A Comparison of the Effects of Divalent and Trivalent Cations on Parathyroid Hormone Release, 3′,5′-Cyclic-Adenosine Monophosphate Accumulation, and the Levels of Inositol Phosphates in Bovine Parathyroid Cells

Brown, Edward M.; el-H, Fuleihan G; Chen, C J; Kifor, Olga

doi:10.1210/endo-127-3-1064

Cited by 94 publications

(46 citation statements)

References 15 publications

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“…The phenylalkylamine compounds thus appear to lack activity at mGluRs. is the primary physiological ligand activating the Ca 2ϩ receptor, a variety of di-and trivalent cations and organic polycations can also act as ligands at this receptor and decrease secretion of PTH (2,(7)(8)(9)(10). Polycationic ligands, however, are of limited utility as pharmacological probes of the Ca 2ϩ receptor because they lack specificity and͞or potency.…”

Section: Resultsmentioning

confidence: 99%

“…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)(9)(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.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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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“…After sedimentation of precipitated debris and removal of trichloroacetic acid by ether extraction, inositol phosphates in the aqueous phase were subsequently separated on Dowex anion exchange columns. The radioactive inositol monophosphate, bisphosphate, trisphosphate, and tetrakisphosphate were eluted stepwise with 0.2, 0.4, 0.8, and 1.2 M formate containing 0.1 M formic acid, respectively, and quantitated using a liquid scintillation counter (27).…”

Section: Methodsmentioning

confidence: 99%

Sodium and Ionic Strength Sensing by the Calcium Receptor

Quinn

Kifor

Trivedi

et al. 1998

Journal of Biological Chemistry

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130

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within its physiological range of ϳ1.5 mM (1, 2). Initially cloned from bovine parathyroid cells, the CaR is highly expressed in the tissues involved in regulating [Ca 2ϩ ] o including the parathyroid (PT), calcitonin-secreting cells of the thyroid (C cells), and several regions of the kidney (1, 3, 4). Interestingly, the CaR is also distributed in a number of other tissues which do not have well established roles in the control of [Ca 2ϩ ] o . These include several regions of the brain (e.g. the subfornical organ and hypothalamus), the pituitary, collecting duct of the kidney, lung, and the intestines (1,(5)(6)(7)(8). In many of these tissues the physiological role of the CaR is not understood. One possibility is that the CaR senses endogenous ligands other than [Ca 2ϩ ] o , thus allowing the CaR to function in a number of specialized capacities in different CaR-expressing tissues.The CaR is activated by both polyvalent cations and polycationic molecules that interact with the extracellular domain of the receptor (1, 9). This might take place through the screening of charged side chains of acidic or basic amino acids, rather than the more classical binding through hydrogen bonding and salt bridges. If its endogenous agonists act by screening charges on the CaR, then activation of the receptor by these ligands should be modulated by conditions such as changes in ionic strength (10). With the addition of salts, the ionic strength will increase and the ability of the polycationic ligand to activate the CaR should be diminished. Likewise, the removal of salts and the resultant decrease in ionic strength should have the opposite effect. These effects of ionic strength can be explained by changes in the Debye length of the electrical field surrounding the charged agonist. The Debye length is inversely proportional to the square root of the ionic strength of the extracellular solution. For example, addition of NaCl would increase the ionic strength of the solution and should increase the concentration of [Ca 2ϩ ] o required for half-maximal activation of the CaR. Interestingly, the N-methyl-D-aspartate receptor shares some regions of homology with the CaR, and both receptors can be modulated by divalent cations, spermine and polycationic molecules such as neomycin (11)(12)(13)(14). Furthermore, modulation of the N-methyl-D-aspartate receptor by spermine and pH are susceptible to ionic strength, suggesting that they may also act through charge screening (10).Ionic strength can have substantial effects on a number of different cell types, particularly those involved in the regulation of fluid volume, osmolality and extracellular sodium. The subfornical organ and hypothalamus regulate the secretion of vasopressin by sensing the systemic levels of various hormones, including angiotensin II, and the level of NaCl (15-17). Early studies using injections of NaCl into these regions of the brain suggested that there existed a sodium sensor, since NaCl injections were much more effective in the control of vasopressin an...

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“…The increases in [Ca'+]i elicited by extracellular Ca" arise from the mobilization of intracellular Ca*+ and the influx of extracellular Ca*' and, since first demonstrated, have been suggested to result from the ability of extracellular Ca*+ to activate a cell surface Ca2+ receptor [2]. The mobilization of intracellular Ca*' in parathyroid cells can be evoked by a variety of extracellular di-and trivalent cations [3,4] and by certain organic polycations [5,6]. Biochemical studies show that these extracellular polycations cause the rapid formation of inositol 1,4,5-trisphosphate and diacylglycerol in parathyroid cells consistent with receptor-dependent mobilization of intracellular Ca*' .…”

Section: Introductionmentioning

confidence: 99%

Functional expression of the parathyroid cell calcium receptor in Xenopus oocytes

Racke¹,

Hammerland²,

Dubyak³

et al. 1993

FEBS Letters

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Various studies suggest the existence of a plasma membrane receptor on parathyroid cells that senses changes in the concentration of extracellular Ca". To test this hypothesis, Xenopus leavis oocytes were injected with poly(A)'-enriched mRNA from bovine parathyroid cells and examined for their ability to respond to increases in the concentration of extracellular Ca" or other polycations. Cytosolic Ca*' concentrations were measured indirectly by recording Cl-currents through the endogenous, cytosolic Ca2'-activated Cl-channel. Increasing the concentration of extracellular Ca*' (from 0.7 to 5 mM) or MgZ' (from 0.8 to 10 mM) elicited oscillatory increases in the Cl-current. Responses to either divalent cation were not observed in oocytes injected with water or with mRNA prepared from HL-60 cells or rat liver. Responses elicited by extracellular Mg2+ persisted when extracellular Ca" was reduced to low micromolar levels. La", Gd3+, or neomycin B also evoked oscillatory increases in the Cl-current in oocytes under conditions of low extracellular Ca*' levels. These extracellular polycations all cause the mobilization of intracellular Ca*' in oocytes injected with parathyroid cell mRNA like they do in intact parathyroid cells. The injection of parathyroid cell mRNA thus confers on oocytes the ability to detect and respond to changes in the concentration of extracellular polycations. The data provide compelling evidence for the existence of a cell surface Ca*' receptor protein(s) on parathyroid cells that regulates cellular function.

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A Comparison of the Effects of Divalent and Trivalent Cations on Parathyroid Hormone Release, 3′,5′-Cyclic-Adenosine Monophosphate Accumulation, and the Levels of Inositol Phosphates in Bovine Parathyroid Cells

Cited by 94 publications

References 15 publications

Calcimimetics with potent and selective activity on the parathyroid calcium receptor

Calcimimetics with potent and selective activity on the parathyroid calcium receptor

Sodium and Ionic Strength Sensing by the Calcium Receptor

Functional expression of the parathyroid cell calcium receptor in Xenopus oocytes

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