NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist
NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist
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DOI：
10.1073/pnas.0809997106
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发表时间：
2009-06-30
影响因子：
11.1
通讯作者：
Potter, Barry V. L.
中科院分区：
文献类型：
--
作者：
Dammermann, Werner;Zhang, Bo;Potter, Barry V. L.
核苷酸NAADP最近被发现作为参与淋巴瘤T细胞中Ca 2+信号传导的启动和传播的第二信使，但其对原发性T细胞功能的影响仍然未知。设计并合成了一种优化的合成的NAADP作用的小分子抑制剂，称为BZ 194。BZ 194既不干扰D-肌肌醇1，4，5-三磷酸或环ADP-核糖的Ca 2+动员，也不干扰容量性Ca 2+内流。BZ 194特异性和有效地阻断NAADP刺激的[H-3] ryanodine与纯化的1型ryanodine受体的结合。此外，在完整的T细胞中，由NAADP或由初级效应T细胞和星形胶质细胞之间的免疫突触的形成引起的Ca 2+动员被BZ 194抑制。Ca 2+动员的下游事件，如“活化T细胞核因子”（NFAT）的核转位、T细胞受体驱动的白细胞介素-2产生和抗原经历的CD 4（+）效应T细胞的增殖，被NAADP拮抗剂减弱。总之，特异性抑制NAADP信号通路构成了特异性和有效地调节T细胞活化的方式，并且在自身免疫性疾病的治疗中具有潜力。
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.