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

Reference:

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.

Related documents:

Official URL:

http://dx.doi.org/10.1073/pnas.0809997106

Related URLs:

• http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2697110

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.

Export

Actions (login required)