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Physiol. Rev. 77: 1133-1164, 1997;
0031-9333/97 $15.00
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Physiological Reviews, Vol 77, 1133-1164, Copyright © 1997 by American Physiological Society


JOURNAL ARTICLE

Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP

H. C. Lee
Department of Physiology, University of Minnesota, Minneapolis, USA.

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.


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L. Franco, E. Zocchi, C. Usai, L. Guida, S. Bruzzone, A. Costa, and A. De Flora
Paracrine Roles of NAD+ and Cyclic ADP-ribose in Increasing Intracellular Calcium and Enhancing Cell Proliferation of 3T3 Fibroblasts
J. Biol. Chem., June 8, 2001; 276(24): 21642 - 21648.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
R. Graeff, C. Munshi, R. Aarhus, M. Johns, and H. C. Lee
A Single Residue at the Active Site of CD38 Determines Its NAD Cyclizing and Hydrolyzing Activities
J. Biol. Chem., April 6, 2001; 276(15): 12169 - 12173.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
A. H. Guse, A. Y. Tsygankov, K. Weber, and G. W. Mayr
Transient Tyrosine Phosphorylation of Human Ryanodine Receptor upon T Cell Stimulation
J. Biol. Chem., September 7, 2001; 276(37): 34722 - 34727.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
C. Munshi, R. Aarhus, R. Graeff, T. F. Walseth, D. Levitt, and H. C. Lee
Identification of the Enzymatic Active Site of CD38 by Site-directed Mutagenesis
J. Biol. Chem., July 7, 2000; 275(28): 21566 - 21571.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
L. Navazio, M. A. Bewell, A. Siddiqua, G. D. Dickinson, A. Galione, and D. Sanders
Calcium release from the endoplasmic reticulum of higher plants elicited by the NADP metabolite nicotinic acid adenine dinucleotide phosphate
PNAS, July 18, 2000; 97(15): 8693 - 8698.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
M.-K. Sun, T. J. Nelson, and D. L. Alkon
Functional switching of GABAergic synapses by ryanodine receptor activation
PNAS, October 24, 2000; 97(22): 12300 - 12305.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. Shiwa, T. Murayama, and Y. Ogawa
Molecular cloning and characterization of ryanodine receptor from unfertilized sea urchin eggs
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2002; 282(3): R727 - R737.
[Abstract] [Full Text] [PDF]




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