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7-Deaza cyclic adenosine 5'-diphosphate ribose: First example of a Ca2+-mobilizing partial agonist related to cyclic adenosine 5'-diphosphate ribose

7-Deaza cyclic adenosine 5'-diphosphate ribose: First example of a Ca2+-mobilizing partial agonist related to cyclic adenosine 5'-diphosphate ribose
7-Deaza cyclic adenosine 5'-diphosphate ribose: First example of a Ca2+-mobilizing partial agonist related to cyclic adenosine 5'-diphosphate ribose

Background: Cyclic adenosine 5'-diphosphate ribose (cADPR), a naturally occurring metabolite of nicotinamide adenine dinucleotide (NAD+), mobilizes Ca2+ from non-mitochondrial stores in a variety of mammalian and invertebrate tissues. It has been shown that cADPR activates ryanodine-sensitive Ca2+-release channels, working independently of inositol 1,4,5-trisphosphate (IP3) to mobilize intracellular Ca2+ stores. In some systems, cADPR has been shown to be more potent than IP3. The chemo-enzymatic synthesis of structurally modified analogues of cADPR can provide pharmacological tools for probing this new Ca2+-signaling pathway. In this work, we describe the synthesis and evaluation of a structural mimic of cADPR with different Ca2+-releasing properties. Results: 7-Deaza cyclic adenosine 5'-diphosphate ribose (7-deaza cADPR), a novel cADPR analogue modified in the purine ring, was synthesized and its ability to release Ca2+ from non-mitochondrial pools in homogenates made from sea urchin eggs was investigated. 7-Deaza cADPR was more effective in releasing Ca2+ than cADPR, but it only released approximately 66% of the Ca2+ released by a maximal concentration of cADPR. It was also more resistant to hydrolysis than cADPR. If we administered increasing concentrations of 7-deaza cADPR at the same time as a maximal concentration of cADPR, the induction of Ca2+ release by cADPR was antagonized. Conclusions: 7-Deaza cADPR has a Ca2+-release profile consistent with that of a partial agonist, and it is the first reported example of such a compound to act at the cADPR receptor. The imidazole ring of cADPR is clearly important in stimulating the Ca2+-release machinery, and the present results demonstrate that structural modification of a site other than position 8 of the purine ring can affect the efficacy of Ca2+ release. 7-Deaza cADPR represents a significant step forwards in designing modulators of the cADPR signaling pathway.

7-deaza cADPR, cADPR, partial agonist
1074-5521
51-61
Bailey, Victoria C.
8c5211f0-cc09-430c-90f0-e58622cf0881
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Fortt, Simon M.
bb200fd9-bff7-4bb4-b7f9-9a7962144e9b
Galione, Antony
cb0ece65-6c8a-4c54-9f12-7cd954e0955b
Potter, Barry V.L.
a2fd9ce8-0e83-4aee-a362-25a750c5c0c8
Bailey, Victoria C.
8c5211f0-cc09-430c-90f0-e58622cf0881
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Fortt, Simon M.
bb200fd9-bff7-4bb4-b7f9-9a7962144e9b
Galione, Antony
cb0ece65-6c8a-4c54-9f12-7cd954e0955b
Potter, Barry V.L.
a2fd9ce8-0e83-4aee-a362-25a750c5c0c8

Bailey, Victoria C., Sethi, Jaswinder K., Fortt, Simon M., Galione, Antony and Potter, Barry V.L. (1997) 7-Deaza cyclic adenosine 5'-diphosphate ribose: First example of a Ca2+-mobilizing partial agonist related to cyclic adenosine 5'-diphosphate ribose. Chemistry & Biology, 4 (1), 51-61. (doi:10.1016/S1074-5521(97)90236-2).

Record type: Article

Abstract

Background: Cyclic adenosine 5'-diphosphate ribose (cADPR), a naturally occurring metabolite of nicotinamide adenine dinucleotide (NAD+), mobilizes Ca2+ from non-mitochondrial stores in a variety of mammalian and invertebrate tissues. It has been shown that cADPR activates ryanodine-sensitive Ca2+-release channels, working independently of inositol 1,4,5-trisphosphate (IP3) to mobilize intracellular Ca2+ stores. In some systems, cADPR has been shown to be more potent than IP3. The chemo-enzymatic synthesis of structurally modified analogues of cADPR can provide pharmacological tools for probing this new Ca2+-signaling pathway. In this work, we describe the synthesis and evaluation of a structural mimic of cADPR with different Ca2+-releasing properties. Results: 7-Deaza cyclic adenosine 5'-diphosphate ribose (7-deaza cADPR), a novel cADPR analogue modified in the purine ring, was synthesized and its ability to release Ca2+ from non-mitochondrial pools in homogenates made from sea urchin eggs was investigated. 7-Deaza cADPR was more effective in releasing Ca2+ than cADPR, but it only released approximately 66% of the Ca2+ released by a maximal concentration of cADPR. It was also more resistant to hydrolysis than cADPR. If we administered increasing concentrations of 7-deaza cADPR at the same time as a maximal concentration of cADPR, the induction of Ca2+ release by cADPR was antagonized. Conclusions: 7-Deaza cADPR has a Ca2+-release profile consistent with that of a partial agonist, and it is the first reported example of such a compound to act at the cADPR receptor. The imidazole ring of cADPR is clearly important in stimulating the Ca2+-release machinery, and the present results demonstrate that structural modification of a site other than position 8 of the purine ring can affect the efficacy of Ca2+ release. 7-Deaza cADPR represents a significant step forwards in designing modulators of the cADPR signaling pathway.

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Accepted/In Press date: 24 December 1996
Published date: January 1997
Keywords: 7-deaza cADPR, cADPR, partial agonist

Identifiers

Local EPrints ID: 415400
URI: https://eprints.soton.ac.uk/id/eprint/415400
ISSN: 1074-5521
PURE UUID: 71a527d7-7a7a-41e7-a2f6-8fd9dcdc3178
ORCID for Jaswinder K. Sethi: ORCID iD orcid.org/0000-0003-4157-0475

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Date deposited: 09 Nov 2017 17:30
Last modified: 14 Mar 2019 01:25

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Contributors

Author: Victoria C. Bailey
Author: Simon M. Fortt
Author: Antony Galione
Author: Barry V.L. Potter

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