NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist
Dammermann, W., Zhang, B., Nebel, M., Cordiglieric, C., Odoardi, F., Kirchberger, T., Kawakami, N., Dowden, J., Schmid, F., Dornmair, K., Hohenegger, M., Flugel, A., Guse, A. H. and Potter, B. V. L., 2009. NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist. Proceedings of the National Academy of Sciences of the United States of America, 106 (26), pp. 10678-10683.
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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 [3H]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.
|Creators||Dammermann, W., Zhang, B., Nebel, M., Cordiglieric, C., Odoardi, F., Kirchberger, T., Kawakami, N., Dowden, J., Schmid, F., Dornmair, K., Hohenegger, M., Flugel, A., Guse, A. H. and Potter, B. V. L.|
|Uncontrolled Keywords||antagonism, second messenger, nucleotide, synthesis|
|Departments||Faculty of Science > Pharmacy & Pharmacology|
|Additional Information||Acknowledgements and Funding: The authors thank Sabine Kosin, Karin Weber and Martina Sölch for excellent technical assistance. We thank Markus Hammer and Hans-Dieter Volk (Charité-Universitätsmedizin, Berlin) for providing us with human taqman primers and probes. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 455-A8 to A.F., SFB571-A1 to K.D., GU 360/7–1,7–2,7–3,7–5 to A.H.G.), the Gemeinnützige Hertie Foundation (Grant 1.01.1/04/010 and 1.01.1/07/005 to A.F. and A.H.G.), an Enterprise Development Grant from the University of Bath (to B.V.L.P), the Fonds zur Förderung der wissenschaftlichen Forschung (FWF; Grant P-14940 to M.H.), and the Wellcome Trust (Biomedical Research Collaboration Grant 068065 to B.V.L.P. and A.H.G.).|
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