Changes in cytoplasmic calcium determine the secretory response to extracellular cations in human parathyroid cells: a confocal microscopy study using FM1-43 dye

Mihai, Radu; Lai, Teresa; Schofield, G.; Farndon, John

doi:10.1042/bj3520353

Cited by 10 publications

(3 citation statements)

References 38 publications

(44 reference statements)

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“…Once exocytosis takes place, the slight increase in the total cell surface leads to an increased uptake of the fluorescent dye on the surface of the cell and this process can be visualised and quantified in real time on confocal microscopy (Plate 1 ] ext , which should have stimulated secretion. 10 We also found that after long incubation (5-30 min) in the presence of FM1-43, the dye accumulates in the cytoplasm with a granular distribution suggesting targeting of the secretory compartment. This led to a cell model in which the granule movements could be visualised and exocytosis monitored and quantified based on the destaining kinetics.…”

Section: Car Controls Exocytosis In Human Parathyroid Cellsmentioning

confidence: 72%

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The Calcium Sensing Receptor: From Understanding Parathyroid Calcium Homeostasis to Bone Metastases

Mihai

2008

annals

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Ann R Coll Surg Engl 2008; 90: 271-277 271The parathyroid glands were first described at autopsy in 1862 in an Indian rhinoceros by Sir Richard Owen from the Hunterian Museum of the Royal College of Surgeons of England, 1 but their role in calcium homeostasis was only recognised decades later. Calcium is an essential element throughout the phylogenetic tree and the free extracellular calcium concentration ([Ca 2+ ] ext ) is maintained within a narrow range (1.0-1.3 mM). A central role in the rapid control of calcium homeostasis is played by the parathyroid hormone (PTH), whose co-ordinated actions on bone, kidney and intestine increase the flow of calcium into the extracellular fluid. There is an inverse sigmoidal relationship between PTH secretion and [Ca 2+ ] ext . The initial changes in the secretory rate of PTH in response to low [Ca 2+ ] ext take place within seconds through the release of preformed hormones from storage granules. Within 15-30 min, there is also an increase in the net rate of PTH synthesis. Prolonged hypocalcaemia promotes parathyroid cellular hypertrophy and proliferation within days to weeks. ] ext ) via a receptor-type mechanism. This lead to the hypothesis that abnormalities in the expression and/or function of the CaR could explain the biochemical abnormalities in primary hyperparathyroidism (PHPT). HUNTERIAN LECTURE Ann R Coll Surg EnglCultured cells from parathyroid adenomas of patients operated for PHPT were used to monitor real-time changes in intracellular calcium concentration ([Ca 2+ ] i ) as measured by fluorescent microscopy using the Fura-2/AM dye. We found that CaR agonists trigger release of intracellular calcium pools and such responses are amplified by increasing the affinity of IP 3 receptors. Using confocal microscopy to monitor membrane trafficking in living parathyroid cells labelled with the fluorescent dye FM1-43, we found that a decrease in [Ca 2+ ] i rather than an absolute change in [Ca 2+ ] ext is the main stimulus for exocytosis from human parathyroid cells. These data suggest that, in PHPT, a defective signalling mechanism from the CaR allows cells from parathyroid adenomas to maintain low [Ca 2+ ] i with uninhibited PTH secretion in the face of hypercalcaemia. Over longer periods of time, CaR controls parathyroid proliferation via changes in tyrosine phosphorylation. We found that multiple proteins of molecular weight 20-65 kDa are phosphorylated within 10-60 min in response to CaR agonists.Further work demonstrated that high [Ca 2+ ] i stimulates the expression of bcl-2 oncoprotein in cultured human parathyroid cells and that, in parathyroid adenomas, predominant expression of bcl-2 rather than bax oncoprotein might prevent apoptosis and explain the slow growth rate of these tumours.More recently, it became apparent that CaR stimulates cell proliferation in several cell types not involved in calcium homeostasis. Using archived histological material from 65 patients who died with metastatic breast cancer, we identified ...

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Section: Car Controls Exocytosis In Human Parathyroid Cellsmentioning

confidence: 72%

“…This led to a cell model in which the granule movements could be visualised and exocytosis monitored and quantified based on the destaining kinetics. 10 These data …”

Section: Car Controls Exocytosis In Human Parathyroid Cellsmentioning

confidence: 85%

The Calcium Sensing Receptor: From Understanding Parathyroid Calcium Homeostasis to Bone Metastases

Mihai

2008

annals

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“…In primary hyperparathyroidism, a defective Ca 2? -sensing mechanism could result in the maintenance of low [Ca 2? i ] by the parathyroid cells under the condition of hypercalcemia, leading to uninhibited PTH secretion [30]. Alterations in the expression levels of the CaR as well as its coupling to signaling apparatus could also represent defective Ca 2?…”

Section: Car and Pt Adenomamentioning

confidence: 99%

Calcium-sensing receptor in cancer: good cop or bad cop?

Chakravarti

Dwivedi

Mithal

et al. 2008

Endocr

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The extracellular calcium-sensing receptor (CaR) is a versatile 'sensor' for di- and polycationic molecules in the body. CaR plays a key role in the defense against hypercalcemia by "sensing" extracellular calcium levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. Although mutation of CaR gene has so far not been associated with any malignancy, aberrant functions of CaR have implications in malignant progression. One situation is loss of CaR expression, resulting in loss of growth suppressing effects of elevated extracellular Ca(2+) by CaR, reported in parathyroid adenoma and in colon carcinoma. Another situation is activation of CaR, resulting in increased production of parathyroid hormone-related peptide (PTHrP), a primary causal factor in hypercalcemia of malignancy and a contributor to metastatic processes involving bone. CaR signaling and effects have been studied in several cancers including ovarian cancers, gastrinomas, and gliomas in addition to comparatively detailed studies in breast, prostate, and colon cancers. Studies on H-500 rat Leydig cells, a xenotransplantable model of humoral hypercalcemia of malignancy has shed much light on the mechanisms of CaR-induced cancer cell growth and survival. Pharmacological agonists and antagonists of CaR hold therapeutic promise depending on whether activation of CaR is required such as in case of colon cancer or inactivating the receptor is required as in the case of breast- and prostate tumors.

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John Richard Farndon

Lennard

2015

Surgical Endocrinopathies

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Changes in cytoplasmic calcium determine the secretory response to extracellular cations in human parathyroid cells: a confocal microscopy study using FM1-43 dye

Cited by 10 publications

References 38 publications

The Calcium Sensing Receptor: From Understanding Parathyroid Calcium Homeostasis to Bone Metastases

The Calcium Sensing Receptor: From Understanding Parathyroid Calcium Homeostasis to Bone Metastases

Calcium-sensing receptor in cancer: good cop or bad cop?

John Richard Farndon

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