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

As a nongenomic action, 1,25-dihydroxyvitamin D 3 (1,25D 3 ) 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 D 3 and D 2 analogs to stimulate the ectodomain shedding of TNFR1 in HASMCs. 25-Hydroxyvitamin D 3 (25D 3 ), a precursor of 1,25D 3 , and elocalcitol, an analog of 1,25D 3 , caused ectodomain shedding of TNFR1 within 30 min, whereas 1,25-dihydroxyvitamin D 2 (1,25D 2 ) and paricalcitol, a derivative of 1,25D 2 , did not. Both 25D 3 and elocalcitol rapidly induced extracellular Ca 2+ influx and markedly increased intracellular Ca 2+ , while 1,25D 2 and paricalcitol caused only small increases in intracellular Ca 2+ . 25D 3 - and elocalcitol-induced TNFR1 ectodomain sheddings were abolished by verapamil and in Ca 2+ -free media. Both 25D 3 and elocalcitol caused the translocation of ADAM10 to the cell surface, which was inhibited by verapamil, while 1,25D 2 and paricalcitol did not cause ADAM10 translocation. When ADAM10 was depleted by ADAM10-siRNA, 25D 3 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 1,25D 3 , 25D 3 and elocalcitol caused ADAM10-mediated ectodomain shedding of TNFR1, whereas 1,25D 2 and paricalcitol did not. The difference may depend on their affinities to ERp57 through which extracellular Ca 2+ influx is induced. [ABSTRACT FROM AUTHOR]