Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP.
Cells possess various mechanisms for transducing external signals to intracellular responses. The discovery of inositol 1,4,5-trisphosphate (IP3) as a messenger for mobilizing internal Ca2+ stores has centralized Ca2+ mobilization among signaling mechanisms. Results reviewed in this article establish that, in addition to IP3, the internal Ca2+ 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 Ca2+ release, a major mechanism of Ca2+ mobilization in addition to the IP3 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 Ca2+ stores. The release mechanism and the stores on which NAADP acts are distinct from cADPR and IP3. Nicotinic acid adenine dinucleotide phosphate may play a role in generating Ca2+ oscillations, since liberation of NAADP in live cells by photolyzing its caged analog produces long lasting Ca2+ oscillations. These two new Ca2+ 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 Ca2+ mobilization pathways is likely to have an important impact on our understanding of cellular signaling mechanisms.
Lee
H C
HC
Department of Physiology, University of Minnesota, Minneapolis, USA.
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000819:agonists / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives; D018922:HL-60 Cells; D006801:Humans; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009244:NAD+ Nucleosidase / Q000378:metabolism; D009249:NADP / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D012617:Sea Urchins; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D002147:Calmodulin; D008562:Membrane Glycoproteins; C092958:caged cyclic ADP-ribose; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D009569:Nitric Oxide; D009249:NADP; C024376:NAADP; D014212:Tretinoin; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium