Activation and Inactivation of Ca▪ Release by NAADP▪(∗)

Nicotinic acid adenine dinucleotide phosphate (NAADP▪) is a recently identified metabolite of NADP▪ that is as potent as inositol trisphosphate (IP▪) and cyclic ADP-ribose (cADPR) in mobilizing intracellular Ca2▪ in sea urchin eggs and microsomes (Clapper, D. L., Walseth, T. F., Dargie, P. J., and Lee, H. C.(1987) J. Biol. Chem. 262, 9561-9568; Lee, H. C., and Aarhus, R.(1995) J. Biol. Chem. 270, 2152-2157). The mechanism of Ca▪ release activated by NAADP▪ and the Ca▪ stores it acts on are different from those of IP▪ and cADPR. In this study we show that photolyzing caged NAADP▪ in intact sea urchin eggs elicits long term Ca▪ oscillations. On the other hand, uncaging threshold amounts of NAADP▪ produces desensitization. In microsomes, this self-inactivation mechanism exhibits concentration and time dependence. Binding studies show that the NAADP▪ receptor is distinct from that of cADPR, and at subthreshold concentrations, NAADP▪ can fully inactivate subsequent binding to the receptor in a time-dependent manner. Thus, the NAADP▪-sensitive Ca▪ release process has novel regulatory characteristics, which are distinguishable from Ca▪ release mediated by either IP▪ or cADPR. This battery of release mechanisms may provide the necessary versatility for cells to respond to diverse signals that lead to Ca▪ mobilization.