NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist

Werner Dammermann, Bo Zhang, Merle Nebel, Chiara Cordiglieric, Francesca Odoardi, Tanja Kirchberger, Naoto Kawakami, James Dowden, Frederike Schmid, Klaus Dornmair, Martin Hohenegger, Alexander Flugel, Aandreas H. Guse, Barry V. L. Potter

Research output: Contribution to journalArticlepeer-review

92 Citations (SciVal)

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 languageEnglish
Pages (from-to)10678-10683
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number26
Early online date15 Jun 2009
DOIs
Publication statusPublished - 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

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