1,25-DIHYDROXYVITAMIN D-3 UP-REGULATES THE PHOSPHATIDYLINOSITOL SIGNALING PATHWAY IN HUMAN KERATINOCYTES BY INCREASING PHOSPHOLIPASE-C LEVELS

1,25-Dihydroxyvitamin D-3 (1,25(OH)(2)D-3) induces the differentiation of normal human keratinocytes, in part by increasing their basal intracellular calcium levels (Ca-i) over a period of hours, Agonists such as ATP acting through membrane receptors cause an immediate but transient increase in Ca accompanied by an increase in inositol trisphosphate (IP3). Treatment of keratinocytes for 24 h with 1 nM 1,25(OH)(2)D-3 resulted in a two- to four-fold potentiation of the Ca-i response of these cells to ATP. This potentiation was inhibitable with cycloheximide, unaccompanied by a change in total intracellular calcium pools, but associated with an increase in basal IP3 levels and ATP-stimulated IP3 production, Treatment with 1,25(OH)(2)D-3 raised the protein and mRNA levels of phospholipase C isoenzymes, particularly phospholipase C-beta 1 in a dose-dependent manner. These studies indicate that 1,25(OH)(2)D-3 modulates the keratinocyte signal transduction pathway by induction of phospholipase isoenzymes, a previously undescribed action for this hormone.