The Regulation of Parathyroid Hormone Secretion and Synthesis

Kumar, Rajiv; Thompson, James R.

doi:10.1681/asn.2010020186

Cited by 183 publications

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“…FHH1 (OMIM #145980) is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor (GPCR)3 that initiates activation of the G‐protein subunit αq/11 (Gα q/11 ) family, leading to enhancement of phospholipase C (PLC) activity4 and elevation of inositol 1,4,5‐trisphosphate (IP 3 ) with rapid increase in intracellular calcium (Ca 2+ i ) concentrations 5, 6. These signal transduction events allow the parathyroid CaSR to respond to small fluctuations in the prevailing extracellular calcium concentration ([Ca 2+ ] o ) by inducing alterations in PTH secretion through mechanisms that likely involve effects on PTH mRNA stability7 and PTH granule exocytosis from the apical pole of parathyroid cells 8. Moreover, the kidney CaSR is considered to influence urinary calcium excretion by modulating expression of claudin proteins that mediate the paracellular reabsorption of calcium in the renal thick ascending limb 9, 10.…”

Section: Introductionmentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

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Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα11) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα11, encoded by GNA11, and to date only two FHH2‐associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR‐mediated intracellular calcium (Ca2+ i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca2+ o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca2+ i responses after stimulation with Ca2+ o of the mutant Met54 Gα11 led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC50) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC50 of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca2+ o homeostasis. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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Section: Introductionmentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

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“…The normal serum PTH level range is 15-72 pg/mL, with a half-life of 2-4 min. Seventy percent of PTH metabolism occurs in the liver and 30% in the kidneys [9][10][11]. PTH is regulated by serum calcium, phosphorus, and vitamin D metabolites.…”

Section: Anatomy and Physiologymentioning

confidence: 99%

“…PTH levels are inversely proportional to serum calcium levels, as high serum calcium levels decrease PTH release [5][6][7] and low serum calcium levels increase PTH secretion. This relationship enhances renal tubular calcium reabsorption, urinary phosphate excretion, osteoclastmediated bone resorption, and the conversion of 25-hydroxyvitamin D3 into 1,25-hydroxyvitamin D3, which increases calcium absorption from the bowel [9][10][11].…”

Section: Anatomy and Physiologymentioning

confidence: 99%

“…PTH is regulated by serum calcium, phosphorus, and vitamin D metabolites. The total normal calcium level should be 8.8-10.2 mg/dL (ionized calcium 2.2-2.6 mmol/L) to ensure optimum physiological functions [9][10][11]. PTH levels are inversely proportional to serum calcium levels, as high serum calcium levels decrease PTH release [5][6][7] and low serum calcium levels increase PTH secretion.…”

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Current Concepts in the Presentation, Diagnosis and Management of Primary Hyperparathyroidism

Alhefdhi¹

2015

Surgery

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Review ArticleOpen Access IntroductionPrimary hyperparathyroidism (PHPT) is defined by an abnormal increase in the intrinsic activity of the parathyroid gland(s) that result in elevated parathyroid hormone (PTH) levels [1,2]. It is one of the most common endocrine disorders and is the most common cause of hypercalcemia. PHPT is one of the most common endocrine disorders and is the most common cause of hypercalcemia, which increases morbidity and mortality that result from cardiovascular, renal, and musculoskeletal pathologies. PHPT affects 1 in 500 females and 1 in 2,000 males aged >40 years, with a peak incidence in post-menopausal women. In the US, Europe, and Australia, the reported estimated incidence rates range from 25 to 30 per 100,000 person years, and the prevalence range from 1 to 21 per 1,000 individuals [1][2][3][4].PHPT has been a recognizable disease since the 1920s in both Europe and the US [5]. The first parathyroidectomy was performed in 1925 by Felix Mandl in Vienna, Austria; since then, the diagnosis and management of PHPT have progressed [5]. The purpose of this article is to review the current trends of PPT presentation, work-up, and management. Anatomy and PhysiologyHumans typically have four parathyroid glands located at the posterior capsule of the thyroid gland; in up to 15% of individuals have more than four and up to 3% have three identifiable glands [6]. The superior parathyroid glands arise from the IV pharyngeal pouch and migrate to the cephalad thyroid gland; they are usually located at the cricothyroid junction, 1 cm from the recurrent laryngeal nerve and the inferior thyroid artery. Inferior parathyroid glands arise from the III pharyngeal pouch and migrate caudally with the thymus; they are usually located on the posterolateral aspect of the inferior pole of the thyroid gland. Normal parathyroid glands are yellow or brown in color, oval in shape, 3-7 mm in length, and 30-40 mg in weight [7,8].A parathyroid gland consists of chief cells, oxyphilic cells, a thin fibrous capsule, and a network of adipose tissue, blood vessels, and glandular parenchyma [8]. Chief cells secrete PTH, which consists of 84 amino acid polypeptides. The normal serum PTH level range is 15-72 pg/mL, with a half-life of 2-4 min. Seventy percent of PTH metabolism occurs in the liver and 30% in the kidneys [9][10][11]. PTH is regulated by serum calcium, phosphorus, and vitamin D metabolites. The total normal calcium level should be 8.8-10.2 mg/dL (ionized calcium 2.2-2.6 mmol/L) to ensure optimum physiological functions [9][10][11]. PTH levels are inversely proportional to serum calcium levels, as high serum calcium levels decrease PTH release [5][6][7] and low serum calcium levels increase PTH secretion. This relationship enhances renal tubular calcium reabsorption, urinary phosphate excretion, osteoclastmediated bone resorption, and the conversion of 25-hydroxyvitamin D3 into 1,25-hydroxyvitamin D3, which increases calcium absorption from the bowel [9-11]. EtiologyNinety-five percent of PHPT cases are spora...

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“…Assim, níveis séricos elevados de fosfato e produção diminuída de vitamina D causam hipocalcemia e elevam os níveis de PTH circulante. Como consequência prolongada, há hiperplasia de células paratireóideas e aumento na secreção de PTH (1,2,4,5,8,13,19,20,22,23,27,31,(36)(37)(38)(39).…”

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Tratamento cirúrgico do hiperparatireoidismo secundário: revisão sistematizada da literatura

Magnabosco

Tavares

Montenegro

2014

Arq Bras Endocrinol Metab

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RESUMOO hiperparatireoidismo (HPT) secundário tem prevalência elevada em doentes renais crônicos. Decorre de alterações na homeostase mineral, principalmente do cálcio, que estimulam as glându-las paratireoides, com aumento na secreção de paratormônio (PTH). O estímulo prolongado pode levar à autonomia na função paratireóidea. Inicialmente, o tratamento é clínico, mas a paratireoidectomia (PTx) pode ser necessária. A PTx pode ser total, subtotal e total seguida de autoimplante de tecido paratireóideo. Este trabalho compara as indicações e resultados dessas técnicas na literatura. Foi realizada revisão sistematizada dos trabalhos publicados entre janeiro de 2008 e março de 2014 sobre tratamento cirúrgico do hiperparatireoidismo secundário nas bases de dados MedLine e LILACS. Foram utilizados os termos: hiperparatireoidismo; hiperparatireoidismo secundário; glândulas paratireoides e paratireoidectomia. Foram restritos a pesquisas apenas em humanos; artigos disponíveis em meio eletrônico; publicados em português, espanhol, inglês ou francês. A amostra final foi constituída de 49 artigos. A PTx subtotal e a total mais autoimplante foram as técnicas mais utilizadas, sem consenso sobre a técnica mais efetiva. Embora haja certa preferência pela última, a escolha depende da experiência do cirurgião. Há consenso sobre a necessidade de identificar todas as paratireoides e sobre a criopreservação de tecido paratireóideo, quando possí-vel, para enxerto em caso de hipoparatireoidismo. Exames de imagem podem ser úteis, especialmente nas recidivas. Tratamentos alternativos do HPT secundário, tanto intervencionistas quanto conservadores, carecem de estudos mais aprofundados. Arq Bras Endocrinol Metab. 2014;58(5):562-71 Descritores Hiperparatireoidismo; hiperparatireoidismo secundário; glândulas paratireoides; paratireoidectomia ABSTRACT Secondary hyperparathyroidism (HPT) has a high prevalence in renal patients. Secondary HPT results from disturbances in mineral homeostasis, particularly calcium, which stimulates the parathyroid glands, increasing the secretion of parathyroid hormone (PTH). Prolonged stimulation can lead to autonomy in parathyroid function. Initial treatment is clinical, but parathyroidectomy (PTx) may be required. PTx can be subtotal or total followed or not followed by parathyroid tissue autograft. We compared the indications and results of these strategies as shown in the literature through a systematic literature review on surgical treatment of secondary HPT presented in MedLine and LILACS from January 2008 to March 2014. The search terms were: hyperparathyroidism; secondary hyperparathyroidism; parathyroidectomy and parathyroid glands, restricted to research only in humans, articles available in electronic media, published in Portuguese, Spanish, English or French. We selected 49 articles. Subtotal and total PTx followed by parathyroid tissue autograft were the most used techniques, without consensus on the most effective surgical procedure, although there was a preference for the latter. The choice depend...

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The Regulation of Parathyroid Hormone Secretion and Synthesis

Cited by 183 publications

References 129 publications

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Current Concepts in the Presentation, Diagnosis and Management of Primary Hyperparathyroidism

Tratamento cirúrgico do hiperparatireoidismo secundário: revisão sistematizada da literatura

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