Cell-permeant small-molecule modulators of NAADP-mediated Ca2+ release.
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.
Dowden
James
J
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom. james.dowden@nottingham.ac.uk
Berridge
Georgina
G
Moreau
Christelle
C
Yamasaki
Michiko
M
Churchill
Grant C
GC
Potter
Barry V L
BV
Galione
Antony
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D002463:Cell Membrane Permeability; D002766:Cholecystokinin / Q000494:pharmacology; D015394:Molecular Structure; D009249:NADP / Q000031:analogs & derivatives* / Q000494:pharmacology; D010063:Ovum / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D012617:Sea Urchins / Q000166:cytology
D002413:Cations, Divalent; D011725:Pyridines; D009249:NADP; C024376:NAADP; D002766:Cholecystokinin; D002118:Calcium