Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP

Abstract

Cells possess various mechanisms for transducing external signals to intracellular responses. The discovery of inositol 1,4,5-trisphosphate (IP 3) as a messenger for mobilizing internal Ca 2+ stores has centralized Ca 2+ mobilization among signaling mechanisms. Results reviewed in this article establish that, in addition to IP 3, the internal Ca 2+ stores can be mobilized by at least two other molecules, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), via totally independent mechanisms. Cyclic ADP-ribose is a newly discovered cyclic nucleotide derived from NAD, but, unlike adenosine 3',5'-cyclic monophosphate, its main signaling function is modulation of Ca 2+-induced Ca 2+ release, a major mechanism of Ca 2+ mobilization in addition to the IP 3 pathway. Evidence shows that cADPR may in fact be responsible for mediating the Ca 2+-mobilizing activity of the gaseous messenger nitric oxide. Cells responsive to cADPR are widespread and include species from plant to mammal, indicating the generality of cADPR as a signaling molecule. In addition to cADPR, NAADP, a metabolite of NADP, can also mobilize Ca 2+ stores. The release mechanism and the stores on which NAADP acts are distinct from cADPR and IP 3. Nicotinic acid adenine dinucleotide phosphate may play a role in generating Ca 2+ oscillations, since liberation of NAADP in live cells by photolyzing its caged analog produces long-lasting Ca 2+ oscillations. These two new Ca 2+ agonists are intimately related, since the same metabolic enzymes can, under appropriate conditions, synthesize either one, suggesting a unified mechanism may regulate both pathways. Elucidation of these two new Ca 2+ mobilization pathways is likely to have an important impact on our understanding of cellular signaling mechanisms.