NITRIC OXIDE-INDUCED MOBILIZATION OF INTRACELLULAR CALCIUM VIA THE CYCLIC ADP-RIBOSE SIGNALING PATHWAY

Cyclic adenosine diphosphate ribose (cADPR) is a potent endogenous cal cium-mobilizing agent synthesized from beta-NAD(+) by ADP-ribosyl cycl ases in sea urchin eggs and in several mammalian cells (Galione, A, an d White, A (1994) Trends Cell Biol, 4, 431-436), Pharmacological studi es suggest that cADPR is an endogenous modulator of Ca2+-induced Ca2release mediated by ryanodine-sensitive Ca2+ release channels, An unre solved question is whether cADPR can act as a Ca2+-mobilizing intracel lular messenger, We show that exogenous application of nitric oxide (N O) mobilizes Ca2+ from intracellular stores in intact sea urchin eggs and that it releases Ca2+ and elevates cADPR levels in egg homogenates , 8-Amino-cADPR, a selective competitive antagonist of cADPR-mediated Ca2+ release, and nicotinamide, an inhibitor of ADP-ribosyl cyclase, i nhibit the Ca2+-mobilizing actions of NO, while, heparin, a competitiv e antagonist of the inositol 1,4,5-trisphosphate receptor, did not aff ect NO-induced Ca2+ release, Since the Ca2+-mobilizing effects of NO c an be mimicked by cGRIP, are inhibited by the cGMP-dependent-protein k inase inhibitor, R(p)-8-pCPT-cGMPS, and in egg homogenates show a requ irement for the guanylyl cyclase substrate, GTP, we suggest a novel ac tion of NO in mobilizing intracellular calcium from microsomal stores via a signaling pathway involving cGMP and cADPR, These results sugges t that cADPR has the capacity to act as a Ca2+-mobilizing intracellula r messenger.