Activation and inactivation of Ca2+ release by NAADP(+)

Nicotinic acid adenine dinucleotide phosphate (NAADP(+)) is a recently identified metabolite of NADP(+) that is as potent as inositol trisphosphate (IP3) 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 Ca2+ release activated by NAADP(+) and the Ca2+ stores it acts on are different from those of IP3 and cADPR. In this study we show that photolyzing caged NAADP(+) in intact sea urchin eggs elicits long term Ca2+ oscillations, On the other hand, uncaging threshold amounts of NAADP(+) produces desensitization. In microsomes, this self-inac tivation 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 Ca2+ release process has novel regulatory characteristics, which are distinguishable from Ca2+ release mediated by either IP3 or cADPR. This battery of release mechanisms may provide the necessary versatility for cells to respond to diverse signals that lead to Ca2+ mobilization.