Heparin‐insensitive calcium release from intracellular stores triggered by the recombinant human parathyroid hormone receptor

1 In the present study we have characterized the parathyroid hormone (PTH)‐induced calcium signalling in 293 cells stably transfected with the human PTH receptor cDNA. In these cells, human PTH‐l(l‐38) strongly stimulates adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) formation (EC50 = 0.39 nM) but fails to activate phosphoinositide (PI) turnover. The latter pathway is strongly activated, however, by carbachol (CCh) acting through endogenous M3‐muscarinic receptors. 2 Despite the lack of detectable inositol phosphate (IP) formation, hPTH‐(l‐38) elicited calcium transients (EC50 =11.2 nM) which were comparable to the signals evoked by CCh. These signals are independent of cyclic AMP generation as cyclic AMP elevating agents did not mimic or modify the PTH response. 3 The PTH‐stimulated calcium signal still occurred in calcium‐free medium but was absent in cells pretreated with thapsigargin, an inhibitor of the calcium pump of the endoplasmic reticulum (ER). hPTH‐(l‐38) did not accelerate Mn2+‐influx through the plasma membrane. These data indicate that PTH releases calcium from intracellular stores. 4 Using heparin, an inhibitor of the IP3‐activated calcium release channel of the ER, we tested whether the formation of a low amount of IP3, escaping detection by our biochemical assay, might be the origin of the PTH‐induced calcium response. However, intracellular infusion of heparin through patch pipettes in voltage clamp experiments failed to block hPTH‐(l‐38)‐induced calcium signals, whereas it abolished the CCh response. 5 The PTH response, like the CCh response, was insensitive to micromolar concentrations of ryanodine and ruthenium red, eliminating the possibility that hPTH‐(l‐38) stimulates calcium‐induced calcium release through ryanodine receptors. 6 We conclude that the recombinant human PTH receptor stimulates calcium release from intracellular stores through a novel pathway not involving IP3‐ or ryanodine receptors.

[1]  L. Avioli,et al.  Activation of the Ca2+ message system by parathyroid hormone is dependent on the cell cycle. , 1995, Mineral and electrolyte metabolism.

[2]  H. Boddeke,et al.  The amyloid precursor protein fragment his 657-lys 676 inhibits noradrenaline- and enkephaline-induced suppression of voltage sensitive calcium currents in ng108-15 hybrid cells , 1994, Neuroscience.

[3]  K. Seuwen,et al.  A C‐terminally truncated human parathyroid hormone receptor is functional and activates multiple G proteins , 1994, FEBS letters.

[4]  B. Lanske,et al.  The rat, mouse and human genes encoding the receptor for parathyroid hormone and parathyroid hormone-related peptide are highly homologous. , 1994, Biochemical and biophysical research communications.

[5]  L. Mosekilde,et al.  The effect on vertebral bone mass and strength of long term treatment with antiresorptive agents (estrogen and calcitonin), human parathyroid hormone-(1-38), and combination therapy, assessed in aged ovariectomized rats. , 1994, Endocrinology.

[6]  S. Jones,et al.  Bromophenacyl bromide binding to the actin-bundling protein l-plastin inhibits inositol trisphosphate-independent increase in Ca2+ in human neutrophils. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S. Spiegel,et al.  Sphingosine-1-phosphate, a putative second messenger, mobilizes calcium from internal stores via an inositol trisphosphate-independent pathway. , 1994, The Journal of biological chemistry.

[8]  A. Galione.  Cyclic ADP-ribose, the ADP-ribosyl cyclase pathway and calcium signalling , 1994, Molecular and Cellular Endocrinology.

[9]  R. Lindsay,et al.  Anabolic actions of parathyroid hormone on bone. , 1993, Endocrine reviews.

[10]  D. Ypey,et al.  Heterogeneity of intracellular calcium responses to parathyroid hormone and thrombin in primary osteoblast-like cells and UMR106-01 cells: correlations with culture conditions, intracellular calcium concentration and differentiation state. , 1993, Cell calcium.

[11]  J. Putney,et al.  Sulfhydryl reagents and cAMP-dependent kinase increase the sensitivity of the inositol 1,4,5-trisphosphate receptor in hepatocytes. , 1993, The Journal of biological chemistry.

[12]  H. Jüppner,et al.  Parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acids are widely distributed in rat tissues. , 1993, Endocrinology.

[13]  K. Seuwen,et al.  Cloning and functional expression of a human parathyroid hormone receptor. , 1993, European journal of pharmacology.

[14]  K. Campbell,et al.  The ryanodine receptor/Ca2+ release channel. , 1993, The Journal of biological chemistry.

[15]  A. Chu,et al.  Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca2+ channel , 1993, Nature.

[16]  H. Kronenberg,et al.  Cloned, stably expressed parathyroid hormone (PTH)/PTH-related peptide receptors activate multiple messenger signals and biological responses in LLC-PK1 kidney cells. , 1993, Endocrinology.

[17]  H. Jüppner,et al.  Identical complementary deoxyribonucleic acids encode a human renal and bone parathyroid hormone (PTH)/PTH-related peptide receptor. , 1993, Endocrinology.

[18]  P. Vigne,et al.  ADP induces inositol phosphate-independent intracellular Ca2+ mobilization in brain capillary endothelial cells. , 1993, The Journal of biological chemistry.

[19]  G. Matthews,et al.  Ca2+ and Mn2+ influx through receptor-mediated activation of nonspecific cation channels in mast cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Massry,et al.  Parathyroid hormone raises cytosolic calcium in pancreatic islets: study on mechanisms. , 1993, Kidney international.

[21]  F. Gesek,et al.  Calcium transport in renal epithelial cells. , 1993, The American journal of physiology.

[22]  Hon Cheung Lee,et al.  Potentiation of calcium- and caffeine-induced calcium release by cyclic ADP-ribose. , 1993, The Journal of biological chemistry.

[23]  S. Massry,et al.  Parathyroid hormone increases cytosolic calcium of thymocytes. , 1993, Nephron.

[24]  G. Vassaux,et al.  Prostacyclin is a specific effector of adipose cell differentiation. Its dual role as a cAMP- and Ca(2+)-elevating agent. , 1992, The Journal of biological chemistry.

[25]  W. Rascher,et al.  NPY-stimulated Ca2+ mobilization in SK-N-MC cells is enhanced after isoproterenol treatment. , 1992, The American journal of physiology.

[26]  A. Fujimori,et al.  Heterogeneous intracellular free calcium responses to parathyroid hormone correlate with morphology and receptor distribution in osteogenic sarcoma cells. , 1992, Endocrinology.

[27]  M. Freeman,et al.  Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Lodish,et al.  A recombinant calcitonin receptor independently stimulates 3',5'-cyclic adenosine monophosphate and Ca2+/inositol phosphate signaling pathways. , 1992, Molecular endocrinology.

[29]  A. Fujimori,et al.  Structure-function relationship of parathyroid hormone: activation of phospholipase-C, protein kinase-A and -C in osteosarcoma cells. , 1992, Endocrinology.

[30]  J. Lytton,et al.  Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. , 1991, The Journal of biological chemistry.

[31]  R. Johnson,et al.  Thrombin and parathyroid hormone mobilize intracellular calcium in rat osteosarcoma cells by distinct pathways. , 1991, Endocrinology.

[32]  P. A. Friedman,et al.  Activation of latent Ca2+ channels in renal epithelial cells by parathyroid hormone , 1990, Nature.

[33]  C. Filburn,et al.  Parathyroid hormone 1-34, but not 3-34 or 7-34, transiently translocates protein kinase C in cultured renal (OK) cells. , 1989, Biochemical and biophysical research communications.

[34]  A. Abou-Samra,et al.  Parathyroid hormone causes translocation of protein kinase-C from cytosol to membranes in rat osteosarcoma cells. , 1989, Endocrinology.

[35]  T. Hallam,et al.  Use of manganese to discriminate between calcium influx and mobilization from internal stores in stimulated human neutrophils. , 1989, The Journal of biological chemistry.

[36]  J. Mullaney,et al.  Competitive, reversible, and potent antagonism of inositol 1,4,5-trisphosphate-activated calcium release by heparin. , 1988, Journal of Biological Chemistry.

[37]  J. Pouysségur,et al.  Deregulation of hamster fibroblast proliferation by mutated ras oncogenes is not mediated by constitutive activation of phosphoinositide‐specific phospholipase C. , 1988, The EMBO journal.

[38]  I. Reid,et al.  Parathyroid hormone acutely elevates intracellular calcium in osteoblastlike cells. , 1987, The American journal of physiology.

[39]  S. Muallem,et al.  Parathyroid hormone-activated calcium channels in an osteoblast-like clonal osteosarcoma cell line. cAMP-dependent and cAMP-independent calcium channels. , 1987, The Journal of biological chemistry.

[40]  J. V. van Leeuwen,et al.  A two-receptor model for the action of parathyroid hormone on osteoblasts: a role for intracellular free calcium and cAMP. , 1985, Cell calcium.

[41]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[42]  J. Heersche,et al.  Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. , 1982, Endocrinology.

[43]  Y. Salomon.  Adenylate cyclase assay. , 1979, Advances in cyclic nucleotide research.