High Calcium and Other Divalent Cations Increase Inositol Trisphosphate in Bovine Parathyroid Cells*

Shoback, Dolores; Membreno, Linda A.; McGHEE, Janet G.

doi:10.1210/endo-123-1-382

Cited by 98 publications

(35 citation statements)

References 35 publications

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“…The parathyroid cell contains a cell membrane CaR thought to mediate this response to Cao. This receptor can activate the PLC pathway, leading to an increase in IP 3 levels as well as stimulating calcium influx and chloride currents (25,26,39). As in keratinocytes, the response of Cai to Cao in parathyroid cells is saturated at 2.0-2.5 mM Cao.…”

Section: Discussionmentioning

confidence: 99%

Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor.

Bikle¹,

Ratnam²,

Mauro³

et al. 1996

J. Clin. Invest.

182

130

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Extracellular calcium concentrations (Cao) Ͼ 0.1 mM are required for the differentiation of normal human keratinocytes in culture. Increments in Cao result in acute and sustained increases in the intracellular calcium level (Cai), postulated to involve both a release of calcium from intracellular stores and a subsequent increase in calcium influx through nonspecific cation channels. The sustained rise in Cai appears to be necessary for keratinocyte differentiation. To understand the mechanism by which keratinocytes respond to Cao, we measured the acute effects of Cao on Cai and calcium influx in keratinocytes at various stages of differentiation. We then demonstrated the existence of the calcium receptor (CaR) in keratinocytes and determined the effect of calcium-induced differentiation on its mRNA levels. Finally, we examined the role of Cai in regulating both the initial rise in Cai after the switch to higher Cao and the activity of the nonspecific cation channel through which calcium influx occurs. Our data indicate that the acute Cai response to Cao is lost as the cells differentiate and increase their basal Cai. These data correlated with the decrease in CaR mRNA levels in cells grown in low calcium. However, calcium influx as measured by 45 Ca uptake increased with differentiation in 1.2 mM calcium, consistent with the increase in CaR mRNA in these cells as well as the calciuminduced opening of the nonspecific cation channels. We conclude that the keratinocyte contains a CaR that regulates both the initial release of Cai from intracellular stores and the subsequent increase in calcium flux through nonspecific calcium channels. A rising level of Cai may turn off the release of calcium from intracellular stores while potentiating the influx through the nonspecific cation channels.

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Section: Discussionmentioning

confidence: 99%

Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor.

Bikle¹,

Ratnam²,

Mauro³

et al. 1996

J. Clin. Invest.

182

130

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“…The human (1,078 amino acids) and bovine (1,085 amino acids) parathyroid cell Ca 2ϩ receptors are glycosylated proteins of ϳ120 kDa and are 93% identical (5). The Ca 2ϩ receptor expressed on authentic parathyroid cells or in heterologous cellular systems couples to phospholipase C and, when activated by increased concentrations of extracellular Ca 2ϩ , elicits rapid increases in inositol 1,4,5-trisphosphate and [Ca 2ϩ ] i (2,4,6). Thus, in its functional and structural properties, the parathyroid Ca 2ϩ receptor is akin to other cell surface receptors that initially transduce extracellular signals into functional cellular responses.…”

mentioning

confidence: 99%

Calcimimetics with potent and selective activity on the parathyroid calcium receptor

Nemeth

Steffey

Hammerland

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

563

355

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Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca 2؉ receptor that detects small changes in the level of plasma Ca 2؉ . Because this G protein-coupled receptor conceivably provides a distinct molecular target for drugs useful in treating bone and mineral-related disorders, we sought to design small organic molecules that act on the Ca 2؉ receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS receptor are termed calcimimetics. The discovery of calcimimetic compounds with potent and selective activity enables a pharmacological approach to regulating plasma levels of PTH. Calcimimetic compounds could conceivably provide a specific medical therapy for primary hyperparathyroidism.The concentration of ionized calcium (Ca 2ϩ ) in plasma is regulated largely by parathyroid hormone (PTH), which acts on the kidney and on bone to increase the level of plasma Ca The Ca 2ϩ receptor is a member of the G protein-coupled receptor superfamily and possesses an unusually large extracellular domain, the characteristic seven transmembrane domain, and a relatively long cytoplasmic tail. In these topological aspects, the Ca 2ϩ receptor is similar to metabotropic glutamate receptors (mGluR), although the sequence homology between these receptors is only about 25%. The human (1,078 amino acids) and bovine (1,085 amino acids) parathyroid cell Ca 2ϩ receptors are glycosylated proteins of ϳ120 kDa and are 93% identical (5). The Ca 2ϩ receptor expressed on authentic parathyroid cells or in heterologous cellular systems couples to phospholipase C and, when activated by increased concentrations of extracellular Ca 2ϩ , elicits rapid increases in inositol 1,4,5-trisphosphate and [Ca 2ϩ ] i (2, 4, 6). Thus, in its functional and structural properties, the parathyroid Ca 2ϩ receptor is akin to other cell surface receptors that initially transduce extracellular signals into functional cellular responses. The difference is that the physiological ligand for the Ca 2ϩ receptor is an inorganic ion, rather than an organic molecule.G protein-coupled receptors have been a classic site of action for drugs useful in treating various diseases. As a member of the G protein-coupled receptor superfamily, the Ca 2ϩ receptor is seemingly an ideal target for new pharmaceuticals useful in treating disorders of bone and mineral metabolism, such as hyperparathyroidism and osteoporosis. At present, however, the only ligands known to act on the Ca 2ϩ receptor are other inorganic di-and trivalent cations (2, 7) and organic polycations (8-10) that are nonselective and lack utility as systematic therapeutics. The present report describes the results of our initial efforts to devise a small organic compound that selectively acts on the parathyroid Ca 2ϩ receptor yet lacks a polycationic structure. NPS R-467 and NPS R-568 (Fig. 1) are two compounds that emerged from this effort. They are potent and selective activators of the Ca 2ϩ receptor and inhibit PTH secretion in vitro....

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confidence: 99%

Evidence that Ca2+ cycling by the plasma membrane Ca2+-ATPase increases the `excitability' of the extracellular Ca2+-sensing receptor

Luisi

Hofer

2003

Journal of Cell Science

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IntroductionThe extracellular Ca 2+ -sensing receptor (CaR) is a cell surface receptor for divalent cations whose existence was originally suspected in the parathyroid gland (Brown et al., 1987;Nemeth and Scarpa, 1987;Shoback et al., 1988). Cloning of the receptor by Brown and colleagues (Brown et al., 1993) confirmed the essential role of CaR as a Ca 2+ sensor in the parathyroid, and also set the stage for the identification of the receptor in a wide variety of tissues not involved in systemic Ca 2+ homeostasis . This seventransmembrane-spanning receptor couples, via heterotrimeric G-proteins, to several different signaling cascades, including the phospholipase C (PLC)/phosphoinositide/Ca 2+ pathway (Brown and MacLeod, 2001). The binding of Ca 2+ to the human parathyroid receptor is known to be a highly cooperative process, making CaR a good Ca 2+ 'increment detector'. Although half-maximal activation of the receptor occurs around 3.5 mM, with maximal stimulation at 5.5 mM (Conigrave et al., 2000a;Quinn et al., 1997), CaR is able to sense small [Ca 2+ ] changes (±0.2 mM) in the physiological range (around 1.8 mM Ca 2+ ).It is important to note that CaR is also stimulated by Mg 2+ and certain polycations [including some endogenous polyamines such as spermine and spermidine (Quinn et al., 1997)]. Synthetic small molecule agonists of the receptor, such as the allosteric modulator NPS R-467 (Nemeth et al., 1998), have also been prepared. Brown and colleagues recently showed that the CaR is activated by physiological concentrations of amino acids [particularly aromatic and small aliphatic L-amino acids (Conigrave et al., 2000b)], and that it is modulated by ionic strength . It is therefore likely that multiple agonists act in concert to stimulate the receptor physiologically.We noted previously that stimulation of CaR with maximal doses of CaR agonists was frequently manifested by an oscillatory Ca 2+ signal in HEK293 cells transfected with the human extracellular Ca 2+ -sensing receptor (HEK CaR cells) (Hofer et al., 2000). The same observation was made in CaRtransfected HEK cells by Breitwieser and Gama (Breitwieser and Gama, 2001), who also reported that Ca 2+ spiking was acutely sensitive to small incremental increases in extracellular [Ca 2+ ]. Such oscillations were sustained for up to 40 minutes, until they gradually diminished in amplitude. Young and Rozengurt recently extended these findings, showing that aromatic amino acids can sensitize the receptor to small incremental increases in external [Ca 2+ ] in HEK CaR cells, producing distinctive patterns of oscillations (Young and Rozengurt, 2002). Native tissues that express CaR endogenously, including parathyroid cells (Miki et al., 1995)

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High Calcium and Other Divalent Cations Increase Inositol Trisphosphate in Bovine Parathyroid Cells*

Cited by 98 publications

References 35 publications

Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor.

Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor.

Calcimimetics with potent and selective activity on the parathyroid calcium receptor

Evidence that Ca2+ cycling by the plasma membrane Ca2+-ATPase increases the `excitability' of the extracellular Ca2+-sensing receptor

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