MECHANISM OF LONG-RANGE CA2+ SIGNALING IN THE NUCLEUS OF ISOLATED RATHEPATOCYTES

Ca2+ regulates a wide range of cell proteins, in both the cytosol and nucleus. It enters the nucleus from stores along the nuclear envelope, but how it then spreads through the nuclear interior is unknown. Here we used high-speed confocal line-scanning microscopy to examine the p ropagation of Ca2+ waves across nuclei in isolated rat hepatocytes. Nu clear Ca2+ waves began at the nucleus/cytosol border as expected, then spread across the nucleus at less than half the speed of cytosolic Ca 2+ waves. High concentrations of caffeine slowed Ca2+ waves in the cyt osol but not in the nucleus. We developed a mathematical model based o n diffusion to analyse these data, and the model was able to describe the nuclear but not cytosolic Ca2+ waves that were experimentally obse rved. These findings suggest that Ca2+ waves cross the nucleus by simp le diffusion, which is distinct from the reaction-diffusion mechanism by which Ca2+ waves propagate across the cytosol. Since the range of m essenger action for Ca2+ in the cytosol is much smaller than the dista nce across the nucleus, this also suggests that the unique environment and geometry of the nuclear interior may permit this simple mechanism of Ca2+ wave propagation to control Ca2+-mediated processes in a rela tively large region despite Ca2+ release pools that are spatially limi ted.