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2'-Phospho-cyclic ADP-ribose, a calcium-mobilizing agent derived from NADP
1Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy and the Lucille P. Markey Cancer Center, University of Kentucky, Lexington, 40536-0082, USA.
The Journal of Biological Chemistry
|March 1, 1996
Summary
Cyclic adenosine diphosphoribose (cADPR) and its metabolite 2'-phospho-cyclic adenosine diphosphoribose (2'-P-cADPR) regulate intracellular calcium (Ca2+). This study identifies 2'-P-cADPR as a novel Ca2+ signaling molecule.
Area of Science:
- Biochemistry
- Cellular Biology
- Molecular Signaling
Background:
- Cyclic adenosine diphosphoribose (cADPR) modulates intracellular Ca2+ via ryanodine-sensitive channels.
- NAD metabolites play crucial roles in cellular signaling pathways.
Purpose of the Study:
- To investigate the role of 2 -phospho-cyclic adenosine diphosphoribose (2 -P-cADPR) as a potential Ca2+ signaling molecule.
- To compare the activity and mechanism of 2 -P-cADPR with cADPR and inositol trisphosphate (IP3).
Main Methods:
- Purification and characterization of ADPR cyclase from Aplysia californica.
- Enzymatic assays using NADP and NAD substrates.
- Measurement of Ca2+ release from rat brain microsomes in response to 2 -P-cADPR and cADPR.
- Comparative analysis of signaling mechanisms with IP3.
Main Results:
- An enzyme readily converts NADP to 2 -P-cADPR, with higher affinity and Vmax than NAD.
- 2 -P-cADPR elicits Ca2+ release from microsomes, comparable to cADPR.
- 2 -P-cADPR and cADPR appear to act via similar mechanisms, distinct from IP3.
- 2 -P-cADPR acts as a substrate for NAD glycohydrolase, forming 2 -P-ADPR.
Conclusions:
- 2 -P-cADPR is a likely metabolite in mammalian cells and functions as a novel Ca2+ signaling molecule.
- This finding suggests a potential link between NADP metabolism and Ca2+ homeostasis.
- The distinct mechanism of 2 -P-cADPR from IP3 expands our understanding of Ca2+ signaling pathways.