Vitamin D pp 195-205 | Cite as

Nongenomic Rapid Effects of Vitamin D

  • Daniel T. Baran
Part of the Nutrition and Health book series (NH)


1α,25-Dihydroxyvitamin D3 [lα,25(OH)2D3] is the most potent vitamin D metabolite. The mechanism(s) by which the hormone alters cell growth and differentiation is largely unknown. Specific nuclear vitamin D receptors (nVDRs) for this secosteroid have been found in numerous organs and cell lines (1). The binding of 1α,25(OH)2D3 to the nVDR and subsequent binding of the hormone-receptor complex to selected DNA sequences were thought to be the mechanisms explaining all the hormone’s actions.


Rapid Action Rapid Effect Nongenomic Action Nongenomic Effect Pregnenolone Sulfate 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Minghetti PP, Norman AW. 1α,25-(OH)2D3 Vitamin D3 receptors: Gene regulation and genetic circuitry. FASEB J 1988; 2: 3043–3053.Google Scholar
  2. 2.
    Evans RM. The steroid and thyroid hormone receptor superfamily Science 1988; 240: 889–895.Google Scholar
  3. 3.
    Haussier MR, Mangeldorf DJ, Komm BS, Terpening CM, Yamaoka K, Allegretto EA, Baker AR, Shine J, McDonnel DP, Hughes M, Weigel NL, O’Malley BW, Pike JW. Molecular biology of the vitamin D hormone. Rec Prog Horm Res 1988; 44: 263–305.Google Scholar
  4. 4.
    Barsony J, Pike JW, DeLuca HF, Marx SJ Immunocytology with microwave fixed fibroblasts show lα,25-dihydroxyvitamin D3-dependent rapid and estrogen-dependent slow reorganization of vitamin D receptors. J Cell Biol 1990; 111:28, 355–28, 395.Google Scholar
  5. 5.
    Barsony J, McKoy W. Molybdate increases intracellular 3’, 5’-guanosine cyclic monophosphate and stabilizes vitamin D receptor association with tubulin-containing filaments. J Biol Chem 1992; 267: 24, 457–465.Google Scholar
  6. 6.
    Hsieh JC, Jurutka PW, Nakajima S, Galligan MA, Haussler CA, Shimizu Y, Shimizu N, Whitfield GK, Haussier MR. Phosphorylation of the human vitamin D receptor by protein kinase C: biochemical and functional evaluation of the serine 51 recognition site. J Biol Chem 1993; 268:15, 118–15, 126.Google Scholar
  7. 7.
    Jurutka PW, Hsieh JC, MacDonald PW, Terpening CM, Haussier CA, Haussler MR, Whitfield GK. Phosphorylation of serine 208 in the human vitamin D receptor: the predominant amino acid phosphorylated by casein kinase II in vitro, and identification as a significant phosphorylation site. J Biol Chem 1993; 268: 6791–6799.PubMedGoogle Scholar
  8. 8.
    Jurutka PW, Hsieh JC, Haussier MR. Phosphorylation of the human 1,25-dihydroxyvitamin D3 receptor by cAMP dependent protein kinase in vitro and in transfected COS-7 cells. Biochem Biophys Res Commun 1993; 191: 1089–1096.PubMedCrossRefGoogle Scholar
  9. 9.
    Haussier MR, Jurutka PW, Hsieh JC, Thompson PD, Seiznick SH, Haussier CA, Whitfield GK. Receptor mediated genomic actions of 1,25-(OH)2D3: modulation by phosphorylation. In: Proceedings of the Ninth Workshop on Vitamin D, Orlando, FL, May 28—June 2, 1994, pp. 209–216.Google Scholar
  10. 10.
    Baran DT, Sorensen AM. Rapid actions of la,25-dihydroxyvitamin D: physiologic role. Proc Soc Exp Biol Med 1994; 207: 175–179.PubMedGoogle Scholar
  11. 11.
    Lieberherr M. Effects of vitamin D3 metabolites on cytosolic free calcium in confluent mouse osteoblasts. J. Biol Chem 1987; 262:13, 168–13, 173.Google Scholar
  12. 12.
    Civitelli R, Kim YS, Gunsten SL, Fugimori A, Huskey M, Avioli LV, Hruska KA. Nongenomic activation of the calcium message system by vitamin D metabolites in osteoblast-like cells. Endocrinology 1990; 127: 2253–2262.PubMedCrossRefGoogle Scholar
  13. 13.
    Nemere I, Yoshimoto Y, Norman AW. Calcium transport in perfused duodena from normal chicks: enhancement within fourteen minutes of exposure to 1,25-dihydroxyvitamin D3. Endocrinology 1984; 115: 1476–1483.PubMedCrossRefGoogle Scholar
  14. 14.
    Suzuki M, Kurihara S, Kawaguchi Y, Sakai O. Vitamin D3 metabolites increase [Ca2+]i in rabbit renal proximal straight tubule cells. Am J Physiol 1991; 260: F757 - F763.PubMedGoogle Scholar
  15. 15.
    Boudreau A, Atmani F, Grosse B, Lieberherr M. Rapid effects of 1,25-dihydroxyvitamin D3 and extracellular Cat+ on phospholipid metabolism in dispersed porcine parathyroid cells. Endocrinology 1990; 127: 2738–2743.CrossRefGoogle Scholar
  16. 16.
    Desai SS, Appel MC, Baran DT. Differential effects of 1,25- dihydroxyvitamin D3 on cytosolic calcium in two human cell lines (HL-60 and U-937). J Bone Miner Res 1986; 1: 497–501.PubMedCrossRefGoogle Scholar
  17. 17.
    Selles J, Boland R. Evidence on the participation of the 3’, 5’-cyclic AMP pathway in the nongenomic action of 1,25-dihydroxyvitamin D3 in cardiac muscle. Mol Cell Endocrinol 1991; 82: 229–235.PubMedCrossRefGoogle Scholar
  18. 18.
    Schwartz Z, Schlader DL, Swain LD, Boyan BD. Direct effects of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 on growth zone and resting zone chondrocyte membrane alkaline phosphatase and phospholipase A2 specific activities. Endocrinology 1988; 123: 2878–2884.PubMedCrossRefGoogle Scholar
  19. 19.
    Barsony J, Marx SJ. Receptor mediated rapid action of la,25-dihydroxycholecalciferol: increase of intracellular cGMP in human skin fibroblasts. Proc Natl Acad Sci USA 1988; 85: 1223–1226.PubMedCrossRefGoogle Scholar
  20. 20.
    Baran DT, Milne ML. 1,25-Dihydroxyvitamin D3 increases hepatocyte cytosolic calcium levels: a potential regulator of vitamin D-25-hydroxylase. J Clin Invest 1986; 77: 1622–1626.PubMedCrossRefGoogle Scholar
  21. 21.
    Smith EL, Holick MF. The skin: the site of vitamin D3 synthesis and a target tissue for its metabolite 1,25-dihydroxyvitamin D3. Steroids 1987; 49: 103–131.PubMedCrossRefGoogle Scholar
  22. 22.
    Segrev IN, Rhoten WB. Video imaging of intracellular calcium in insulinoma cells: effects of 1,25(OH)2D3. In: Proceedings of the Ninth Workshop on Vitamin D, Orlando, FL, May 28-June 2, 1994, pp. 355–356.Google Scholar
  23. 23.
    Walters MR. Newly identified actions of the vitamin D endocrine system. Endocr Rev 1992; 13: 719–764.PubMedGoogle Scholar
  24. 24.
    Duval D, Durant S, Homo-DeLarch F. Nongenomic effects of steroids: interactions of steroid molecules with membrane structures and functions. Biochim Biophys Acta 1983; 737: 409–442.PubMedCrossRefGoogle Scholar
  25. 25.
    Aronica SM, Kraus WL, Katzenellenbogen BS. Estrogen action via the cAMP signalling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 1994; 91: 8517–8521.PubMedCrossRefGoogle Scholar
  26. 26.
    Lieberherr M, Grosse B. Androgens increase intracellular calcium concentration and inositol 1,4,5-triphosphate and diacylglycerol formation via a pertussis-sensitive G protein. J Biol Chem 1994; 269: 7217–7223.PubMedGoogle Scholar
  27. 27.
    Wehling M, Ulsenheimer A, Schneider M, Neylon C, Christ M. Rapid effects of aldosterone on free intracellular calcium in vascular smooth muscle and endothelial cells: cellular localization of calcium elevation by single cell imaging. Biochem Biophys Res Commun 1994; 204: 475–441.PubMedCrossRefGoogle Scholar
  28. 28.
    Blackmore PF, Neulen J, Lattanzio F, Beebe SJ. Cell surface binding sites for progesterone mediate calcium uptake in human sperm. J Biol Chem 1991; 266:18, 655–18, 659.Google Scholar
  29. 29.
    Wehling M. Nongenomic actions of steroid hormones. Trends Endocr Metab 1994; 5: 347–353.CrossRefGoogle Scholar
  30. 30.
    Lieberherr M, Grosse B, Tassin M-T, Kachkache M, Bourdeau A. Transmembrane signal pathways induced by calcitriol, estradiol testosterone, and progesterone in osteoblasts. In: Proceedings of the Ninth Workshop on Vitamin D, Orlando, FL, May 28-June 2, 1994, pp. 315–323.Google Scholar
  31. 31.
    Kim YS, Birge SJ, Avioli LV, Miller R. Early manifestations of vitamin D effects in rat osteogenic sarcoma cells. Calcif Tissue Int 1987; 41: 223–227.PubMedCrossRefGoogle Scholar
  32. 32.
    Oshima J, Watanabe M, Hirosumi J, Orimo H. la,25-(OH)2D3 increases cytosolic Ca++concentration of osteoblastic cells, clone MC3T3-El. Biochem Biophys Res Commun 1987; 145: 956–960.PubMedCrossRefGoogle Scholar
  33. 33.
    Caffrey JM, Farach-Carson MC. Vitamin D3 metabolites modulate dihydropyridine-sensitive calcium currents in clonal rat osteosarcoma cells. J Biol Chem 1989; 264:20, 265–20, 274.Google Scholar
  34. 34.
    Yukihiro S, Posner GH, Guggino SE. Vitamin D3 analogs stimulate calcium currents in rat osteosarcoma cells. J Biol Chem 1994; 269:23, 889–23, 893.Google Scholar
  35. 35.
    Sorensen AM, Bowman D, Baran DT. la,25-Dihydroxyvitamin D3 rapidly increases nuclear calcium levels in rat osteosarcoma cell. J Cell Biochem 1993; 52: 237–242.PubMedCrossRefGoogle Scholar
  36. 36.
    Grosse B, Bourdeau A, Lieberherr M. Oscillations in inositol 1,4,5,-triphosphate and diacylglycerol induced by vitamin D3 metabolites in confluent mouse osteoblasts. J Bone Miner Res 1993; 8: 1059–1069.PubMedCrossRefGoogle Scholar
  37. 37.
    Sorensen AM, Baran DT. 1a,25-dihydroxyvitamin D3 rapidly alters phospholipid metabolism in the nuclear envelope of osteoblasts. J Cell Biochem 1995; 58: 15–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Capitani S, Bertagnolo Y, Mazzoni M, Santi P, Previati M, Antonucci A, Manzoli FA. Lipid phosphorylation in isolated rat liver nuclei: synthesis of polyphosphoinositides at subnuclear level. FEBS Lett 1989; 254: 194–198.PubMedCrossRefGoogle Scholar
  39. 39.
    Payrastre B, Nievers M, Boonstra J, Breton M, Verkleij AJ, Van Bergen en Henegouwen PMP. A differential location of phosphoinositide kinases, diacylglycerol kinase, and phospholipase C in the nuclear matrix. J Biol Chem 1992; 267: 5078–5084.PubMedGoogle Scholar
  40. 40.
    York JD, Majerus PW. Nuclear phosphatidylinositols decrease during S-phase of the cell cycle in HeLa cells. J Biol Chem 1994; 269: 7847–7850.PubMedGoogle Scholar
  41. 41.
    Baran DT, Sorensen AM, Shalhoub V, Owen T, Oberdorf A, Stein G, Lian J. 1a,25-dihydroxyvitamin D3 rapidly increases cytosolic calcium in clonal rat osteosarcoma cells lacking the vitamin D receptor. J Bone Miner Res 1991; 6: 1269–1275.PubMedCrossRefGoogle Scholar
  42. 42.
    Holick SA, Holick MF, MacLaughlin JA. Chemical synthesis of [113–3H] la,25-dihydroxyvitamin D3 and [1a-3H] 113,25-dihydroxyvitamin D3: biological activity of 113,25-dihydroxyvitamin D3. Biochem Biophys Res Commun 1980; 97: 1031–1037.PubMedCrossRefGoogle Scholar
  43. 43.
    Farach-Carson MC, Sergeev I, Norman AW. Nongenomic actions of 1,25-dihydroxyvitamin D3 in rat osteosarcoma cells: structure-function studies using ligand analogs. Endocrinology 1991; 129: 1876–1884.PubMedCrossRefGoogle Scholar
  44. 44.
    Norman AW, Okamura WH, Farach-Carson MC, Allewaert K, Branisteanu D, Nemers I, Muralidharan KR, Bouillon R. Structure function studies of 1,25-dihydroxyvitamin D3 and the vitamin D endocrine system. J Biol Chem 1993; 268:13, 811–13, 819.Google Scholar
  45. 45.
    Norman AW, Bouillon R, Farach-Carson MC, Bishop JE, Zhou L- X, Nemere I, Zhao J, Muralidharan KR, Okamura WH Demonstration that 113,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1a,25-dihydroxyvitamin D3. J Biol Chem 1993; 268:20, 022–20, 030.Google Scholar
  46. 46.
    Christ M, Sippel K, Eisen C, Wehling, M. Nonclassical receptors for aldosterone in plasma membranes from pig kidney. J Mol Cell Endocrinol 1994; 99: R31–34.CrossRefGoogle Scholar
  47. 47.
    Orchinik M, Murray TF, Moore FL. A corticosteroid receptor in neuronal membranes. Science 1991; 252: 1848–1851.PubMedCrossRefGoogle Scholar
  48. 48.
    Quelle FW, Smith RV, Hrycyna CA, Kaliban TD, Crooks JA, O’Brien JM. 3H-dexamethasone binding to plasma membrane enriched fractions from liver of nonadrenalectomized rats. Endocrinology 1988; 123: 1642–1651.PubMedCrossRefGoogle Scholar
  49. 49.
    Bression D, Michard M. LeDafniet M, Pagesy P, Peillon F. Evidence for a specific estradiol binding site on rat pituitary membranes. Endocrinology 1986; 119: 1048–1051.PubMedCrossRefGoogle Scholar
  50. 50.
    Pappas TC, Gametchu B, Watso CS. Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J 1995; 9: 404–410.Google Scholar
  51. 51.
    Ke FC, Ramirez VD. Binding of progesterone to nerve cell membranes of rat brain using progesterone conjugated to 125I-bovine serum albumin as a ligand. J Neurochem 1990; 54: 467–472.PubMedCrossRefGoogle Scholar
  52. 52.
    Majewska MD, Demirogoren S, London ED. Binding pregnenolone sulfate to rat brain membranes suggests multiple sites of steroid action at the GABAA receptor. Eur J Pharmacol 1990; 189: 307–315.PubMedCrossRefGoogle Scholar
  53. 53.
    Baran DT, Ray R, Sorensen AM, Honeyman T, Holick MF, Baran DT. Binding characteristics of a membrane receptor that recognizes 1a,25-dihydroxyvitamin D3 and its epimer, 113,25-dihydroxyvitamin D3. J Cell Biochem 1994; 56: 510–517.PubMedCrossRefGoogle Scholar
  54. 54.
    Ray R, Ray S, Holick MF. la,25-Dihydroxyvitamin D3–313-bromo acetate, an affinity labeling analog of 1a,25-dihydroxyvitamin D3 receptor. Bioorganic Chem 1994; 22: 276–283.CrossRefGoogle Scholar
  55. 55.
    Van Auken M, Buckley D, Ray R, Holick MF, Baran DT. The effects of the vitamin D3 analog la,25dihydroxyvitamin D3–3f3-bromo acetate on rat osteosarcoma cells: comparison with 1a,25-dihydroxyvitamin D3. J Cell Biochem 1996; 63: 302–310.PubMedCrossRefGoogle Scholar
  56. 56.
    Baran D, Merriman H, Ray R, Sorensen A, Quail J. Characteristics of an osteoblast membrane protein that recognizes 1a,25-(OH)2D3. J Bone Miner Res 1994; 10: S292.Google Scholar
  57. 57.
    Kim Y, Dedhar S, Hruska K. Binding of the occupied vitamin D receptor to extranuclear sites: a potential mechanism of nongenomic actions of la,25-(OH)2D3. In: Proceedings of the Ninth Workshop on Vitamin D, Orlando, FL, May 28-June 2, 1994, pp. 341–344.Google Scholar
  58. 58.
    Baran DT, Sorensen AM, Shalhoub V, Owen T, Stein GS, Lian JB. The rapid nongenomic actions of 1a,25-dihydroxyvitamin D3 modulate the hormone-induced increments in osteocalcin gene transcription in osteoblast-like cells. J Cell Biochem 1992; 50: 124–129.PubMedCrossRefGoogle Scholar
  59. 59.
    Jenis LG, Lian JB, Stein GS, Baran DT. la,25-Dihydroxyvitamin D3-induced changes in intracellular pH in osteoblast-like cells modulate gene expression. J Cell Biochem 1993; 53: 234–239.PubMedCrossRefGoogle Scholar
  60. 60.
    Khoury R, Ridall AL, Norman AW, Farach-Carson MC. Target gene activation by 1,25-dihydroxyvitamin D3 in osteosarcoma cells is independent of calcium influx. Endocrinology 1994; 135: 2446–2453.PubMedCrossRefGoogle Scholar
  61. 61.
    Nemere I, Norman AW. Parathyroid hormone stimulates calcium transport in perfused duodena from normal chicks: comparison with the rapid (transcaltachic) effect of 1,25-dihydroxyvitamin D3. Endocrinology 1986; 119: 1406–1408.PubMedCrossRefGoogle Scholar
  62. 62.
    deBoland AR, Nemere I, Norman AW. Ca2+ channel agonist bay k 8644 mimics 1,25(OH)2-vitamin D3 rapid enhancement of Ca2+ transport in chick perfused duodena. Biochem Biophys Res Commun 1990; 166: 217–222.CrossRefGoogle Scholar
  63. 63.
    deBoland AR, Norman AW. Influx of extracellular calcium mediates 1,25-dihydroxyvitamin D3 dependent transcaltachia (the rapid stimulation of duodenal Ca2+ transport). Endocrinology 1990; 127: 2475–2480.CrossRefGoogle Scholar
  64. 64.
    Zhou L-X, Nemere I, Norman AW. 1,25-Dihydroxyvitamin D3 analog structure-function assessment of the rapid stimulation of intestinal calcium absorption (transcaltachia). J Bone Miner Res 1992; 7: 457–463.PubMedCrossRefGoogle Scholar
  65. 65.
    Dormanen MC, Bishop JE, Hammond MW, Okamura WH, Nemere I, Norman AW. Non-nuclear effects of the steroid hormone la,25-(OH)2-vitamin D3: analogs are able to functionally differentiate between nuclear and membrane receptors. Biochem Biophys Res Commun 1994; 201: 394–401.PubMedCrossRefGoogle Scholar
  66. 66.
    Norman AW, Bishop JE, Collins ED, Seo E-G, Satchell DP, Dormanen MC, Zanello SB, FarachCarson MC, Bouillon R, Okamura WH. Differing shapes of la,25-dihydroxyvitamin D3 functions as ligands for the D-binding protein, nuclear receptor, and membrane receptor: a status report. J Steroid Biochem Mol Biol 1996; 56: 13–22.PubMedCrossRefGoogle Scholar
  67. 67.
    Nemere I. Apparent non-nuclear regulation of intestinal phosphate transport: effects of 1,25-dihydroxyvitamin D3, 24–25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3. Endocrinology 1996; 137: 2254–2261.Google Scholar
  68. 68.
    Nemere I, Szego CM. Early actions of parathyroid hormone and 1,25-dihydroxycholecalciferol isolated epithelial cells from rat intestine. Endocrinology 1981; 108: 1450–1462.PubMedCrossRefGoogle Scholar
  69. 69.
    Lucas PA, Roullet C, Duchambon P, Lacour B, Drueke T. Rapid stimulation of calcium uptake by isolated rat enterocytes by 1,25(OH)2D3. Pflugers Arch 1989; 413: 407–413.PubMedCrossRefGoogle Scholar
  70. 70.
    Wali RK, Baum CL, Sitrin MD, Brasitus TA. 1,25(OH)2 vitamin D3 stimulates membrane phosphoinositide turnover, activates protein kinase C, and increases cytosolic calcium in rat colonic epithelium. J Clin Invest 1990; 85: 1296–1303.PubMedCrossRefGoogle Scholar
  71. 71.
    Wali RK, Baum CL, Bolt MJG, Brasitus TA, Sitrin MD. 1,25-Dihydroxyvitamin D3 inhibits Na+-H+ exchange by stimulating membrane phosphoinositide turnover and increasing cytosolic calcium in CaCo-2 cells. Endocrinology 1992; 131: 1125–1133.PubMedCrossRefGoogle Scholar
  72. 72.
    Tien X-Y, Katnik C, Qasawa BM, Sitrin MD, Nelson DJ, Brasitus TA. Characterization of the 1,25dihydroxycholecalciferol-stimulated calcium influx pathway in CaCo-2 cells. J Membr Biol 1993; 136: 159–168.PubMedCrossRefGoogle Scholar
  73. 73.
    Tien X-Y, Brasitus TA, Qasawa BM, Norman AW, Sitrin MD. Effect of 1,25(OH)2D3 and its analogues on membrane phosphoinositide turnover and [Ca2+]i in CaCo-2 cells. Am J Physiol 1993; 265: G143 - G148.PubMedGoogle Scholar
  74. 74.
    Lieberherr M, Grosse B, Duchambon P, Drueke T. A functional cell surface type receptor is required for the early action of 1,25-dihydroxyvitamin D3 on the phosphoinositide metabolism in rat enterocytes. J Biol Chem 1989; 264:20, 403–20, 406.Google Scholar
  75. 75.
    Norman AW, Bouillon R, Farach-Carson MC, Bishop JE, Zhou L- X, Nemere I, Zhao J, Muralidharan KR, Okamura WH. Demonstration that 1(3,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1a,25-dihydroxyvitamin D3 J Biol Chem 1993; 268:20, 022–20, 030.Google Scholar
  76. 76.
    Nemere I, Dormanen MC, Hammond MW, Okamura MW, Norman AW. Identification of a specific binding protein for la,25-dihydroxyvitamin D3 in basal-lateral membranes of chick intestinal epithelium and relationship to transcaltachia. J Biol Chem 1994; 269:23, 750–23, 756.Google Scholar
  77. 77.
    Kim YS, MacDonald PN, Dedhar S, Hruska KA. Association of 1a,25-dihydroxyvitamin D3-occupied vitamin D receptors with cellular membrane acceptance sites. Endocrinology 1996; 137: 3649–3658.PubMedCrossRefGoogle Scholar
  78. 78.
    Baran DT. Nongenomic actions of the steroid hormone 1a,25-dihydroxyvitamin D3. J Cell Biochem 1994; 56: 303–306.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Daniel T. Baran

There are no affiliations available

Personalised recommendations