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

TY - JOUR

T1 - 8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist.

AU - Kirchberger, Tanja

AU - Moreau, Christelle

AU - Wagner, Gerd

AU - Fliegert, Ralf

AU - Siebrands, Cornelia

AU - Nebel, Merle

AU - Schmid, Frederike

AU - Harneit, Angelika

AU - Francesca, Odoardi

AU - Flügel, Alexander

AU - Potter, Barry

AU - Guse, Andreas H.

PY - 2009

Y1 - 2009

N2 - Cyclic ADP-ribose (cADPR) is a universal Ca2+ mobilizing second messenger. In T cells cADPR is involved in sustained Ca2+ release and also in Ca2+ entry. Potential mechanisms for the latter include either capacitative Ca2+ entry secondary to store depletion by cADPR or direct activation of the non-selective cation channel transient receptor potential - melastatin type 2 (TRPM2). Here we characterize the molecular target of the newly-described membrane-permeant cADPR agonist 8-bromo-cyclic inosine diphosphoribose (8-Br-N1-cIDPR). 8-Br-N1-cIDPR evoked Ca2+ signalling in the human T-lymphoma cell line Jurkat and in primary rat T-lymphocytes. Ca2+ signalling induced by 8-Br-N1-cIDPR consisted of Ca2+ release and Ca2+ entry. While Ca2+ release was sensitive to both the ryanodine receptor blocker ruthenium red and the cADPR antagonist 8-bromo-cyclic adenosine diphosphoribose (8-Br-cADPR), Ca2+ entry was inhibited by the Ca2+ entry blockers Gd3+ and SKF 96365 as well as by 8-Br-cADPR. To unravel a potential role for TRPM2 in sustained Ca2+ entry evoked by 8-Br-N1-cIDPR, TRPM2 was overexpressed in HEK 293 cells. However, though activation by hydrogen peroxide was enhanced dramatically in those cells, Ca2+ signalling induced by 8-Br-N1-cIDPR was almost unaffected. Similarly, direct analysis of TRPM2 currents did not reveal activation or co-activation of TRPM2 by 8-Br-N1-cIDPR. In summary, the sensitivity to the Ca2+ entry blockers Gd3+ and SKF 96365 is in favour of the concept of capacitative Ca2+ entry secondary to store depletion by 8-Br-N1-cIDPR. Taken together, 8-Br-N1-cIDPR appears to be the first cADPR agonist affecting Ca2+ release (and secondary Ca2+ entry), but without effect on TRPM2.

AB - Cyclic ADP-ribose (cADPR) is a universal Ca2+ mobilizing second messenger. In T cells cADPR is involved in sustained Ca2+ release and also in Ca2+ entry. Potential mechanisms for the latter include either capacitative Ca2+ entry secondary to store depletion by cADPR or direct activation of the non-selective cation channel transient receptor potential - melastatin type 2 (TRPM2). Here we characterize the molecular target of the newly-described membrane-permeant cADPR agonist 8-bromo-cyclic inosine diphosphoribose (8-Br-N1-cIDPR). 8-Br-N1-cIDPR evoked Ca2+ signalling in the human T-lymphoma cell line Jurkat and in primary rat T-lymphocytes. Ca2+ signalling induced by 8-Br-N1-cIDPR consisted of Ca2+ release and Ca2+ entry. While Ca2+ release was sensitive to both the ryanodine receptor blocker ruthenium red and the cADPR antagonist 8-bromo-cyclic adenosine diphosphoribose (8-Br-cADPR), Ca2+ entry was inhibited by the Ca2+ entry blockers Gd3+ and SKF 96365 as well as by 8-Br-cADPR. To unravel a potential role for TRPM2 in sustained Ca2+ entry evoked by 8-Br-N1-cIDPR, TRPM2 was overexpressed in HEK 293 cells. However, though activation by hydrogen peroxide was enhanced dramatically in those cells, Ca2+ signalling induced by 8-Br-N1-cIDPR was almost unaffected. Similarly, direct analysis of TRPM2 currents did not reveal activation or co-activation of TRPM2 by 8-Br-N1-cIDPR. In summary, the sensitivity to the Ca2+ entry blockers Gd3+ and SKF 96365 is in favour of the concept of capacitative Ca2+ entry secondary to store depletion by 8-Br-N1-cIDPR. Taken together, 8-Br-N1-cIDPR appears to be the first cADPR agonist affecting Ca2+ release (and secondary Ca2+ entry), but without effect on TRPM2.

M3 - SCORING: Zeitschriftenaufsatz

JO - BIOCHEM J

JF - BIOCHEM J

SN - 0264-6021

ER -