Volume 272, Number 34, Issue of August 22, 1997 pp. 20967-20970
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
Cyclic ADP-ribose Enhances Coupling between Voltage-gated Ca²⁺ Entry and Intracellular Ca²⁺ Release

(Received for publication, May 22, 1997, and in revised form, June 11, 1997)

From the Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom

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.

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