Cyclic 3-deaza-adenosine diphosphoribose: a potent and stable analog of cyclic ADP-ribose

• Published in: Biochimica et biophysica acta Vol. 1472; no. 3; pp. 555 - 564
• Main Authors: Wong, Long, Aarhus, Robert, Cheung Lee, Hon, Walseth, Timothy F
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 16.11.1999
• Subjects: 3-deaza-cyclic ADP-ribose; Adenosine Diphosphate Ribose - analogs & derivatives; Adenosine Diphosphate Ribose - chemical synthesis; Adenosine Diphosphate Ribose - pharmacology; Aniline Compounds; Animals; cADPR; Calcium - metabolism; Calcium release; Cyclic ADP-Ribose; Embryo, Nonmammalian; Hot Temperature; Microinjections; Molecular Structure; Sea Urchins; Xanthenes; 3-deaza-cyclic ADP-ribose; Calcium release; IM, intracellular medium; cADPR; cADPR, cyclic adenosine diphosphoribose; CICR, calcium-induced calcium release; Cyclic ADP-ribose; β-NMN, β-nicotinamide mononucleotide; 3-deaza-cADPR, cyclic 3-deaza-adenosine diphosphoribose; TEAB, triethylammonium bicarbonate
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/S0304-4165(99)00161-0

Cyclic 3-deaza-adenosine diphosphoribose (3-deaza-cADPR), an analog of cyclic adenosine diphosphoribose (cADPR) was synthesized. 3-deaza-cADPR differs from cADPR by only the substitution of carbon for nitrogen at the 3-position of the purine ring. Similar to cADPR, the analog has potent calcium releasing activity in sea urchin egg homogenates and was able to induce calcium release at concentrations as low as 0.3 nM. The EC 50 value for 3-deaza-cADPR-induced calcium release was 1 nM, which is about 70 times more potent than cADPR. The properties of calcium release induced by 3-deaza-cADPR in all other respects were similar to those of cADPR. Thus, 3-deaza-cADPR and cADPR were capable of cross-desensitizing each other and their calcium releasing activities were potentiated by Sr 2+ as well as caffeine. 8-amino-cADPR, a selective antagonist of cADPR, was also able to inhibit 3-deaza-cADPR induced calcium release. Taken together, these data suggest that 3-deaza-cADPR releases calcium through the same mechanism as cADPR. 3-deaza-cADPR was found to be resistant to both heat and enzymatic hydrolysis. Only 15% of 3-deaza-cADPR was destroyed after boiling this compound for 2 h. No loss of 3-deaza-cADPR was observed when treated with CD38 under conditions where cADPR was completely hydrolyzed. Thus, 3-deaza-cADPR is a potent and stable analog of cADPR. These properties should make 3-deaza-cADPR a useful probe in studies focused on the mechanism of cADPR action.