• Clinical and Experimental Pediatrics
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• 제58권4호
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• pp.148-153
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• 2015

The calcium sensing receptor (CaSR) plays an important role in calcium homeostasis. Activating mutations of CaSR cause autosomal dominant hypocalcemia by affecting parathyroid hormone secretion in parathyroid gland and calcium resorption in kidney. They can also cause a type 5 Bartter syndrome by inhibiting the apical potassium channel in the thick ascending limb of the loop of Henle in the kidney. This study presents a patient who had autosomal dominant hypocalcemia with Bartter syndrome due to an activating mutation Y829C in the transmembrane domain of the CaSR. Symptoms of hypocalcemia occurred 12 days after birth and medication was started immediately. Medullary nephrocalcinosis and basal ganglia calcification were found at 7 years old and at 17 years old. Three hypercalcemic episodes occurred, one at 14 years old and two at 17 years old. The Bartter syndrome was not severe while the serum calcium concentration was controlled, but during hypercalcemic periods, the symptoms of Bartter syndrome were aggravated.

• Asian Pacific Journal of Cancer Prevention
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• 제13권8호
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• pp.3561-3568
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• 2012

The calcium sensing receptor (CaSR) is a member of the largest family of cell surface receptors, the G protein-coupled receptors involved in calcium homeostasis. The role of the CaSR in neoplasia appears to be homeostatic; loss of normal CaSR-induced response to extracellular calcium is observed in cancers of the colon and ovary, while increased release of PTHrP is observed in cancers of the breast, prostate and Leydig cells. Currently CaSR can be considered as a molecule that can either promote or prevent tumor growth depending on the type of cancer. Therefore, recognition of the multifaceted role of CaSR in gliomas and other malignant tumors in general is fundamental to elucidating the mechanisms of tumor progression and the development of novel therapeutic agents. Emphasis should be placed on development of drug-targeting methods to modulate CaSR activity in cancer cells.

• 한국식품영양학회지
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• 제35권6호
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• pp.531-536
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• 2022

Umami taste-yielding foods, such as, Joseonganjang, dried anchovies, dried shiitake, dried Konbu (kelp), and Yukjeot, are widely used in the Korean cuisine as soup base. While Umami taste enhancement related to Kokumi taste substances has been proposed in human sensory studies, the potential action of Kokumi taste substances has not been explored on calcium-sensing receptors (CaSR), here referred to as Kokumi taste receptors. In this study, we investigated the effect of Umami taste-yielding foods on Kokumi taste receptors using cells expressing human CaSR. We monitored the temporal changes in intracellular Ca²⁺ in HEK293T cells expressing CaSR in response to aqueous extract of Joseonganjang, dried anchovies, dried shiitake, dried Konbu, and Yukjeot. Kokumi substances tested-glutathione and γ-Glu-Val-Gly- evoked intracellular Ca²⁺ influx in a concentration-dependent manner. A similar increment of intracellular Ca²⁺ influx was induced by Joseonganjang, Yukjeot, and dried anchovies, but not by dried shiitake and dried Konbu. Only Joseonganjang- and Yukjeot-evoked intracellular Ca²⁺ influx was significantly reduced by NPS 2143, a CaSR-specific antagonist. These data indicated that some Umami substances/Umami-yielding materials could activate CaSR, but this property was not observed for all the Umami tasting substances.

• 한국임상약학회지
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• 제23권2호
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• pp.142-150
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• 2013

Background: Secondary hyperparathyroidism (SHPT) is common in patients with chronic kidney disease, affecting most of those who are receiving dialysis. Cinacalcet, a novel calcimimetic, targets the calcium-sensing receptor to lower PTH levels in dialysis patients. Objective: This study aimed to assess efficacy, safety and appropriateness of use of cinacalcet in dialysis patients. Method: This retrospective study was performed on total 24 cases with identified intact parathyroid hormone (iPTH), serum calcium and phosphorus levels before and 4 weeks after cinacalcet initiation at a teaching hospital from July 1st, 2011 to October 31st, 2012. Results: Cinacalcet decreased iPTH by 19% from baseline after 4weeks treatment and it was statistically significant (p<0.001). Cinacalcet also significantly decreased iPTH levels regardless of dialysis modality (hemodialysis group versus peritoneal dialysis group) and severity of SHPT (iPTH 300-800 pg/ml group versus iPTH >800 pg/ml group). Serum calcium, phosphorus and Ca x P levels were decreased without statistical significance. Gastrointestinal events, headache and hypocalcemia were the most common side effects. Monitoring for iPTH and serum calcium was not performed appropriately. 43.7% patients initiated cinacalcet therapy at serum calcium level< 9.0 mg/dl. Conclusion: In conclusion, cinacalcet lowers parathyroid hormone levels with no serious side effects. However, it is required to avoid cinacalcet treatment in patients with low serum calcium levels and monitor iPTH and serum calcium levels during cinacalcet administration.

• Journal of Interdisciplinary Genomics
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• 제3권1호
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• pp.21-24
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• 2021

Purpose: Activating mutations of the calcium-sensing receptor (CASR) are a rare genetic disorder, and result in autosomal dominant hypocalcemia with hypercalciuria (ADHH). ADHH exhibited varying degrees of hypocalcemia. In this study, we report the clinical and molecular characteristics of activating variants in CASR patients diagnosed in Korea. Methods: This study included three patients with activating variants of CASR confirmed by biochemical and molecular analysis of CASR. Clinical and biochemical findings were reviewed chart retrospectively. Mutation analysis of CASR was performed by Sanger sequencing. Results: Subject 1 showed severe symptoms from the neonatal period and had difficulty in controlling the medications that were administered. Subject 2 was identified as having a novel variant of CASR with hypocalcemia and a low parathyroid hormone that were found in the neonatal period. During a course without medication, hypocalcemia occurred suddenly around 2 years of age. Subject 3 was diagnosed with hypoparathyroidism with hypocalcemic seizures starting from the neonatal period. About 4 years without taking medication with any symptom. However, at 10 years old revisited by repetitive hypocalcemic seizure events. Subject 1 and 3, were heterozygous for c.2474A>T (p.Y825F), c.2395G>A (p.E799K) located in the transmembrane domain (TMD) of CASR. Subject 2 was heterozygous for c.403A>C (S430L) located in the extracellular domain (ECD) of CASR. Conclusion: We reported 3 patients who have activating CASR variant with different onset and severity of symptoms. In the future, further study is needed to determine how the protein level according to the location of the mutation of CASR affects the degree of symptoms.

• Journal of Ginseng Research
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• 제45권6호
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• pp.683-694
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• 2021

Background: Ginsenoside Rg1 (Rg1) has been well documented to be effective against various cardiovascular disease. The aim of this study is to evaluate the effect of Rg1 on mechanical stress-induced cardiac injury and its possible mechanism with a focus on the calcium sensing receptor (CaSR) signaling pathway. Methods: Mechanical stress was implemented on rats through abdominal aortic constriction (AAC) procedure and on cardiomyocytes and cardiac fibroblasts by mechanical stretching with Bioflex Collagen I plates. The effects of Rg1 on cell hypertrophy, fibrosis, cardiac function, [Ca²⁺]_i, and the expression of CaSR and calcineurin (CaN) were assayed both on rat and cellular level. Results: Rg1 alleviated cardiac hypertrophy and fibrosis, and improved cardiac decompensation induced by AAC in rat myocardial tissue and cultured cardiomyocytes and cardiac fibroblasts. Importantly, Rg1 treatment inhibited CaSR expression and increase of [Ca²⁺]_i, which similar to the CaSR inhibitor NPS2143. In addition, Rg1 treatment inhibited CaN and TGF-b1 pathways activation. Mechanistic analysis showed that the CaSR agonist GdCl₃ could not further increase the [Ca²⁺]_i and CaN pathway related protein expression induced by mechanical stretching in cultured cardiomyocytes. CsA, an inhibitor of CaN, inhibited cardiac hypertrophy, cardiac fibrosis, [Ca²⁺]_i and CaN signaling but had no effect on CaSR expression. Conclusion: The activation of CaN pathway and the increase of [Ca²⁺]_i mediated by CaSR are involved in cardiac hypertrophy and fibrosis, that may be the target of cardioprotection of Rg1 against myocardial injury.

• International Journal of Oral Biology
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• 제31권2호
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• pp.53-65
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• 2006

Calcium concentration in the bone resorption lacunae is high and is in the mM concentration range. Both osteoblast and osteoclast have calcium sensing receptor in the cell surface, suggesting the regulatory role of high extracellular calcium in bone metabolism. In vitro, high extracellular calcium stimulated osteoclastogenesis in coculture of mouse osteoblasts and bone marrow cells. Therefore we examined the genes that were commonly regulated by both high extracellular calcium and $1,25(OH)_2vitaminD_3(VD3)$ by using mouse oligo 11 K gene chip. In the presence of 10 mM $[Ca^{2+}]e$ or 10 nM VD3, mouse calvarial osteoblasts and bone marrow cells were co-cultured for 4 days when tartrate resistant acid phosphatase-positive multinucleated cells start to appear. Of 11,000 genes examined, the genes commonly regulated both by high extracellular calcium and by VD3 were as follows; 1) the expression of genes which were osteoclast differentiation markers or were associated with osteoclastogenesis were up-regulated both by high extracellular calcium and by VD3; trap, mmp9, car2, ctsk, ckb, atp6b2, tm7sf4, rab7, 2) several chemokine and chemokine receptor genes such as sdf1, scya2, scyb5, scya6, scya8, scya9, and ccr1 were up-regulated both by high extracellular calcium and by VD3, 3) the genes such as mmp1b, mmp3 and c3 which possibly stimulate bone resorption by osteoclast, were commonly up-regulated, 4) the gene such as c1q and msr2 which were related with macrophage function, were commonly down-regulated, 5) the genes which possibly stimulate osteoblast differentiation and/or mineralization of extracellular matrix, were commonly down-regulated; slc8a1, admr, plod2, lox, fosb, 6) the genes which possibly suppress osteoblast differentiation and/or mineralization of extracellular matrix, were commonly up-regulated; s100a4, npr3, mme, 7) the genes such as calponin 1 and tgfbi which possibly suppress osteoblast differentiation and/or mineralization of extracellular matrix, were up-regulated by high extracellular calcium but were down-regulated by VD3. These results suggest that in coculture condition, both high extracellular calcium and VD3 commonly induce osteoclastogenesis but suppress osteoblast differentiation/mineralization by regulating the expression of related genes.

• 한국동물생명공학회지
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• 제36권3호
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• pp.129-136
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• 2021

This study identified single nucleotide polymorphisms (SNPs) that affect the body weight of chickens. Analysis of body weight showed that the Cornish breed had the highest body weight, and the Korean native chicken (Gray Brown) had the lowest body weight. TSH is composed of an α-subunit and a β-subunit, and the TSH-β gene encoding the β-subunit has been reported to be associated with obesity. In chickens, it is located on chromosome 26 and is reported to be associated with growth. The calcium-sensing receptor gene (CaSR) plays a role in the regulation of extracellular calcium homeostasis and is responsible for calcium absorption in the urinary tract, which affects the eggshell quality in poultry. It was shown that TSH-β was strongly correlated with weight in Cornish and Korean native (Gray Brown) chickens, particularly in those with the CC trait. However, CaSR showed no association with body weight in poultry; it was associated with calcium and the eggshell. Thus, selection for TSH-β can be used to produce individuals with more favorable traits in terms of body weight.

• Asian Pacific Journal of Cancer Prevention
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• 제15권15호
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• pp.6035-6039
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• 2014

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 < $25kg/m^2$) cases and overweight/obese (BMI ${\geq}25kg/m^2$) 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.

• 한국산학기술학회논문지
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• 제16권2호
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• pp.1200-1206
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• 2015

신약 개발의 주요 표적이 되는 G-protein coupled receptor (GPCR)은 대부분의 생리적 활동에 관여하며 다양한 질병과 질환들에 관련되어 있다. GPCR을 타겟으로 하는 의약개발 연구에서 필수적인 실험방법으로 많이 활용되고 있는 세포기반 스크리닝 기술들은 사용되는 세포의 상태에 따라 데이터의 질이 좌우되는데 최근, 실험에 사용할 세포를 매번 배양하면서 소모되는 비용과 데이터의 변동을 줄이기 위해 냉동보관 세포를 적용하는 추세이다. 이에 본 연구에서는 단일 세포를 많은 양으로 배양하고 냉동 보관한 다음 사용되는 세포의 반응을 최적화하기 위하여 칼슘 검출을 위한 광 단백질이 포함된 세포주에 calcium sensing receptor와 urotensin II receptor가 안정적으로 발현되는 안정화 세포를 제작하고 $-80^{\circ}C$에서 보관한 다음 7 일 간격으로 실험했을 때 효능제와 길항제 반응을 비교하였다. 실험결과 보관기간이 증가함에 따라 세포 신호 값이 감소하였지만 $EC_{50}$와 $IC_{50}$ 값의 변화는 나타나지 않았다($EC_{50}:3.46{\pm}1.36mM$, $IC_{50}:0.49{\pm}0.15{\mu}M$). 그러나 액체질소에서 보관한 세포의 경우에서는 비냉동 세포와 비교하여 세포 신호 값이 감소했지만 보존기간에 따른 변화가 나타나지 않았으며 기간에 따른 $IC_{50}:0.49{\pm}0.15{\mu}M$와 $IC_{50}$의 변화도 없었다. 보관기간이 경과 될수록 세포의 신호 값이 감소하는 것은 세포 손상도 증가가 원인인 것으로 판단되며, 이러한 결과들로부터 장기간 냉동 보관을 위해서는 액체질소를 이용하는 것이 가장 효과적이고 한 달 이내 단기간 사용의 목적으로는 $-80^{\circ}C$ 보관조건도 가능할 것으로 판단된다. 이와 같이 냉동세포의 적극적인 활용을 통하여 초기 스크리닝 과정에서 나타나는 실험 유동성을 감소시킬 수 있을 것으로 예상된다.