Rapid modulation of osteoblast ion channel responses by 1α,25(OH) ₂ -vitamin D ₃ requires the presence of a functional vitamin D nuclear receptor

<jats:p> 1α,25(OH) <jats:sub>2</jats:sub> -Vitamin D <jats:sub>3</jats:sub> (1,25D) modulates osteoblast gene expression of bone matrix proteins via a nuclear vitamin D receptor (VDR) and also modifies the electrical state of the plasma membrane through rapid nongenomic mechanisms still not fully understood. The physiological significance of 1,25D membrane-initiated effects remains unclear. To elucidate whether the VDR is required for 1,25D-promoted electrical responses, we studied 1,25D modulation of ion channel activities in calvarial osteoblasts isolated from VDR knockout (KO) and WT mice. At depolarizing potentials, Cl <jats:sup>-</jats:sup> currents were significantly potentiated (13.5 ± 1.6-fold increase, <jats:italic>n</jats:italic> = 12) by 5 nM 1,25D in VDR WT but not in KO (0.96 ± 0.3 fold increase, <jats:italic>n</jats:italic> = 11) osteoblasts. L-type Ca <jats:sup>2+</jats:sup> currents significantly shift their peak activation by -9.3 ± 0.7 mV ( <jats:italic>n</jats:italic> = 10) in the presence of 5 nM 1,25D in VDR WT but not in KO cells, thus facilitating Ca <jats:sup>2+</jats:sup> influx. Furthermore, we found that 1,25D significantly increased wholecell capacitance in VDR WT (ΔCap = 2.3 ± 0.4 pF, <jats:italic>n</jats:italic> = 8) but not in KO osteoblasts (ΔCap = 0.3 ± 0.1 pF, <jats:italic>n</jats:italic> = 8); this corresponds to a rapid (1–2 min) fusion in WT of 71 ± 33 versus in KO only 9 ± 6 individual secretory granules. We conclude that, in calvarial osteoblasts, 1,25D modulates ion channel activities only in cells with a functional VDR and that this effect is coupled to exocytosis. This is a demonstration of the requirement of a functional classic steroid receptor for the rapid hormonal modulation of electric currents linked to secretory activities in a target cell. </jats:p>