Multistep mechanism of polarized Ca2+ wave patterns in hepatocytes

The spatial organization of cytosolic Ca2+ (Ca2+i) signals is thought to be important for regulation of cell function. In epithelial cells, the involvement of inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release in evoking Ca2+i signals is appreciated, but the location of IP3-sensitive Ca2+ stores and the role of Ca(2+)-induced Ca2+ release (CICR) for Ca2+ signaling are less defined. Here, we demonstrate that IP3 receptors are localized to the apical region in hepatocytes. We also show that hormone-induced Ca2+i waves propagate across the cell at a rate that depends on mobilization of Ca2+ stores that are sensitive to caffeine, ryanodine, and dantrolene, and that these agents, at concentrations that inhibit CICR, decrease the magnitude of Ca2+i signals. Furthermore, Ca2+i wave speed is not reduced in Ca(2+)-free medium. These findings suggest that Ca2+i signals in epithelial cells begin as apical-to-basal Ca2+i waves that result from sequential release of Ca2+, first from IP3-sensitive stores in the apex and then from Ca(2+)-sensitive stores distributed across the remainder of the cell.