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Ca2+ release from intracellular stores can be activated in neurons by influx of Ca2+ through voltage-gated Ca2+ channels. This process, called Ca2+-induced Ca2+ release, relies on the properties of the ryanodine receptor and represents a mechanism by which Ca2+ influx during neuronal 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+ from intracellular stores in a Ca2+-dependent and ryanodine-sensitive manner. The pyridine nucleotide, cyclic ADP-ribose, thought to be an endogenous modulator of ryanodine receptors also amplified Ca2+-induced Ca2+ release in these neurons. Cyclic ADP-ribose enhanced the total cytoplasmic Ca2+ levels during controlled Ca2+ influx through voltage gated channels, in a concentration-dependent and ryanodine-sensitive manner 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 the Ca2+ influx, cyclic ADP-ribose enhanced the spatial spread of the Ca2+ signal from the edge of the cell into its center. These powerful actions suggest a role for cyclic ADP-ribose in the functional coupling of neuronal depolarization, Ca2+ entry, and global intracellular Ca2+ signaling.

Original publication

DOI

10.1074/jbc.272.34.20967

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

08/1997

Volume

272

Pages

20967 - 20970

Addresses

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom. ruth.empson@pharm.ox.ac.uk

Keywords

Neurons, Cells, Cultured, Hybrid Cells, Animals, Mice, Rats, Calcium, Inositol 1,4,5-Trisphosphate, Caffeine, Adenosine Diphosphate Ribose, Cyclic ADP-Ribose, Calcium Channels, Ryanodine Receptor Calcium Release Channel, Muscle Proteins, Cell Compartmentation, Ion Channel Gating, Membrane Potentials