Cell-permeant small-molecule modulators of NAADP-mediated Ca2+ release
Cell-permeant small-molecule modulators of NAADP-mediated Ca2+ release
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DOI：
10.1016/j.chembiol.2006.05.005
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发表时间：
2006-06-01
影响因子：
--
通讯作者：
Galione, Antony
中科院分区：
文献类型：
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作者：
Dowden, James;Berridge, Georgina;Galione, Antony
烟酸腺嘌呤二核苷酸磷酸 (NAADP, 1) 是重要哺乳动物细胞和组织中最有效的细胞内 Ca2+ 动员剂，但 NAADP 受体的身份尚不清楚。值得注意的是，辅酶 NADP 在这方面完全没有活性。目前的研究受到除了 NAADP 本身之外缺乏任何化学探针的限制，而且重要的是，没有一种化学探针是细胞渗透性的。我们报道了简单的烟酸衍生的吡啶鎓类似物作为低分子量化合物，其（1）通过NAADP受体抑制Ca2+释放，IC50类似于15 muM - 1 mM），（2）与NAADP结合竞争，（3）穿过海胆卵的细胞膜抑制NAADP诱发的Ca2+释放，以及（4）选择性消除由外部胃肽激素诱导的NAADP依赖性Ca2+振荡小鼠胰腺腺泡细胞中的激动剂胆囊收缩素（CCK）。
Nicotinic acid adenine dinucleotide phosphate (NAADP, 1) is the most potent intracellular Ca2+ mobilizing agent in important mammalian cells and tissues, yet the identity of the NAADP receptor is elusive. Significantly, the coenzyme NADP is completely inactive in this respect. Current studies are restricted by the paucity of any chemical probes beyond NAADP itself, and importantly, none is cell permeant. We report simple nicotinic acid-derived pyridinium analogs as low molecular weight compounds that (1) inhibit Ca2+ release via the NAADP receptor IC50 similar to 15 mu M - 1 mM), (2) compete with NAADP binding, (3) cross the cell membrane of sea urchin eggs to inhibit NAADP-evoked Ca2+ release, and (4) selectively ablate NAADP-dependent Ca2+ oscillations induced by the external gastric peptide hormone agonist cholecystokinin (CCK) in murine pancreatic acinar cells.