CYCLIC ADP-RIBOSE ENHANCES COUPLING BETWEEN VOLTAGE-GATED CA2+ ENTRY AND INTRACELLULAR CA2+ RELEASE

Ca2+ release from intracellular stores can be activated in neurons by influx of Ca2+ through voltage-gated Ca2+ channels, This process, call ed Ca2+-induced Ca2+ release, relies on the properties of the ryanodin e receptor and represents a mechanism by which Ca2+ influx during neur onal activity can be amplified into large intracellular Ca2+ signals, In a differentiated neuroblastoma cell line, we show that caffeine, a pharmacological activator of the ryanodine receptor, released Ca2+ fro m intracellular stores in a Ca2+-dependent and ryanodine-sensitive man ner. The pyridine nucleotide, cyclic ADP-ribose, thought to be an endo genous modulator of ryanodine receptors also amplified Ca2+-induced Ca 2+ release in these neurons. Cyclic ADP-ribose enhanced the total cyto plasmic Ca2+ levels during controlled Ca2+ influx through voltage gate d channels, in a concentration-dependent and ryanodine-sensitive manne r and also increased the sensitivity with which a small amount of Ca2 influx could trigger additional release from the ryanodine sensitive intracellular Ca2+ stores, Single cell imaging showed that following t he Ca2+ influx, cyclic ADP-ribose enhanced the spatial spread of the C a2+ signal from the edge of the cell into its center. These powerful a ctions suggest a role for cyclic ADP-ribose in the functional coupling of neuronal depolarization, Ca2+ entry, and global intracellular Ca2 signaling.