[Physiological role of cyclic ADP-ribose as a novel endogenous agonist of ryanodine receptor in adrenal chromaffin cells].

Cyclic ADP-ribose (cADPR) is suggested to be a novel messenger of ryanodine receptors (RyR) in various cellular systems. However, the regulation of its synthesis in response to cell stimulation and its functional roles are still unclear. We examined the physiological relevance of cADPR to the messenger role in stimulation-secretion coupling in bovine adrenal chromaffin cells. In digitonin-permeabilized cells, cADPR-induced Ca2+ release but not caffeine-, ryanodine-, and IP3-induced Ca2+ release was inhibited by FK506 which bind to FKBP and dissociate it from the RyR. These evidence suggesting that cADPR may be the ligand for FKBP-RyR complex, resulting in a dynamic regulation of RyR-mediated Ca2+ release. ACh causes biphasic [Ca2+]i rise, an initial transient rise followed by sustained rise, in intact cells. 8Br-cADPR, an antagonist of cADPR and FK506 specifically reduced the sustained phases of ACh-induced [Ca2+]i rise. Imperatoxin inhibitor (IpTxi) blocked the inhibitory effect of 8Br-cADPR and FK506, suggesting that cADPR contributes to sustained [Ca2+]i rise. 8Br-cADPR, FK506, and IpTxi reduced CA release in response to ACh in chromaffin cells. These results provide evidence that the synthesis of cADPR is regulated by cell stimulation, and the cADPR/Ca(2+)-induced Ca2+ release pathway forms a positive feedback to stimulation-induced secretory response in the chromaffin cells.