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7-deaza-8-bromo-cyclic ADP-ribose, the first membrane-permeant, hydrolysis-resistant cyclic ADP-ribose antagonist

7-deaza-8-bromo-cyclic ADP-ribose, the first membrane-permeant, hydrolysis-resistant cyclic ADP-ribose antagonist
7-deaza-8-bromo-cyclic ADP-ribose, the first membrane-permeant, hydrolysis-resistant cyclic ADP-ribose antagonist

Cyclic ADP-ribose (cADPR) is a putative second messenger that has been demonstrated to mobilize Ca2+ in many cell types. Its postulated role as the endogenous regulator of ryanodine-sensitive Ca2+ release channels has been greatly supported by the advent and use of specific cADPR receptor antagonists such as 8-NH2-cADPR (Walseth, T. F., and Lee, H. C. (1993) Biochim. Biophys. Acta 1178, 235-242). However, investigations of the role of cADPR in physiological responses, such as fertilization, stimulus-secretion coupling, and excitation-contraction coupling, have been hindered by the susceptibility of cADPR receptor antagonists to hydrolysis and the need to introduce these molecules into cells by microinjection or patch clamp techniques. We have recently reported on the discovery of a poorly hydrolyzable analogue of cADPR, 7-deaza-cADPR (Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., and Potter, B. V. L. (1997) Chem. Biol. 4, 41-51) but this, like cADPR, is an agonist of ryanodine-sensitive Ca2+ release channels. We therefore explored the possibility of combining antagonistic activity with that of hydrolytic resistance and now report on the biological properties of the first hydrolysis-resistant cADPR receptor antagonist, 7- deaza-8-bromo-cADPR. In addition this compound has the advantage of being membrane-permeable. Together these properties make this hybrid molecule the most powerful tool to date for studying cADPR-mediated Ca2+ signaling in intact cells.

0021-9258
16358-16363
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Empson, Ruth M.
8900f024-f907-41ae-ad6d-64d72676546f
Bailey, Victoria C.
8c5211f0-cc09-430c-90f0-e58622cf0881
Potter, Barry V.L.
a2fd9ce8-0e83-4aee-a362-25a750c5c0c8
Galione, Antony
cb0ece65-6c8a-4c54-9f12-7cd954e0955b
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Empson, Ruth M.
8900f024-f907-41ae-ad6d-64d72676546f
Bailey, Victoria C.
8c5211f0-cc09-430c-90f0-e58622cf0881
Potter, Barry V.L.
a2fd9ce8-0e83-4aee-a362-25a750c5c0c8
Galione, Antony
cb0ece65-6c8a-4c54-9f12-7cd954e0955b

Sethi, Jaswinder K., Empson, Ruth M., Bailey, Victoria C., Potter, Barry V.L. and Galione, Antony (1997) 7-deaza-8-bromo-cyclic ADP-ribose, the first membrane-permeant, hydrolysis-resistant cyclic ADP-ribose antagonist. The Journal of Biological Chemistry, 272 (26), 16358-16363. (doi:10.1074/jbc.272.26.16358).

Record type: Article

Abstract

Cyclic ADP-ribose (cADPR) is a putative second messenger that has been demonstrated to mobilize Ca2+ in many cell types. Its postulated role as the endogenous regulator of ryanodine-sensitive Ca2+ release channels has been greatly supported by the advent and use of specific cADPR receptor antagonists such as 8-NH2-cADPR (Walseth, T. F., and Lee, H. C. (1993) Biochim. Biophys. Acta 1178, 235-242). However, investigations of the role of cADPR in physiological responses, such as fertilization, stimulus-secretion coupling, and excitation-contraction coupling, have been hindered by the susceptibility of cADPR receptor antagonists to hydrolysis and the need to introduce these molecules into cells by microinjection or patch clamp techniques. We have recently reported on the discovery of a poorly hydrolyzable analogue of cADPR, 7-deaza-cADPR (Bailey, V. C., Sethi, J. K., Fortt, S. M., Galione, A., and Potter, B. V. L. (1997) Chem. Biol. 4, 41-51) but this, like cADPR, is an agonist of ryanodine-sensitive Ca2+ release channels. We therefore explored the possibility of combining antagonistic activity with that of hydrolytic resistance and now report on the biological properties of the first hydrolysis-resistant cADPR receptor antagonist, 7- deaza-8-bromo-cADPR. In addition this compound has the advantage of being membrane-permeable. Together these properties make this hybrid molecule the most powerful tool to date for studying cADPR-mediated Ca2+ signaling in intact cells.

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Published date: 27 June 1997

Identifiers

Local EPrints ID: 415406
URI: https://eprints.soton.ac.uk/id/eprint/415406
ISSN: 0021-9258
PURE UUID: ecab7f51-3198-4953-adce-500a536880f0
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: 20 Jul 2019 00:26

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