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

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).

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.

This record has no associated files available for download.

Contributors

Author: Jaswinder K. Sethi

Download statistics