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Calcium Receptor-mediated Signaling

  • Chapter
Calcium-Sensing Receptor

Part of the book series: Endocrine updates ((ENDO,volume 19))

  • 139 Accesses

Abstract

Signal transduction from the calcium-sensing receptor (CaR) has the potential to exhibit any or all of the complexities demonstrated for other G-protein coupled receptors (GPCR). Biological responses associated with activation of the CaR include regulation of hormone secretion, activation of ion channels, migration, proliferation, differentiation, and apoptosis. The mechanisms linking other G-protein coupled receptors to these diverse responses are complex and multi-layered, with numerous opportunities for cross-talk between pathways. Furthermore, the predominant biological response to activation of the CaR is highly cell-type specific, implying that presence or absence of specific signaling intermediaries may have a profound effect on the outcome.

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References

  1. Chen C, Barnett J, Congo D, Brown E 1989 Divalent cations suppress 3′, 5′-adenosine monophosphate accumulation by stimulating a pertussis toxin-sensitive guanine nucleotide-binding protein in cultured bovine parathyroid cells. Endocrinology 124:233–239

    Article  PubMed  CAS  Google Scholar 

  2. Varrault A, Pena MS, Goldsmith PK, Mithai A, Brown EM 1995 Expression of G protein alpha-subunits in bovine parathyroid. Endocrinology 136:4390–4396

    Article  PubMed  CAS  Google Scholar 

  3. Arthur JM, Collinsworth GP, Gettys TW, Quartes LD, Raymond JR 1997 Specific coupling of a cation-sensing receptor to G protein alpha subunits in MDCK cells. Am J Physiol 273:F129–135

    PubMed  CAS  Google Scholar 

  4. Hawkins D, Enyedi P, Brown EM 1989 The effects of high extracellular Ca2+ and Mg2+ concentrations on the levels of inositol 1,3,4,5-tetrakisphosphate in bovine parathyroid cells. Endocrinology 124:838–844

    Article  PubMed  CAS  Google Scholar 

  5. McNeil SE, Hobson SA, Nipper V, Rodland KD 1998 Functional calcium sensing receptors in rat fibroblasts are required for activation of Src kinase and MAP kinase in response to extracellular calcium. J Biol Chem 273:1114–1120

    Article  PubMed  CAS  Google Scholar 

  6. Emanuel R, Adler G, Kifor O, Brown E 1996 Calcium-sensing receptor expression and regulation by extracellular calcium in the AtT-20 pituitary cell line. Mol Endocrinol 10:555–65

    Article  PubMed  CAS  Google Scholar 

  7. Brown E, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger M, Lytton J, Hebert S 1993 Cloning, expression, and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 366:575–580

    Article  PubMed  CAS  Google Scholar 

  8. Chang W, Chen TH, Pratt S, Shoback D 2000 Amino acids in the second and third intracellular loops of the parathyroid Ca2+-sensing receptor mediate efficient coupling to phospholipase C. J Biol Chem 275:19955–19963

    Article  PubMed  CAS  Google Scholar 

  9. Berridge MJ 1987 Inositol trisphosphate and diacylglycerol: two interacting second messengers. Ann Rev Biochem 56:159–193

    Article  PubMed  CAS  Google Scholar 

  10. Nishizuka Y 1992 Intracellular Signaling by Hydrolysis of Phospholipids and Activation of Protein Kinase C Nature 258: 607–613.

    CAS  Google Scholar 

  11. Berridge M 1993 Inositol trisphosphate and calcium signaling. Nature 361:315–325

    Article  PubMed  CAS  Google Scholar 

  12. Ferris CD, Huganir RL, Supattapone S, Snyder SH 1989 Purified inositol 1,4,5-trisphosphate receptor mediates calcium flux in reconstituted lipid vesicles. Nature 342:87–89

    Article  PubMed  CAS  Google Scholar 

  13. Bai M, Quinn S, Trivedi S, Kifor O, Pearce SHS, Pollak MR, Krapcho K, Hebert SC, Brown EM 1996 Expression and characterization of inactiviating and activating mutations in the human Ca2+-sensing receptor. J Biol Chem 271:19537–19545

    Article  PubMed  CAS  Google Scholar 

  14. Huang K-P 1989 The mechanism of protein kinase C activation. Trends Neurosci 12:425–432

    Article  PubMed  CAS  Google Scholar 

  15. May WS, Sahyoun N, Wolf M, Cuatrecasas P 1985 Role of intracellular calcium mobilization in the regulation of protein kinase C-mediated membrane processes. Nature 317:549–551

    Article  PubMed  CAS  Google Scholar 

  16. Kifor O, Diaz R, Butters R, Brown E 1997 The Ca2+-sensing receptor (CaR) activates phospholipases C, A2, and D in bovine parathyroid and CaR-transfected, human embryonic kidney (HEK293) cells. J Bone Miner Res 12:715–725

    Article  PubMed  CAS  Google Scholar 

  17. Kifor O, MacLeod RJ, Diaz R, Bai M, Yamaguchi T, Yao T, Kifor I, Brown EM 2001 Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and CaR-transfected HEK293 cells. Am J Physiol Renal Physiol 280:F291–F302

    PubMed  CAS  Google Scholar 

  18. Morris AJ 1999 One wheel on my wagon: lysolipid phosphate signaling. Trends Pharmacol 20:393–395

    Article  CAS  Google Scholar 

  19. Luttrell L, van Biesen T, Hawes B, Koch W, Touhara K, Lefkowitz R 1995 Gβγ subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor. J Biol Chem 270:16495–16498

    Article  PubMed  CAS  Google Scholar 

  20. Luttrell L, Delia Rocca G, van Biesen T, Luttrell D, Lefkowitz R 1997 Gbetagamma subunits mediate Src-dependent phophorylation of the epidermal growth factor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation. J Biol Chem 272:4637–4644.

    Article  PubMed  CAS  Google Scholar 

  21. van Biesen T, Hawes B, Luttrell D, Luttrell L, Lefkowitz R 1995 Receptor-tyrosine-kinase-and Gbg-mediated MAP kinase activation by a common signalling pathway. Nature 376:781–784

    Article  PubMed  Google Scholar 

  22. Hobson SA, McNeil SE, Lee F, Rodland KD 2000 Signal transduction mechanisms linking increased extracellular calcium to proliferation in ovarian surface epithelial cells. Exp Cell Res 258: 1–11

    Article  PubMed  CAS  Google Scholar 

  23. McNeil L, Hobson S, Nipper V, Rodland KD 1998 Functional calcium sensing receptor expression in ovarian surface epithelial cells. Am J Obstet Gyn 178:305–313

    Article  CAS  Google Scholar 

  24. McNeil SE 1997 Signal transduction in Rat-1 fibroblasts in response to extracellular calcium. Ph.D. Dissertation, Oregon Health Sciences University.

    Google Scholar 

  25. Luttrell L, Hawes B, van Biesen T, Luttrell D, Lefkowitz R 1996 Role of c-Src Tyrosine Kinase in G Protein-coupled Receptor and Gbg Subunit-mediated Activation of Mitogen-activated Protein Kinases. J Biol Chem 271:19443–19450

    Article  PubMed  CAS  Google Scholar 

  26. Yano S, Sugimoto T, Tsukamoto T, Chihara K, Kobayashi A, Kitazawa S, Maeda S, Kitazawa R 2000 Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 58:1980–1986

    Article  PubMed  CAS  Google Scholar 

  27. Kallay E, Kifor O, Chattopadhyay N, Brown EM, Bischof MG, Peterlik M, Cross HS 1997 Calcium-dependent c-myc proto-oncogene expression and proliferation of CACO-2 cells: a role for a luminal extracellular calcium-sensing receptor. Biochem Biophys Res Commun 232:80–83

    Article  PubMed  CAS  Google Scholar 

  28. Kallay E, Bajna E, Wrba F, Kriwanek S, Peterlik M, Cross H 2000 Dietary calcium and growth modulation of human colon cancer cells: role of the extracellular calcium-sensing receptor. Cancer Detect Prev 24:127–136

    PubMed  CAS  Google Scholar 

  29. Chattopadhyay N, Ye CP, Yamaguchi T, Kifor O, Vassilev PM, Nishimura R, Brown EM 1998 Extracellular calcium-sensing receptor in rat oligodendrocytes: expression and potential role in regulation of cellular proliferation and an outward K+ channel. Glia 24: 449–458

    Article  PubMed  CAS  Google Scholar 

  30. Chattopadhyay N, Ye CP, Yamguchi T, Kerner R, Vassilev PM, Brown EM 1999 Extracellular calcium-sensing receptor induces cellular proliferation and activation of a nonselective cation channel in U373 human astrocytoma cells. Brain Res 851:116–124

    Article  PubMed  CAS  Google Scholar 

  31. Mailland M, Waelchli R, Ruat M, Boddeke HG, Seuwen K 1997 Stimulation of cell proliferation by calcium and a calimimetic compound. Endocrinology 138:3601–3605

    Article  PubMed  CAS  Google Scholar 

  32. Yamaguchi T, Chattopadhyay N, Kifor O, Sanders JL, Brown EM 2000 Activation of p42/p44 and p38 mitogen-activated protein kinases by extracellular calcium-sensing receptor agonists induces mitogenic responses in the mouse osteoblastic MC3T3-E1 cell line. Biochem Biophys Res Commun 279:363–368

    Article  PubMed  CAS  Google Scholar 

  33. Cobb MH, Goldsmith EJ 1995 How MAP kinases are regulated. J BiolChem 270:14843–14846

    CAS  Google Scholar 

  34. Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R 1997 Linkage of G-protein-coupled receptors to the MRPK signaling pathway through PI 3-kinasey. Science 275:394–397

    Article  PubMed  CAS  Google Scholar 

  35. Vossler MR, Yao H, York RD, Pan M-G, Rim CS, Stork PJS 1997 cAMP activates MAP kinase and Elk-1 through a B-Raf and Rapl-dependent pathway. Cell 89:73–82

    Article  PubMed  CAS  Google Scholar 

  36. Berra E, D’iaz-Meco MT, Lozano J, Frutos S, Municio MM, S’anchez P, Sanz L, Moscat J 1995 Evidence for a role of MEK and MRPK during signal transduction by protein kinase C zeta. EMBO J 14:6157–6163

    PubMed  CAS  Google Scholar 

  37. Arthur JM, Lawrence MS, Payne CR, Rane MJ, McLeish KR 2000 The calcium-sensing receptor stimulates JNK in MDCK cells. Biochem Biophys Res Commun 275:538–541

    Article  PubMed  CAS  Google Scholar 

  38. Quinn SJ, Kifor O, Trivedi S, Diaz R, Vassilev P, Brown EM 1998 Sodium and ionic strength sensing by the calcium receptor. J Biol Chem 273:19579–19586

    Article  PubMed  CAS  Google Scholar 

  39. Murga C, Laguinge L, Wetzker R, Cuadrado A, Gutkind J 1998 Activation of Akt/protein kinase B by G protein-coupled receptors. A role for alpha and beta gamma subunits of heterotrimeric G proteins acting through phosphatidylinositol-3-OH kinase gamma. J Biol Chem 273:19080–19085

    Article  PubMed  CAS  Google Scholar 

  40. Zimmerman S, Moelling K 1999 Phosphorylation and regulation of Raf by Akt (Protein Kinase B). Science 286:1741–1744

    Article  Google Scholar 

  41. Hobson SA, Passavant C, Rodland KD 1999 Involvement of phosphatidyl inositol 3 kinase and MAP kinases in the proliferative rsponse of human ovarian surface epithelial cells to extracellular calcium. Am Assoc Cancer Res Proceedings 40: Abstract #2205

    Google Scholar 

  42. Lin K-I, Chattopadhyay N, Bai M, Alvarez R, Dang C, Baraban J, Brown E, Ratan R 1998 Elevated extracellular calcium can prevent apoptosis via the Calcium-Sensing Receptor. Biochem Biophys Res Commun 249:325–331

    Article  PubMed  CAS  Google Scholar 

  43. Brown EM 1991 Extracellular Ca2+-sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 71:371–411

    PubMed  CAS  Google Scholar 

  44. Chang W, Pratt S, Chen TH, Nemeth E, Huang Z, Shoback D 1998 Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor proein by region-specific antipeptide antisera. J Bone Miner Res 13:570–580

    Article  PubMed  CAS  Google Scholar 

  45. Chattopadhyay N, Evilyaoglu C, Heese O, Carroll R, Sanders J, Black P, Brown EM 2000 Regulation of secretion of PTHrP by Ca2+-sensing receptor in human astrocytes, astrocytomas, and meningiomas. Am J Physiol Cell Physiol 279:C691–C699

    PubMed  CAS  Google Scholar 

  46. Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Butters R, Brown EM 2000 Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human breast cancer cell lines. Endocrinology 141:4357–4364

    Article  PubMed  CAS  Google Scholar 

  47. Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Brown EM 2000 Extracellular calcium-sensing receptor (CaR) expression and its potential role inparathyroid hormone-related peptide (PTHrP) secretion in the H-500 rat Leydig cell model of humoral hypercalcemia or malignancy. Biochem Biophys Res Commun 269:427–432

    Article  PubMed  CAS  Google Scholar 

  48. Squires PE, Harris TE, Persaud SJ, Curtis SB, Buchan AM, Jones PM 2000 The extracellular calcium-sensing receptor on human beta cells negatively modulates insulin secretion. Diabetes 49:409–417

    Article  PubMed  CAS  Google Scholar 

  49. Malaisse WJ, Louchani K, Laghmich A, Ladriere L, Morales M, Villanueva-Penacarrillo ML, Vlaverde I, Rasschaert J 1999 Possible participation of an islet B-cell calcium-sensing receptor in insulin release. Endocrine 11:293–300

    Article  PubMed  CAS  Google Scholar 

  50. Chattopadhyay N, Ye CP, Yamaguchi T, Vassilev PM, Brown EM 1999 Evidence for extracellular calcium-sensing receptor mediated opening of an outward K+ channel in human astrocytoma cell line (U87). Glia 26:64–72

    Article  PubMed  CAS  Google Scholar 

  51. Ye C, Kanazirska M, Quinn S, Brown EM, Vassilev PM 1996 Modulation by polycationic Ca2+-sensing receptor agonists of nonselective cation channels in rat hippocampal neurons. Biochem Bophys Res Commun 224:271–280

    Article  CAS  Google Scholar 

  52. Bai M, Travedi S, Lane CR, Yang Y, J QS, Brown EM 1998 Protein kinase C phosphorylation of threonine at position 888 in in Ca2+ o-sensing receptor (CaR) inhibits coupling to Ca2+ store release. J Biol Chem 273: 21267–21275

    Article  PubMed  CAS  Google Scholar 

  53. Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S 1996 Changes in calcium responsiveness and handling during keratinocyte differentiation. J Clin Invest 97:1085–1093

    Article  PubMed  CAS  Google Scholar 

  54. Chattopadhyay N, Cheng I, Rogers K, Riccardi D, Hall A, Diaz R, Hebert S, Soybel D, Brown E 1998 Identification and localization of extracellular Ca2+-sensing receptor in rat intestine. Am J Physiol 274: G122–130

    PubMed  CAS  Google Scholar 

  55. Gama L, Baxendale-Cox LM, Breitweisser GE 1997 Ca2+-sensing receptors in intestinal epithelium. Am J Physiol 273:0168–0175.

    Google Scholar 

  56. Godwin SL, Soltoff SP 1997 Extracellular calcium and platelet-derived growth factor promote receptor-mediated Chemotaxis in osteoblasts through different signaling pathways. J Biol Chem 272:11307–11312

    Article  PubMed  CAS  Google Scholar 

  57. Hoff AO, Cote GJ, Fritsche HAJ, Qiu H, Schultz PN, Gagel RF 1999 Calcium-induced activation of a mutant G protein-coupled receptor causes in vitro transformation of NIH 3T3 cells. Neoplasia 1:485–491

    Article  PubMed  CAS  Google Scholar 

  58. Yamaguchi T, Ye C, Chattopadhyay N, Sanders JL, Vassilev PM, Brown EM 2000 Enhanced expression of extracellular calcium sensing receptor in monocyte-differentiated versus undifferentiated HL-60 cells: potential role regulation of a non-selective cation channel. Calcif Tissue Int 66:375–382

    Article  PubMed  CAS  Google Scholar 

  59. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME 1995 Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331

    Article  PubMed  CAS  Google Scholar 

  60. Marshall C 1995 Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185

    Article  PubMed  CAS  Google Scholar 

  61. Teng KK, Lander H, Fajardo JE, Hanafusa H, Hempstead BL, Birge B 1995 v-Crk modulation of growth factor-induced PC 12 cell differentiation involves the src homology2 domain of v-crk and sustained activation of the ras/mitogen-activated protein kinase pathway. J Biol Chem 270:20677–20685

    Article  PubMed  CAS  Google Scholar 

  62. Cook SJ, McCormick F 1996 Kinetic and biochemical correlation between sustained p44ERKl (44 kDa extracellular signal-regulated kinase 1) activation and lysophosphatidic acid-stimulated DNA synthesis in Rat-1 cells. Biochem J 320:237–245

    PubMed  CAS  Google Scholar 

  63. Tu CL, Oda Y, Bikle DD 1999 Effects of a calcium receptor activator on the cellular response to calcium in human keratinocytes. J Invest Dermatol 113:340–345

    Article  PubMed  CAS  Google Scholar 

  64. Oda Y, Tu CL, Chang W, Crumrine D, Kumuves L, Mauro T, Elias PM, Bikle DD 2000 The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation. J Biol Chem 275: 1183–1190

    Article  PubMed  CAS  Google Scholar 

  65. Wang WH, Lu M, Balazy M, Hebert SC 1997 Phospholipase A2 is involved in mediating the effects of extracellular Ca2+ on apical K+ channels in rat TAL. Am J Physiol Renal Physiol 273:C103–C111

    Google Scholar 

  66. Wakita H, Furukawa F, Bab S, Takigawa M 1997 Human squamouscell-carcinoma cell line (DJM-1) cells synthesize P-cadherin molecules via an elevation of extracellular calcium: calcium regulates P-cadherin gene expression at the translational level via protein tyrosine phophorylation. Int J Cancer 73:432–439

    Article  PubMed  CAS  Google Scholar 

  67. Zhao Y, Sudol M, Hanafus H, Krueger J 1992 Increased tyrosine kinase activity of c-Src during calcium-induced keratinocyte differentiation. Proc Natl Acad Sci USA 89:8298–8302

    Article  PubMed  CAS  Google Scholar 

  68. Calautti E, Missero C, Stein PL, Ezzell RM, Dotto GP 1995 fyn tyrosine kinase is involved in keratinocyte differentiation control. Genes & Devel 9:2279–2291

    Article  CAS  Google Scholar 

  69. Filvaroff E, Stern D, Dotto P 1990 Tyrosine Phosphorylation is an Early and Specific Event Involved in Primary Keratinocyte Differentiation. Mol Cell Biol 10:1164–1173

    PubMed  CAS  Google Scholar 

  70. Filvaroff E, Calautti E, Reiss M, Dotto GP 1994 Functional evidence for an extracellular calcium receptor mechanism triggering tyrosine kinase activation associated with mouse keratinocyte differentiation. J Biol Chem 269:21735–21740

    PubMed  CAS  Google Scholar 

  71. Hofer AM, Curei S, Doble MA, Brown EM, Soybel DI 2000 Intercellular communication mediated by the extracellular calcium-sensing receptor. Nat Cell Biol 2:E126–E127

    Article  Google Scholar 

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Authors and Affiliations

  1. Pacific Northwest National Laboratory P7-56, Battelle for the US DOE, Richland, WA, 99352, USA

    Karin D. Rodland Ph.D.

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  1. Karin D. Rodland Ph.D.
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Editors and Affiliations

  1. Endocrine-Hypertension Division Department of Medicine, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts, USA

    Naibedya Chattopadhyay  & Edward M. Brown  & 

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Rodland, K.D. (2003). Calcium Receptor-mediated Signaling. In: Chattopadhyay, N., Brown, E.M. (eds) Calcium-Sensing Receptor. Endocrine updates, vol 19. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9256-7_3

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  • DOI: https://doi.org/10.1007/978-1-4419-9256-7_3

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4861-0

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