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

Research output: Contribution to journalArticle

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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Cyclic ADP-Ribose
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Chemical activation
T-cells
Transient Receptor Potential Channels
T-Lymphocytes
8-bromo-cyclic inosine diphosphoribose
Ruthenium Red
Ryanodine Receptor Calcium Release Channel
Gadolinium
Second Messenger Systems
Cations
Rats
Lymphoma
Cells
Ions

Cite this

Kirchberger, T., Moreau, C., Wagner, G. K., Fliegert, R., Siebrands, C. C., Nebel, M., ... 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

8-Bromo-cyclic inosine diphosphoribose : towards a selective cyclic ADP-ribose agonist. / Kirchberger, Tanja; Moreau, Christelle; Wagner, Gerd K.; Fliegert, Ralf; Siebrands, Cornelia C.; Nebel, Merle; Schmid, Frederike; Harneit, Angelika; Odoardi, Francesca; Flugel, Alexander; Potter, Barry V. L.; Guse, Andreas H.

In: Biochemical Journal, Vol. 422, No. 1, 2009, p. 139-149.

Research output: Contribution to journalArticle

Kirchberger, T, Moreau, C, Wagner, GK, Fliegert, R, Siebrands, CC, Nebel, M, Schmid, F, Harneit, A, Odoardi, F, Flugel, A, Potter, BVL & Guse, AH 2009, '8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist', Biochemical Journal, vol. 422, no. 1, pp. 139-149. https://doi.org/10.1042/bj20082308
Kirchberger T, Moreau C, Wagner GK, Fliegert R, Siebrands CC, Nebel M et al. 8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist. Biochemical Journal. 2009;422(1):139-149. https://doi.org/10.1042/bj20082308
Kirchberger, Tanja ; Moreau, Christelle ; Wagner, Gerd K. ; Fliegert, Ralf ; Siebrands, Cornelia C. ; Nebel, Merle ; Schmid, Frederike ; Harneit, Angelika ; Odoardi, Francesca ; Flugel, Alexander ; Potter, Barry V. L. ; Guse, Andreas H. / 8-Bromo-cyclic inosine diphosphoribose : towards a selective cyclic ADP-ribose agonist. In: Biochemical Journal. 2009 ; Vol. 422, No. 1. pp. 139-149.
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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.",
author = "Tanja Kirchberger and Christelle Moreau and Wagner, {Gerd K.} and Ralf Fliegert and Siebrands, {Cornelia C.} and Merle Nebel and Frederike Schmid and Angelika Harneit and Francesca Odoardi and Alexander Flugel and Potter, {Barry V. L.} and Guse, {Andreas H.}",
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T1 - 8-Bromo-cyclic inosine diphosphoribose

T2 - towards a selective cyclic ADP-ribose agonist

AU - Kirchberger, Tanja

AU - Moreau, Christelle

AU - Wagner, Gerd K.

AU - Fliegert, Ralf

AU - Siebrands, Cornelia C.

AU - Nebel, Merle

AU - Schmid, Frederike

AU - Harneit, Angelika

AU - Odoardi, Francesca

AU - Flugel, Alexander

AU - Potter, Barry V. L.

AU - Guse, Andreas H.

N1 - Acknowledgements and Funding: This work was supported by the Deutsche Forschungsgemeinschaft [grant numbers GU 360/9-1, GU 360/9–2]; the Gemeinnützige Hertie-Stiftung [grant number 1.01.1/07/005]; the Wellcome Trust [project grants 55709, 084068]; a Wellcome Trust Value in People award; and by a Wellcome Trust Biomedical Research Collaboration Grant [grant number 068065].

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

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