Cyclic ADP‐ribose as a potential second messenger for neuronal Ca2+ signaling

Cyclic ADP‐ribose (cADPR), a known endogenous modulator of ryanodine receptor Ca2+ releasing channels, is found in the nervous system. Injection of cADPR into neuronal cells primarily induces a transient elevation of intracellular Ca2+ concentration ([Ca2+]i), and/or secondarily potentiates [Ca2+]i increases that are the result of depolarization‐induced Ca2+ influx. Acetylcholine release from cholinergic neurons is facilitated by cADPR. cADPR modifies K+ currents or elicits Ca2+‐dependent inward currents. cADPR is synthesized by both membrane‐bound and cytosolic forms of ADP‐ribosyl cyclase in neuronal cells. cADPR hydrolase activity is weak in the membrane fraction, but high in the cytoplasm. Cytosolic ADP‐ribosyl cyclase activity is upregulated by nitric oxide/cyclic GMP‐dependent phosphorylation. Stimulation of muscarinic and β‐adrenergic receptors activates membrane‐bound ADP‐ribosyl cyclase via G proteins within membranes of neuronal tumor cells and cortical astrocytes. These findings strongly suggest that cADPR is a second messenger in Ca2+ signaling in the nervous system, although many intriguing issues remain to be addressed before this identity is confirmed.