Abstract

Mobilization of intracellular Ca2+ stores is mediated by two major mechanisms, the inositol trisphosphate (IP3)-pathway and the Ca2+-induced Ca2+ release (CICR) mechanism. Our research establishes that Ca2+ stores can also be mobilized by two new messengers via totally independent pathways. Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are novel metabolites of NAD and NADP, respectively. Accumulating evidence indicates cADPR is a general Ca2+ messenger acting via the CICR. The Ca2+ signaling mechanism mediated by NAADP has only recently been characterized. The Ca2+ stores that are sensitive to NAADP are separable from those sensitive to IP3 and cADPR. The Ca2+ release mechanism activated by NAADP is also completely independent of those activated by cADPR and IP3. Nevertheless, NAADP is related to cADPR since both are synthesized by the same enzymes but under different conditions. Elucidation of this hitherto unknown signaling pathway mediated by NAADP is likely to have an important impact on our understanding of signal transduction mechanisms.
Specific aims are: 1. To synthesize analogs of NAADP. 2. To develop assays for endogenous NAADP. 3. To characterize the subcellular distribution of the NAADP-sensitive Ca2+ stores. 4. To characterize the NAADP-sensitive Ca2+ stores biochemically. 5. To determine the role of the NAADP-sensitive Ca2+ stores in propagation of Ca2+ waves.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061568-03
Application #
6520281
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Shapiro, Bert I
Project Start
2000-06-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$255,420
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Zhang, HongMin; Graeff, Richard; Chen, Zhe et al. (2011) Dynamic conformations of the CD38-mediated NAD cyclization captured in a single crystal. J Mol Biol 405:1070-8
Xu, Xiaodong; Graeff, Richard; Xie, Qiguang et al. (2009) Comment on ""The Arabidopsis circadian clock incorporates a cADPR-based feedback loop"". Science 326:230; author reply 230
Liu, Qun; Graeff, Richard; Kriksunov, Irina A et al. (2009) Structural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolase. J Biol Chem 284:27637-45
Graeff, Richard; Liu, Qun; Kriksunov, Irina A et al. (2009) Mechanism of cyclizing NAD to cyclic ADP-ribose by ADP-ribosyl cyclase and CD38. J Biol Chem 284:27629-36
Liu, Qun; Kriksunov, Irina A; Jiang, Hong et al. (2008) Covalent and noncovalent intermediates of an NAD utilizing enzyme, human CD38. Chem Biol 15:1068-78
Liu, Qun; Graeff, Richard; Kriksunov, Irina A et al. (2008) Conformational Closure of the Catalytic Site of Human CD38 Induced by Calcium. Biochemistry 47:13966-73
Liu, Qun; Kriksunov, Irina A; Wang, Zhongwu et al. (2008) Hierarchical and helical self-assembly of ADP-ribosyl cyclase into large-scale protein microtubes. J Phys Chem B 112:14682-6
Liu, Qun; Kriksunov, Irina A; Graeff, Richard et al. (2007) Structural basis for formation and hydrolysis of the calcium messenger cyclic ADP-ribose by human CD38. J Biol Chem 282:5853-61
Liu, Qun; Kriksunov, Irina A; Moreau, Christelle et al. (2007) Catalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog. J Biol Chem 282:24825-32
Graeff, Richard; Liu, Qun; Kriksunov, Irina A et al. (2006) Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine nicotinic acid adenine dinucleotide phosphate (NAADP) synthesis and hydrolysis activities. J Biol Chem 281:28951-7

Showing the most recent 10 out of 19 publications