Abstract
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.
Original language | English |
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Pages (from-to) | 10678-10683 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 106 |
Issue number | 26 |
Early online date | 15 Jun 2009 |
DOIs | |
Publication status | Published - 30 Jun 2009 |
Bibliographical note
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.).Keywords
- antagonism
- second messenger
- nucleotide
- synthesis