8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist

Tanja Kirchberger, Christelle Moreau, Gerd K. Wagner, Ralf Fliegert, Cornelia C. Siebrands, Merle Nebel, Frederike Schmid, Angelika Harneit, Francesca Odoardi, Alexander Flugel, Barry V. L. Potter, Andreas H. Guse

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18 Citations (Scopus)

Abstract

cADPR (cyclic ADP-ribose) is a universal Ca(2+) mobilizing second messenger. In T-cells cADPR is involved in sustained Ca(2+) release and also in Ca(2+) entry. Potential mechanisms for the latter include either capacitative Ca(2+) entry, secondary to store depletion by cADPR, or direct activation of the non-selective cation channel TRPM2 (transient receptor potential cation channel, subfamily melastatin, member 2). Here we characterize the molecular target of the newly-described membrane-permeant cADPR agonist 8-Br-N(1)-cIDPR (8-bromo-cyclic IDP-ribose). 8-Br-N(1)-cIDPR evoked Ca(2+) signalling in the human T-lymphoma cell line Jurkat and in primary rat T-lymphocytes. Ca(2+) signalling induced by 8-Br-N(1)-cIDPR consisted of Ca(2+) release and Ca(2+) entry. Whereas Ca(2+) release was sensitive to both the RyR (ryanodine receptor) blocker RuRed (Ruthenium Red) and the cADPR antagonist 8-Br-cADPR (8-bromo-cyclic ADP-ribose), Ca(2+) entry was inhibited by the Ca(2+) entry blockers Gd(3+) (gadolinium ion) and SKF-96365, as well as by 8-Br-cADPR. To unravel a potential role for TRPM2 in sustained Ca(2+) entry evoked by 8-Br-N(1)-cIDPR, TRPM2 was overexpressed in HEK (human embryonic kidney)-293 cells. However, though activation by H(2)O(2) was enhanced dramatically in those cells, Ca(2+) signalling induced by 8-Br-N(1)-cIDPR was almost unaffected. Similarly, direct analysis of TRPM2 currents did not reveal activation or co-activation of TRPM2 by 8-Br-N(1)-cIDPR. In summary, the sensitivity to the Ca(2+) entry blockers Gd(3+) and SKF-96365 is in favour of the concept of capacitative Ca(2+) entry, secondary to store depletion by 8-Br-N(1)-cIDPR. Taken together, 8-Br-N(1)-cIDPR appears to be the first cADPR agonist affecting Ca(2+) release and secondary Ca(2+) entry, but without effect on TRPM2.
Original languageEnglish
Pages (from-to)139-149
JournalBiochemical Journal
Volume422
Issue number1
DOIs
Publication statusPublished - 2009

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    Kirchberger, T., Moreau, C., Wagner, G. K., Fliegert, R., Siebrands, C. C., Nebel, M., Schmid, F., Harneit, A., Odoardi, F., Flugel, A., Potter, B. V. L., & Guse, A. H. (2009). 8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist. Biochemical Journal, 422(1), 139-149. https://doi.org/10.1042/bj20082308