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, 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.
Empson
R M
RM
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom. ruth.empson@pharm.ox.ac.uk
Galione
A
A
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000502:physiology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D002451:Cell Compartmentation; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose; D006822:Hybrid Cells; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D015640:Ion Channel Gating; D008564:Membrane Potentials; D051379:Mice; D009124:Muscle Proteins / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel
D015220:Calcium Channels; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D002110:Caffeine; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium