title: Vitamin D-induced ectodomain shedding of TNF receptor 1 as a nongenomic action: D3 vs D2 derivatives.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-Ro 43-Gil, SongPa-Gu, Seoul 138-736, Republic of Korea.
authors.forename: Won Seok
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-Ro 43-Gil, SongPa-Gu, Seoul 138-736, Republic of Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Yu
authors.affiliation: Asan Institute for Life Sciences, 88 Olympic-Ro 43-Gil, SongPa-Gu, Seoul 138-736, Republic of Korea.
authors.forename: Jin Ju
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, College of Medicine, Dankook University, Anseo-dong San 16-5, Cheonan, Chungcheongnam-do 330-715, Republic of Korea.
authors.forename: Mee Jeong
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-Ro 43-Gil, SongPa-Gu, Seoul 138-736, Republic of Korea. Electronic address: skpark@amc.seoul.kr.
authors.forename: Su-Kil
authors.initials: SK
authors.lastname: Park
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives*; D004872:Ergocalciferols / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: C487049:BXL628; D020746:Calcium Channels, L-Type; D004872:Ergocalciferols; D008565:Membrane Proteins; D018167:Receptors, Calcitriol; D047888:Receptors, Tumor Necrosis Factor, Type I; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D002762:Cholecalciferol; C003564:1,25-dihydroxyergocalciferol; C084656:paricalcitol; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human; D002117:Calcitriol; D002118:Calcium
keywords: 1,25-Dihydroxyvitamin D(2); 25-Hydroxyvitamin D(3); ADAM10; ERp57; L-type Ca(2+) channel; TNF receptor 1