Mechanism of action of 1,25-dihydroxyvitamin D3 on intestinal calcium absorption

Article
First Online:

Abstract

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the major controlling hormone of intestinal calcium absorption. As the body’s demand for calcium increases from a diet deficient in calcium, from growth, pregnancy or lactation, the synthesis of 1,25(OH)2D3 is increased resulting in the stimulation of intestinal calcium absorption. However a complete description of the molecular mechanisms involved in the 1,25(OH)2D3 regulated calcium absorptive process remains incomplete. Intestinal calcium absorption occurs by both an active saturable transcellular pathway and a passive nonsaturable paracellular pathway. Each step in the process of transcellular calcium transport (apical entry of calcium, translocation of calcium through the interior of the enterocyte and basolateral extrusion of calcium by the plasma membrane pump) has been reported to involve a vitamin D dependent component. This article will review recent studies, including those using knockout mice, that have suggested that 1,25(OH)2D3 mediated calcium absorption is more complex than the traditional three step model of transcellular calcium transport. Current concepts are reviewed and questions that remain are addressed. Evidence for a role of 1,25(OH)2D3 in the regulation of the paracellular pathway is also discussed.

Keywords

1,25-dihydroxyvitamin D3 Intestine Calcium Transient receptor potential vanilloid type 6 (TRPV6) Calbindin Plasma membrane calcium pump PMCA1b Claudin-2 Claudin-12 Cadherin-17 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;116:2062–72.PubMedCrossRefGoogle Scholar
  4. 4.
    Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22:477–501.PubMedCrossRefGoogle Scholar
  5. 5.
    Bouillon R, Bischoff-Ferrari H, Willett W. Vitamin D and health: perspectives from mice and man. J Bone Miner Res. 2008;23:974–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA. 1997;94:9831–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997;16:391–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Wasserman RH. Vitamin D and the dual processes of intestinal calcium absorption. J Nutr. 2004;134:3137–9.PubMedGoogle Scholar
  9. 9.
    Marcus CS, Lengemann FW. Absorption of Ca45 and Sr85 from solid and liquid food at various levels of the alimentary tract of the rat. J Nutr. 1962;77:155–60.PubMedGoogle Scholar
  10. 10.
    Cramer CF. Sites of calcium absorption and the calcium concentration of gut contents in the dog. Can J Physiol Pharmacol. 1965;43:75–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Fleet JC, Schoch RD. Molecular mechanisms for regulation of intestinal calcium and phosphate absorption by vitamin D. In: Feldman D, Pike JW, Adams J, editors. Vitamin D. Chapter 19. 3rd ed. San Diego: Academic; 2011. p. 349–62.Google Scholar
  12. 12.
    Barger-Lux MJ, Heaney RP, Recker RR. Time course of calcium absorption in humans: evidence for a colonic component. Calcif Tissue Int. 1989;44:308–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Favus MJ. Factors that influence absorption and secretion of calcium in the small intestine and colon. Am J Physiol. 1985;248:G147–57.PubMedGoogle Scholar
  14. 14.
    Favus MJ, Kathpalia SC, Coe FL, Mond AE. Effects of diet calcium and 1,25-dihydroxyvitamin D3 on colon calcium active transport. Am J Physiol. 1980;238:G75–8.PubMedGoogle Scholar
  15. 15.
    Vergne-Marini P, Parker TF, Pak CY, Hull AR, DeLuca HF, Fordtran JS. Jejunal and ileal absorption in patients with chronic renal disease. Effect of 1alpha-hydroxycholecalciferol. J Clin Invest. 1976;57:861–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Grinstead WC, Pak CY, Krejs GJ. Effect of 1,25-dihydroxyvitamin D3 on calcium absorption in the colon of healthy humans. Am J Physiol. 1984;247:G189–92.PubMedGoogle Scholar
  17. 17.
    Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science. 1979;206:1188–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Xue Y, Fleet JC. Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology. 2009;136:1317–27. e1–2.PubMedCrossRefGoogle Scholar
  19. 19.
    Hirst MA, Feldman D. 1,25-Dihydroxyvitamin D3 receptors in mouse colon. J Steroid Biochem. 1981;14:315–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Chandra S, Fullmer CS, Smith CA, Wasserman RH, Morrison GH. Ion microscopic imaging of calcium transport in the intestinal tissue of vitamin D-deficient and vitamin D-replete chickens: a 44Ca stable isotope study. Proc Natl Acad Sci USA. 1990;87:5715–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Fullmer CS, Chandra S, Smith CA, Morrison GH, Wasserman RH. Ion microscopic imaging of calcium during 1,25-dihydroxyvitamin D-mediated intestinal absorption. Histochem Cell Biol. 1996;106:215–22.PubMedCrossRefGoogle Scholar
  22. 22.
    Wasserman RH. Vitamin D and intestinal absorption of calcium: a review and overview. In: Feldman D, Pike JW, Glorieux F, editors. Vitamin D. 2nd ed. San Diego: Academic; 2004. p. 411–28.Google Scholar
  23. 23.
    Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, et al. Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem. 1999;274:22739–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Peng JB, Brown EM, Hediger MA. Hediger, Apical entry channels in calcium-transporting epithelia. News Physiol Sci. 2003;18:158–63.PubMedGoogle Scholar
  25. 25.
    Teerapornpuntakit J, Dorkkam N, Wongdee K, Krishnamra N, Charoenphandhu N. Endurance swimming stimulates transepithelial calcium transport and alters the expression of genes related to calcium absorption in the intestine of rats. Am J Physiol Endocrinol Metab. 2009;296:E775–86.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhang W, Na T, Wu G, Jing H, Peng JB. Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2. J Biol Chem. 2010;285:36586–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Song Y, Peng X, Porta A, Takanaga H, Peng JB, Hediger MA, et al. Calcium transporter 1 and epithelial calcium channel messenger ribonucleic acid are differentially regulated by 1,25 dihydroxyvitamin D3 in the intestine and kidney of mice. Endocrinology. 2003;144:3885–94.PubMedCrossRefGoogle Scholar
  28. 28.
    Van Cromphaut SJ, Dewerchin M, Hoenderop JG, Stockmans I, Van Herck E, Kato S, et al. Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects. Proc Natl Acad Sci USA. 2001;98:13324–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Bianco SD, Peng JB, Takanaga H, Suzuki Y, Crescenzi A, Kos CH, et al. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J Bone Miner Res. 2007;22:274–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Benn BS, Ajibade D, Porta A, Dhawan P, Hediger M, Peng JB, et al. Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. Endocrinology. 2008;149:3196–205.PubMedCrossRefGoogle Scholar
  31. 31.
    Kutuzova GD, Sundersingh F, Vaughan J, Tadi BP, Ansay SE, Christakos S, et al. TRPV6 is not required for 1alpha, 25-dihydroxyvitamin D3-induced intestinal calcium absorption in vivo. Proc Natl Acad Sci USA. 2008;105:19655–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Lieben L, Benn BS, Ajibade D, Stockmans I, Moermans K, Hediger MA, et al. Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis. Bone. 2010;47(2):301–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Cui M, Fleet J. Transgenic overexpression of human TRPV6 in intestine increases calcium absorption efficiency and improves bone mass in mice. J Bone Mineral Res. 2010;25:s59.Google Scholar
  34. 34.
    Christakos S, Gabrielides C, Rhoten WB. Vitamin D-dependent calcium binding proteins: chemistry, distribution, functional considerations, and molecular biology. Endocr Rev. 1989;10:3–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Christakos S, Mady LJ, Dhawan P. The calbindins: calbindin −D28k and calbindin −D9k and the epithelial calcium channels TRPV5 and TRPV6. In: Feldman D, Pike JW, Adams J, editors. Vitamin D. Chapter 20. 3rd ed. San Diego: Academic; 2011. p. 363–79.CrossRefGoogle Scholar
  36. 36.
    Taylor AN, Wasserman RH. Correlations between the vitamin D-induced calcium binding protein and intestinal absorption of calcium. Fed Proc. 1969;28:1834–8.PubMedGoogle Scholar
  37. 37.
    Akhter S, Kutuzova GD, Christakos S, DeLuca HF. Calbindin D9k is not required for 1,25-dihydroxyvitamin D3-mediated Ca2+ absorption in small intestine. Arch Biochem Biophys. 2007;460:227–32.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee D, Obukhov AG, Shen Q, Liu Y, Dhawan P, Nowycky MC, et al. Calbindin-D28k decreases L-type calcium channel activity and modulates intracellular calcium homeostasis in response to K+ depolarization in a rat beta cell line RINr1046-38. Cell Calcium. 2006;39:475–85.PubMedCrossRefGoogle Scholar
  39. 39.
    Harteneck C. Proteins modulating TRP channel function. Cell Calcium. 2003;33:303–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Lambers TT, Weidema AF, Nilius B, Hoenderop JG, Bindels RJ. Regulation of the mouse epithelial Ca2(+) channel TRPV6 by the Ca(2+)-sensor calmodulin. J Biol Chem. 2004;279:28855–61.PubMedCrossRefGoogle Scholar
  41. 41.
    Lambers TT, Mahieu F, Oancea E, Hoofd L, de Lange F, Mensenkamp AR, et al. Calbindin-D28K dynamically controls TRPV5-mediated Ca2+ transport. EMBO J. 2006;25:2978–88.PubMedCrossRefGoogle Scholar
  42. 42.
    Ghijsen WE, Van Os CH. 1 alpha, 25-Dihydroxy-vitamin D-3 regulates ATP-dependent calcium transport in basolateral plasma membranes of rat enterocytes. Biochim Biophys Acta. 1982;689:170–2.PubMedCrossRefGoogle Scholar
  43. 43.
    Cai Q, Chandler JS, Wasserman RH, Kumar R, Penniston JT. Vitamin D and adaptation to dietary calcium and phosphate deficiencies increase intestinal plasma membrane calcium pump gene expression. Proc Natl Acad Sci USA. 1993;90:1345–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Ghijsen WE, De Jong MD, Van Os CH. Kinetic properties of Na+/Ca2+ exchange in basolateral plasma membranes of rat small intestine. Biochim Biophys Acta. 1983;730:85–94.PubMedCrossRefGoogle Scholar
  45. 45.
    Wasserman RH, Kallfelz FA. Vitamin D3 and unidirectional calcium fluxes across the rachitic chick duodenum. Am J Physiol. 1962;203:221–4.PubMedGoogle Scholar
  46. 46.
    Dostal LA, Toverud SU. Effect of vitamin D3 on duodenal calcium absorption in vivo during early development. Am J Physiol. 1984;246:G528–34.PubMedGoogle Scholar
  47. 47.
    Chirayath MV, Gajdzik L, Hulla W, Graf J, Cross HS, Peterlik M. Vitamin D increases tight-junction conductance and paracellular Ca2+ transport in Caco-2 cell cultures. Am J Physiol. 1998;274:G389–96.PubMedGoogle Scholar
  48. 48.
    Pansu D, Bellaton C, Bronner F. Effect of Ca intake on saturable and nonsaturable components of duodenal Ca transport. Am J Physiol. 1981;240:G32–7.PubMedGoogle Scholar
  49. 49.
    Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol. 2001;2:285–93.PubMedCrossRefGoogle Scholar
  50. 50.
    Fujita H, Sugimoto K, Inatomi S, Maeda T, Osanai M, Uchiyama Y, et al. Tight junction proteins claudin-2 and −12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Mol Biol Cell. 2008;19:1912–21.PubMedCrossRefGoogle Scholar
  51. 51.
    Holmes JL, Van Itallie CM, Rasmussen JE, Anderson JM. Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Expr Patterns. 2006;6:581–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Christakos S, Dhawan P, Ajibade D, Benn BS, Feng J, Joshi SS. Mechanisms involved in vitamin D mediated intestinal calcium absorption and in non-classical actions of vitamin D. J Steroid Biochem Mol Biol. 2010;121:183–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Kutuzova GD, Deluca HF. Gene expression profiles in rat intestine identify pathways for 1,25-dihydroxyvitamin D(3) stimulated calcium absorption and clarify its immunomodulatory properties. Arch Biochem Biophys. 2004;432:152–66.PubMedCrossRefGoogle Scholar
  54. 54.
    Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, DeLuca HF. Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium. J Clin Invest. 1979;64:729–36.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular Biology, New Jersey Medical SchoolUniversity of Medicine and Dentistry of New JerseyNewarkUSA

Personalised recommendations