Molecular Cloning of a Putative Ca2+-Sensing Receptor cDNA from Human Kidney

Aida, Kaoru; Koishi, Sawako; Tawata, Masato; Onaya, Toshimasa

doi:10.1006/bbrc.1995.2318

Cited by 147 publications

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“…The human CASR gene is located on chromosome 3q13.3-21 (4,5) and spans over 50 kb of genomic DNA. It has a coding region of 3234 bp, which is contained within 6 exons (6).…”

Section: Structure Of the Calcium-sensing Receptormentioning

confidence: 99%

The calcium-sensing receptor and related diseases

D’Souza-Li

2006

Arq Bras Endocrinol Metab

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The calcium-sensing receptor (CASR) adjusts the extracellular calcium set point regulating PTH secretion and renal calcium excretion. The receptor is expressed in several tissues and is also involved in other cellular functions such as proliferation, differentiation and other hormonal secretion. High extracellular calcium levels activate the receptor resulting in modulation of several signaling pathways depending on the target tissues. Mutations in the CASR gene can result in gain or loss of receptor function. Gain of function mutations are associated to Autossomal dominant hypocalcemia and Bartter syndrome type V, while loss of function mutations are associated to Familial hypocalciuric hypercalcemia and Neonatal severe hyperparathyroidism. More than one hundred mutations were described in this gene. In addition to calcium, the receptor also interacts with several ions and polyamines. The CASR is a potential therapeutic target to treatment of diseases including hyperparathyroidism and osteoporosis, since its interaction with pharmacological compounds results in modulation of PTH secretion. RESUMO O Receptor Sensor de Cálcio e Doenças Associadas.O receptor sensor de cálcio (CASR) ajusta o set point do cálcio extracelular através da regulação da secreção de PTH e da excreção renal de cál-cio. O receptor é expresso em diversos tecidos e também está envolvido em outras funções celulares como proliferação, diferenciação e secreção de outros hormônios. Concentrações altas de cálcio extracelular ativam o receptor resultando em modulação de inúmeras vias de sinais intracelulares dependendo do tecido-alvo. Mutações no gene do CASR podem resultar em ganho ou perda de função do receptor. Mutações com ganho de função são associadas à Hipocalcemia autossômica dominante e à Síndrome de Bartter tipo V, enquanto que mutações com perda de função são associadas à Hipercalcemia hipocalciúrica familiar e ao Hiperparatireoidismo neonatal grave. Mais de cem mutações foram descritas neste gene. Além do cálcio, o receptor também interage com inúmeros íons e poliaminas. CASR é um alvo terapêutico potencial para tratamento de doenças incluindo hiperparatireoidismo e osteoporose, pois a sua interação com compostos farmacológicos resulta em modulação da secreção de PTH. [Ca 2+ o ] sensing mechanism that results in changes in phosphoinositide turnover and cytosolic calcium to regulate PTH secretion (1). Extracellular calcium regulates itself by serving as a first messenger and interacting with its receptor, the calcium-sensing receptor (CASR) on target tissues. The receptor was cloned in 1993 from bovine parathyroid (BoPCAR1) by expression cloning in Xenopus laevis oocytes and is a member of the G protein-coupled receptor super family (2). High calcium levels activate the CASR in the parathyroid cell surface to inhibit PTH secretion, and in the kidney to increase calcium excretion (3). STRUCTURE OF THE CALCIUM-SENSING RECEPTORThe human CASR gene is located on chromosome 3q13.3-21 (4,5) and spans over 50 kb of genomic DNA. It has...

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“…The human CASR gene is located on chromosome 3q13.3-21 (4,5) and spans over 50 kb of genomic DNA. It has a coding region of 3234 bp, which is contained within 6 exons (6).…”

Section: Structure Of the Calcium-sensing Receptormentioning

confidence: 99%

The calcium-sensing receptor and related diseases

D’Souza-Li

2006

Arq Bras Endocrinol Metab

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“…Particularly, it was confirmed that several other di-(e.g., Mg 2ϩ , Cd 2ϩ ), tri-(e.g., Gd 3ϩ , La 3ϩ ) or polyvalent (e.g., neomycin) cations can mimic the effect of free calcium on the parathyroid gland cells. Subsequently, the cloning of full-length CaSRs from various mammalian species, including human, rat and rabbit, was performed (1,112).…”

Section: Cloning/geneticsmentioning

confidence: 99%

“…The initial review focused on the preliminary characterization and description of the receptor and how it related to the parathyroid and whole body calcium handling and homeostasis (17). Since that time, not only has there been a great deal of new information concerning CaSR and parathyroid disease come to light, but in addition the receptor has now been identified in many other tissues and organs in the body where it has been shown to have a diverse role in cellular and organismic pathophysiology (1,2,24,28). With the further identification and functional characterization of the receptor in multiple organ systems and at the cellular level ( Fig.…”

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confidence: 99%

Calcium-sensing receptor 20 years later

Alfadda

Saleh

Houillier

et al. 2014

American Journal of Physiology-Cell Physiology

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The calcium-sensing receptor (CaSR) has played an important role as a target in the treatment of a variety of disease states over the past 20 plus years. In this review, we give an overview of the receptor at the cellular level and then provide details as to how this receptor has been targeted to modulate cellular ion transport mechanisms. As a member of the G proteincoupled receptor (GPCR) family, it has a high degree of homology with a variety of other members in this class, which could explain why this receptor has been identified in so many different tissues throughout the body. This diversity of locations sets it apart from other members of the family and may explain how the receptor interacts with so many different organ systems in the body to modulate the physiology and pathophysiology. The receptor is unique in that it has two large exofacial lobes that sit in the extracellular environment and sense changes in a wide variety of environmental cues including salinity, pH, amino acid concentration, and polyamines to name just a few. It is for this reason that there has been a great deal of research associated with normal receptor physiology over the past 20 years. With the ongoing research, in more recent years a focus on the pathophysiology has emerged and the effects of receptor mutations on cellular and organ physiology have been identified. We hope that this review will enhance and update the knowledge about the importance of this receptor and stimulate future potential investigations focused around this receptor in cellular, organ, and systemic physiology and pathophysiology.G protein-coupled receptors; calcimimetics; kidney; gastrointestinal tract; divalent ions IT IS NOW 20 YEARS since the initial review on calcium-sensing receptor (CaSR) was published (17). The initial review focused on the preliminary characterization and description of the receptor and how it related to the parathyroid and whole body calcium handling and homeostasis (17). Since that time, not only has there been a great deal of new information concerning CaSR and parathyroid disease come to light, but in addition the receptor has now been identified in many other tissues and organs in the body where it has been shown to have a diverse role in cellular and organismic pathophysiology (1, 2, 24, 28). With the further identification and functional characterization of the receptor in multiple organ systems and at the cellular level (Fig. 1), we felt it was now time to provide an updated overview of the calcium-sensing receptor and its diverse functions throughout the body.Our review will give a brief historical review of the identification of the receptor in the parathyroid and its role as an important target for parathyroid disease. We include a discussion of the initial cloning studies and the ability of this receptor to "sense" divalent and trivalent ions in the extracellular environment. We follow this with a molecular profile of the receptor based on the many years of research into the structure and function of the receptor. In te...

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“…Subseqüentemente à clonagem do cDNA do CaR em paratiróide bovina (BoPCaR1) (3), homólo-gos do CaR bovino foram isolados em ratos (células C, cérebro, rim) (12), humanos (paratiróide, rim) (13,14), coelho (rim) (15) e galinha (paratiróide) (16), todos muito similares ao BoPCaR1. Os CaRs humano (1078 aminoácidos) e do rato (1079 aminoá-cidos), possuem estruturas altamente conservadas, com 93% de identidade com o BoPCaR1 (2,6,11).…”

Section: Receptor Sensível Ao Cálcio Extracelular (Car)unclassified

Mutações do Gene do Receptor Sensível ao Cálcio Extracelular e Suas Doenças Associadas

Miyashiro

Hauache

2002

Arq Bras Endocrinol Metab

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RESUMOO receptor sensível ao cálcio extracelular (CaR) é um receptor acoplado à proteína G (GPCR), que exerce um papel essencial na regulação da homeostase do cálcio extracelular. O CaR encontra-se expresso em todos os tecidos relacionados com o controle desta homeostase (paratiróides, células C tiroideanas, rins, intestino e ossos ABSTRACT Mutations of the Extracellular Calcium-Sensing Receptor Gene and its Associated Diseases.The extracellular calcium-sensing receptor (CaR) is a G protein coupled receptor (GPCR) that plays a key role in the regulation of extracellular calcium homeostasis, being expressed in all tissues related to this control (parathyroid glands, thyroid C-cells, kidneys, intestine and bones). The cloning of the CaR was immediately followed by the association of genetic human diseases with inactivating and activating mutations of the CaR gene: familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are caused by inactivating mutations of the CaR gene, whereas autosomal dominant hypoparathyroidism is secondary to activating mutations of the CaR gene. In spite of being rare, these diseases should be considered in the differential diagnosis of hypercalcemic and hypocalcemic disorders. Recognition of the important role of the CaR for the regulation of extracellular calcium homeostasis motivated the development of drugs that modulate the CaR function, by either activating (calcimimetic drugs) or antagonizing it (calcilytic drugs). These drugs have potential therapeutic implications, such as medical control of specific cases of primary and uremic hyperparathyroidism with calcimimetic drugs and a potential revisão

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Molecular Cloning of a Putative Ca2+-Sensing Receptor cDNA from Human Kidney

Cited by 147 publications

References 0 publications

The calcium-sensing receptor and related diseases

The calcium-sensing receptor and related diseases

Calcium-sensing receptor 20 years later

Mutações do Gene do Receptor Sensível ao Cálcio Extracelular e Suas Doenças Associadas

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