Vitamin D-induced ectodomain shedding of TNF receptor 1 as a nongenomic action: D3 vs D2 derivatives

J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):18-25. doi: 10.1016/j.jsbmb.2015.09.019. Epub 2015 Sep 15.


As a nongenomic action, 1,25-dihydroxyvitamin D3 (1,25D3) induces L-type Ca(2+) channel-mediated extracellular Ca(2+) influx in human aortic smooth muscle cells (HASMCs), which activates a disintegrin and metalloprotease 10 (ADAM10) to cleave and shed the ectodomain of tumor necrosis factor receptor 1 (TNFR1). In this study, we examined the potencies of other vitamin D3 and D2 analogs to stimulate the ectodomain shedding of TNFR1 in HASMCs. 25-Hydroxyvitamin D3 (25D3), a precursor of 1,25D3, and elocalcitol, an analog of 1,25D3, caused ectodomain shedding of TNFR1 within 30 min, whereas 1,25-dihydroxyvitamin D2 (1,25D2) and paricalcitol, a derivative of 1,25D2, did not. Both 25D3 and elocalcitol rapidly induced extracellular Ca(2+) influx and markedly increased intracellular Ca(2+), while 1,25D2 and paricalcitol caused only small increases in intracellular Ca(2+). 25D3- and elocalcitol-induced TNFR1 ectodomain sheddings were abolished by verapamil and in Ca(2+)-free media. Both 25D3 and elocalcitol caused the translocation of ADAM10 to the cell surface, which was inhibited by verapamil, while 1,25D2 and paricalcitol did not cause ADAM10 translocation. When ADAM10 was depleted by ADAM10-siRNA, 25D3 and elocalcitol could not induce ectodomain shedding of TNFR1. The plasma membrane receptor, endoplasmic reticulum stress protein 57 (ERp57), but not the classic vitamin D receptor, mediated the nongenomic action of vitamin D to induce ectodomain shedding of TNFR1. In summary, like 1,25D3, 25D3 and elocalcitol caused ADAM10-mediated ectodomain shedding of TNFR1, whereas 1,25D2 and paricalcitol did not. The difference may depend on their affinities to ERp57 through which extracellular Ca(2+) influx is induced.

Keywords: 1,25-Dihydroxyvitamin D(2); 25-Hydroxyvitamin D(3); ADAM10; ERp57; L-type Ca(2+) channel; TNF receptor 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM10 Protein
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Calcitriol / analogs & derivatives
  • Calcitriol / metabolism
  • Calcitriol / pharmacology
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism
  • Cells, Cultured / drug effects
  • Cholecalciferol / analogs & derivatives*
  • Ergocalciferols* / metabolism
  • Ergocalciferols* / pharmacology
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Muscle, Smooth, Vascular / cytology
  • Protein Disulfide-Isomerases / genetics
  • Protein Disulfide-Isomerases / metabolism
  • Protein Structure, Tertiary
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / chemistry
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Vitamin D / analogs & derivatives
  • Vitamin D / metabolism
  • Vitamin D / pharmacology


  • BXL628
  • Calcium Channels, L-Type
  • Ergocalciferols
  • Membrane Proteins
  • Receptors, Calcitriol
  • Receptors, Tumor Necrosis Factor, Type I
  • dihydroxy-vitamin D3
  • Vitamin D
  • Cholecalciferol
  • 1,25-dihydroxyergocalciferol
  • paricalcitol
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human
  • Protein Disulfide-Isomerases
  • PDIA3 protein, human
  • Calcitriol
  • Calcium