-null and VDR-null mice, where Casr and VDR gene was removed from keratinocytes. Keratinocyte-specific CaSR-null and VDR-null mice manifest distinct phenotypes. CaSR-null mice display defective epidermal permeability barrier function due to aberrant keratinocyte differentiation. VDR-null mice develop alopecia after completing the first hair follicle cycling. Concurrent ablation of CaSR and VDR genes in keratinocytes delays rate of wound repair and increases incidence of skin tumor formation to a greater extent than deletion of the CaSR or VDR alone, indicative of synergistic effects of calcium and 1,25D3 signaling. Gene expression profiles and subsequent pathway analysis on the epidermis derived from 5-day-old neonates revealed that ablation of CaSR or VDR increased expression of genes associated with cancer progression and metastasis. Deletion of VDR markedly inhibited signaling pathways that regulate hair development. Furthermore, concurrent ablation of CaSR and VDR significantly suppressed calcium, VDR, Wnt/b-catenin signaling, as well as epithelial adherence junction signaling to maintain appropriate keratinocyte adhesion. These results indicated the interplay of calcium/CaSR and 1,25D3/VDR signaling in keratinocyte proliferation and differentiation, and their importance in maintaining normal epidermal adhesion and functions.
2015-07-31 | GSE68724 | GEO
Project description:Optimal fetal lung growth requires anion-driven fluid secretion into the lumen of the developing organ. The fetus is hypercalcemic compared to the mother and here we show that in the developing human lung this hypercalcaemia acts on the extracellular calcium-sensing receptor, CaSR, to promote fluid-driven lung expansion through activation of the cystic fibrosis transmembrane conductance regulator, CFTR. Several chloride channels including TMEM16, bestrophin, CFTR, CLCN2 and CLCA1, are also expressed in the developing human fetal lung at gestational stages when CaSR expression is maximal. Measurements of Cl(-)-driven fluid secretion in organ explant cultures show that pharmacological CaSR activation by calcimimetics stimulates lung fluid secretion through CFTR, an effect which in humans, but not mice, was also mimicked by fetal hypercalcemic conditions, demonstrating that the physiological relevance of such a mechanism appears to be species-specific. Calcimimetics promote CFTR opening by activating adenylate cyclase and we show that Ca(2+)-stimulated type I adenylate cyclase is expressed in the developing human lung. Together, these observations suggest that physiological fetal hypercalcemia, acting on the CaSR, promotes human fetal lung development via cAMP-dependent opening of CFTR. Disturbances in this process would be expected to permanently impact lung structure and might predispose to certain postnatal respiratory diseases.
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Project description:Calcium and 1,25-dihydroxyvitamin D3 (1,25D3), through the actions of their respective receptors, the Ca2+-sensing receptor (CaSR) and the vitamin D receptor (VDR), potentiate keratinocyte differentiation. VDR regulates epidermal keratinocyte proliferation and differentiation by modulating gene transcription, whereas the CaSR, a member of the family C G-protein coupled receptor, calcium mobilizes intracellular calcium and induces the formation of cell-cell junctions. 1,25D3 augments the sensitivity of the prodifferentiating actions of calcium by increasing the expression of CaSR. CaSR- and VDR-deficient keratinocytes share common characteristics such as abnormal intercellular adhesion and sphigolipid metabolism. Both CaSR and VDR are abundantly expressed in epidermal stem cell populations including CD34 expressing bulge keratinocytes in hair follicles and basal cells in interfollicular epidermis. To delineate the role of CaSR- and VDR-dependent pathways in regulating epidermal development and functions in physiological state, we generated conditional CaSR-null and VDR-null mice, where Casr and VDR gene was removed from keratinocytes. Keratinocyte-specific CaSR-null and VDR-null mice manifest distinct phenotypes. CaSR-null mice display defective epidermal permeability barrier function due to aberrant keratinocyte differentiation. VDR-null mice develop alopecia after completing the first hair follicle cycling. Concurrent ablation of CaSR and VDR genes in keratinocytes delays rate of wound repair and increases incidence of skin tumor formation to a greater extent than deletion of the CaSR or VDR alone, indicative of synergistic effects of calcium and 1,25D3 signaling. Gene expression profiles and subsequent pathway analysis on the epidermis derived from 5-day-old neonates revealed that ablation of CaSR or VDR increased expression of genes associated with cancer progression and metastasis. Deletion of VDR markedly inhibited signaling pathways that regulate hair development. Furthermore, concurrent ablation of CaSR and VDR significantly suppressed calcium, VDR, Wnt/b-catenin signaling, as well as epithelial adherence junction signaling to maintain appropriate keratinocyte adhesion. These results indicated the interplay of calcium/CaSR and 1,25D3/VDR signaling in keratinocyte proliferation and differentiation, and their importance in maintaining normal epidermal adhesion and functions. n=3 CON and KO (each sample contain RNA isolated from neonatal epidermis separated from 3 mice)
2015-07-31 | E-GEOD-68724 | biostudies-arrayexpress
Project description:Castration increases fat deposition, improving beef quality in cattle. Here, the steer group exhibited a significantly higher intramuscular fat (IMF) content than the bull group. To determine the potential roles of microRNAs (miRNAs) in castration-induced fat deposition, differential expression patterns of miRNA in liver tissue were investigated in bulls and steers. A total of 7,827,294 clean reads were obtained from the bull liver library, and 8,312,483 were obtained from the steer liver library; 452 conserved bovine miRNAs and 20 novel miRNAs were identified. The results showed that the expression profiles of miRNA in liver tissue were changed by castration, and 12 miRNAs that were differentially expressed between bulls and steers were identified. Their target genes were majorly involved in the metabolic, PI3K-Akt, and MAPK signaling pathways. Furthermore, six differentially expressed miRNAs were validated by quantitative real-time PCR, and luciferase reporter assays verified that calcium-sensing receptor (CASR) was the direct target of miR-27a-5p. Meantime, we found that the expression level of CASR was significantly higher in steers than in bulls, and revealed that CASR gene silencing in bovine hepatocytes significantly inhibited triacylglycerol (TAG) accumulation and reduced secretion of very low density lipoprotein (VLDL). These results obtained in the liver indicate that miR-27a-5p may increase fat deposition partly by targeting CASR in steers.
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Project description:Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
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