NAADP介导的Ca2+释放的细胞渗透性小分子调节剂。

Cell-permeant small-molecule modulators of NAADP-mediated Ca2+ release.

作者信息

Dowden James, Berridge Georgina, Moreau Christelle, Yamasaki Michiko, Churchill Grant C, Potter Barry V L, Galione Antony

机构信息

School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.

出版信息

Chem Biol. 2006 Jun;13(6):659-65. doi: 10.1016/j.chembiol.2006.05.005.

DOI:10.1016/j.chembiol.2006.05.005

PMID:16793523

Abstract

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 approximately 15 microM - 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.

摘要

烟酰胺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钙离子动员剂，然而NAADP受体的身份仍然难以捉摸。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NAADP本身之外缺乏任何化学探针的限制，重要的是，没有一种化学探针能够穿透细胞。我们报道了简单的烟碱酸衍生的吡啶类似物，作为低分子量化合物，它们（1）通过NAADP受体抑制钙离子释放（IC50约为15 microM - 1 mM），（2）与NAADP结合竞争，（3）穿过海胆卵细胞膜以抑制NAADP诱发的钙离子释放，以及（4）在小鼠胰腺腺泡细胞中选择性消除由外部胃肽激素激动剂胆囊收缩素（CCK）诱导的NAADP依赖性钙离子振荡。