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

Summary Nicotinic acid adenine dinucleotide phosphate (NAADP, 1 ) is the most potent intracellular Ca 2+ 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 Ca 2+ release via the NAADP receptor (IC 50 ∼15μM – 1 mM), (2) compete with NAADP binding, (3) cross the cell membrane of sea urchin eggs to inhibit NAADP-evoked Ca 2+ release, and (4) selectively ablate NAADP-dependent Ca 2+ oscillations induced by the external gastric peptide hormone agonist cholecystokinin (CCK) in murine pancreatic acinar cells.