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          Institute: MPI für Neurobiologie     Collection: Neuroimmunology     Display Documents

ID: 433290.0, MPI für Neurobiologie / Neuroimmunology
NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist
Authors:Dammermann, W.; Zhang, B.; Nebel, M.; Cordiglieri, C.; Odoardi, F.; Kirchberger, T.; Kawakami, N.; Dowden, J.; Schmid, F.; Dornmair, K.; Hohenegger, M.; Flügel, A.; Guse, A. H.; Potter, B. V. L.
Date of Publication (YYYY-MM-DD):2009-06-30
Title of Journal:Proceedings of the National Academy of Sciences of the United States of America
Journal Abbrev.:Proc. Natl. Acad. Sci. U. S. A.
Issue / Number:26
Start Page:10678
End Page:10683
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:The nucleotide NAADP was recently discovered as a second messenger involved in the initiation and propagation of Ca2+ signaling in lymphoma T cells, but its impact on primary T cell function is still unknown. An optimized, synthetic, small molecule inhibitor of NAADP action, termed BZ194, was designed and synthesized. BZ194 neither interfered with Ca2+ mobilization by D-myo-inositol 1,4,5-trisphosphate or cyclic ADP-ribose nor with capacitative Ca2+ entry. BZ194 specifically and effectively blocked NAADP-stimulated [H-3] ryanodine binding to the purified type 1 ryanodine receptor. Further, in intact T cells, Ca2+ mobilization evoked by NAADP or by formation of the immunological synapse between primary effector T cells and astrocytes was inhibited by BZ194. Downstream events of Ca2+ mobilization, such as nuclear translocation of "nuclear factor of activated T cells" (NFAT), T cell receptor-driven interleukin-2 production, and proliferation in antigen-experienced CD4(+) effector T cells, were attenuated by the NAADP antagonist. Taken together, specific inhibition of the NAADP signaling pathway constitutes a way to specifically and effectively modulate T-cell activation and has potential in the therapy of autoimmune diseases.
Free Keywords:antagonism; nucleotide; second messenger; synthesis
External Publication Status:published
Document Type:Article
Affiliations:MPI für Neurobiologie/Neuroimmunology (Wekerle)
External Affiliations:[Zhang, Bo; Dowden, James; Potter, Barry V. L.] Univ Bath, Wolfson Lab Med Chem, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England.; [Dammermann, Werner; Nebel, Merle; Kirchberger, Tanja; Schmid, Frederike; Guse, Andreas H.] Univ Med Ctr Hamburg Eppendorf, Calcium Signaling Grp, Ctr Med Expt, Inst Biochem & Mol Biol Cellular Signal Transduct, D-20246 Hamburg, Germany.; [Odoardi, Francesca; Fluegel, Alexander] Gemeinnutzige Hertie Stiftung & Univ Med Ctr Gott, Inst Multiple Sclerosis Res, D-37073 Göttingen, Germany.; [Dornmair, Klaus] Univ Munich, Inst Clin Neuroimmunol, D-82152 Martinsried, Germany.; [Hohenegger, Martin] Med Univ Vienna, Inst Pharmacol, A-1090 Vienna, Austria.; [Fluegel, Alexander] Univ Munich, Inst Immunol, D-80336 Munich, Germany.
Identifiers:ISI:000267564300053 [ID No:1]
ISSN:0027-8424 [ID No:2]
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