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Article Dans Une Revue Biochemical Journal Année : 2009

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

Tanja Kirchberger
  • Fonction : Auteur
Christelle Moreau
  • Fonction : Auteur
Gerd K. Wagner
  • Fonction : Auteur
Ralf Fliegert
  • Fonction : Auteur
Cornelia C. Siebrands
  • Fonction : Auteur
Merle Nebel
  • Fonction : Auteur
Frederike Schmid
  • Fonction : Auteur
Angelika Harneit
  • Fonction : Auteur
Francesca Odoardi
  • Fonction : Auteur
Alexander Flügel
  • Fonction : Auteur
Barry V.L. Potter
  • Fonction : Auteur

Résumé

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.

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Dates et versions

hal-00479133 , version 1 (30-04-2010)

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Tanja Kirchberger, Christelle Moreau, Gerd K. Wagner, Ralf Fliegert, Cornelia C. Siebrands, et al.. 8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist. Biochemical Journal, 2009, 422 (1), pp.139-149. ⟨10.1042/BJ20082308⟩. ⟨hal-00479133⟩

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