8-Bromo-cyclic inosine diphosphoribose: towards a selective cyclic ADP-ribose agonist
| Autor: | Alexander Flügel, Angelika Harneit, Barry V. L. Potter, Francesca Odoardi, Cornelia C. Siebrands, Christelle Moreau, Gerd K. Wagner, Merle Nebel, Ralf Fliegert, Tanja Kirchberger, Frederike Schmid, Andreas H. Guse |
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| Rok vydání: | 2009 |
| Předmět: |
MBP
myelin basic protein Cell Membrane Permeability Gadolinium Orai1/CRACM1 ORAI calcium release-activated calcium modulator 1 cADPR cyclic ADP-ribose NF-AT nuclear factor of activated T-cells ADPR ADP-ribose Biochemistry Jurkat cells Ca2+ release Jurkat Cells chemistry.chemical_compound 0302 clinical medicine T-cell activation cyclic ADP-ribose (cADPR) analogue Inosine Nucleotides Calcium signaling 8-Br-IDPR 8-bromo-IDP-ribose Cyclic ADP-Ribose 0303 health sciences DMEM Dulbecco's modified Eagle's medium Ryanodine receptor Chemistry Imidazoles Fura-2AM Fura-2-acetoxymethyl ester transient receptor potential cation channel subfamily melastatin member 2 (TRPM2) EGFP enhanced green fluorescent protein RP-HPLC reverse-phase HPLC Ruthenium Red 3. Good health TRPM2 transient receptor potential cation channel subfamily melastatin member 2 8-Br-N1-cIDPR 8-bromo-cyclic IDP-ribose Ca2+ entry 030220 oncology & carcinogenesis Second messenger system IP3 D-myo-inositol-1 4 5-trisphosphate 8-Br-cADPR 8-bromo-cyclic ADP-ribose Ion Channel Gating Research Article Agonist Ruthenium red Microinjections medicine.drug_class TRPM Cation Channels TCA trichloroacetic acid Cyclic ADP-ribose TFA trifluoroacetic acid HEK human embryonic kidney 03 medical and health sciences medicine Animals Humans TRPM2 Calcium Signaling 8-Br-NHD 8-bromo-nicotinamide hypoxanthine dinucleotide Molecular Biology 030304 developmental biology Stim1 stromal interaction molecule 1 NAADP nicotinic acid adenine dinucleotide phosphate Cell Biology RyR ryanodine receptor Rats Biophysics RuRed Ruthenium Red cyclic ADP-ribose (cADPR) Extracellular Space |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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